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NATIONAL CLINICAL PRACTICE GUIDELINE

Coronary Artery Disease Secondary Prevention

Clinical Practice Guideline

Approved by the National Guideline Directors

May 2012

This guideline is informational only. It is not intended or designed as a substitute for the reasonable exercise of independent clinical judgment by practitioners, considering each patient’s needs on an individual basis. Guideline recommendations apply to populations of patients. Clinical judgment is necessary to design treatment plans for individual patients.

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National Coronary Artery Disease Clinical Practice Guideline

Table of Contents Introduction................................................................................................................................... 1

Guideline Summary...................................................................................................................... 5

Rationale Statements .................................................................................................................. 14

1. Depression in CAD........................................................................................................... 14 2. Screening for CAD ........................................................................................................... 16

ACEI and ARB Therapy............................................................................................................ 18

3. ACEI Therapy................................................................................................................... 18 4. ARB Therapy .................................................................................................................... 22

Oral Anticoagulant Therapy ...................................................................................................... 24

5. Aspirin versus Oral Anticoagulant Therapy ..................................................................... 24 6. Aspirin Plus Oral Anticoagulant Therapy......................................................................... 27 7. Anticoagulation Post-MI................................................................................................... 39 8. Aspirin............................................................................................................................... 40 9. Clopidogrel Use in Stable Patients ................................................................................... 43 10. Antiplatelet Therapy Post Stent Placement....................................................................... 46

Beta-Blocker Therapy in the Secondary Prevention of CAD.................................................... 65

11. Beta-Blocker Therapy....................................................................................................... 65 12. CAD plus Mild to Moderate Reversible Airway Disease or COPD................................. 75 13. CAD plus Heart Failure .................................................................................................... 76

Calcium Channel Blocker Therapy............................................................................................ 77

14. CAD with Normal Ventricular Systolic Function ............................................................ 77 15. CAD with LVSD............................................................................................................... 80

Lifestyle Modification ............................................................................................................... 81

16. Diet Therapy ..................................................................................................................... 81 17. Dietary Fat Modification................................................................................................... 83 18. Dietary Supplement Therapy ............................................................................................ 87 19. Smoking Cessation............................................................................................................ 92 20. Exercise............................................................................................................................. 93 21. Hormone Therapy ............................................................................................................. 95

Comorbid Conditions................................................................................................................. 98

22. Hypertension: Target Blood Pressure ............................................................................... 98 23. Lipid Management - Choice of Drug.............................................................................. 101 24. Lipid Management - Treatment Strategy........................................................................ 115 25. Acute Management – Statin Initiation ............................................................................ 124

Appendix A: Criteria for Grading the Evidence ................................................................... 141

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Appendix B: Supporting Documentation ............................................................................... 143

Problem Formulation 1 ............................................................................................................ 143 Search Strategy 1 ..................................................................................................................... 144 Evidence Table 1 ..................................................................................................................... 149 Problem Formulation 2 ............................................................................................................ 150 Search Strategy 2 ..................................................................................................................... 151 Evidence Tables 2.................................................................................................................... 152 Problem Formulation 3 ............................................................................................................ 153 Search Strategy 3 ..................................................................................................................... 154 Problem Formulation 4 ............................................................................................................ 156 Search Strategy 4 ..................................................................................................................... 157 Evidence Tables 4.................................................................................................................... 160 Problem Formulation 5 ............................................................................................................ 166 Search Strategy 5 ..................................................................................................................... 167 Problem Formulation 6 ............................................................................................................ 170 Search Strategy 6 ..................................................................................................................... 171 Evidence Table 6 ..................................................................................................................... 172 Problem Formulation 7 ............................................................................................................ 175 Search Strategy 7 ..................................................................................................................... 176 Evidence Table 7 ..................................................................................................................... 179 Problem Formulation 8 ............................................................................................................ 180 Search Strategy 8 ..................................................................................................................... 181 Evidence Table 8 ..................................................................................................................... 188 Problem Formulation 9 ............................................................................................................ 189 Search Strategy 9 ..................................................................................................................... 190 Evidence Table 9 ..................................................................................................................... 192 Problem Formulation 10 .......................................................................................................... 193 Search Strategy 10 ................................................................................................................... 194 Evidence Tables 10.................................................................................................................. 195 Problem Formulation 11 .......................................................................................................... 202 Search Strategy 11 ................................................................................................................... 203 Problem Formulation 12 .......................................................................................................... 205 Problem Formulation 13 .......................................................................................................... 205 Evidence Tables 13.................................................................................................................. 206 Problem Formulation 14 .......................................................................................................... 208

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Problem Formulation 15 .......................................................................................................... 210 Problem Formulation 16 .......................................................................................................... 210 Search Strategy 16 ................................................................................................................... 211 Problem Formulation 17 .......................................................................................................... 212 Problem Formulation 18 .......................................................................................................... 212 Evidence Tables 18.................................................................................................................. 213 Problem Formulation 19 .......................................................................................................... 231 Search Strategy 19 ................................................................................................................... 231 Problem Formulation 20 .......................................................................................................... 232 Search Strategy 20 ................................................................................................................... 232 Evidence Table 20 ................................................................................................................... 233 Problem Formulation 21 .......................................................................................................... 234 Search Strategy 21 ................................................................................................................... 235 Evidence Tables 21.................................................................................................................. 236 Problem Formulation 22 .......................................................................................................... 238 Search Strategy 22 ................................................................................................................... 239 Problem Formulation 23 .......................................................................................................... 242 Search Strategy 23 ................................................................................................................... 243 Evidence Tables 23.................................................................................................................. 245 Problem Formulation 24 .......................................................................................................... 247 Search Strategy 24 ................................................................................................................... 248 Evidence Tables 24.................................................................................................................. 250 Problem Formulation 25 .......................................................................................................... 252 Search Strategy 25 ................................................................................................................... 253 Evidence Tables 25.................................................................................................................. 254

References.................................................................................................................................. 267

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Introduction

Kaiser Permanente’s National Guideline Program

The National Guideline Program (NGP) supports the development of a core set of explicit, scientifically-based clinical practice guidelines, practice resources, and evidence synopses to assist Kaiser Permanente (KP) physicians, administrators, and other health care professionals in determining the most effective medical practices. This core set of evidence-based resources will: Create Programwide economies of scale, Support ongoing performance improvement activities, Consistently provide high quality resources for use in care delivery tools and systems, and Increase KP regions’ abilities to leverage clinical guidelines to improve clinical outcomes.

Clinical practice guidance, based on scientific evidence, is essential for providing high quality care and continuously improving on it. Such guidance needs to be integrated into the electronic medical record and other decision support tools to be accessible to clinicians at the point of care. In addition, engaging our members in collaborative, shared decision-making conversations regarding their personal preferences is an essential component of patient-centered quality care. Furthermore, cost-effectiveness of various evidence-based interventions and resource limitations are important considerations. This involves addressing health problems in ways that maximize the health of the population given the available resources.

Who are the National Guideline Directors’?

The National Guideline Directors (NGD) are a group of experts and advocates of evidence-based medicine who provide direction and oversight to the National Guideline Program (NGP). In this role, the NGD selects and approves topics for evidence-based knowledge products, owns Kaiser Permanente’s Common Methodology, and is responsible for quality assurance review. This group is composed of representatives from the Care Management Institute (CMI) and all eight regions.

What Is the Guideline Quality Committee?

The Guideline Quality (GQ) Committee is a subcommittee of the NGD consisting of a group of evidence experts from various KP regions and CMI who review and approve all the National Guidelines. This review ensures that the processes used to develop guideline content have adhered to KP evidence-based methods and that the labels applied to clinical recommendations therein are accurate (e.g., “evidence-based” or “consensus-based”).



How Are Guidelines Developed?

Guidelines are developed with the use of an “evidence-based methodology” and involve a systematic literature search, critical appraisal of the research design and statistical results of relevant studies, and grading of the sufficiency (quantity, quality, consistency, and relevancy) of the evidence for drawing conclusions. An evidence search includes literature published in peer-reviewed scientific journals, existing evidence-based guidelines, consensus-based statements from external professional societies and government health organizations, and clinical expert opinion of KP regional specialty groups. For additional information on evidence grading, see Appendix A. To develop or revise a guideline, CMI consultants work with a multidisciplinary Guideline Development Team (GDT). Each GDT consists of a core group of physicians, representing primary care and the specialties most affected by the guideline topic, and, as appropriate, other content experts from disciplines such as pharmacy, nursing, and health education. The members of a GDT are nominated by the respective National Guideline Directors to represent their regions. The GDT reviews the appraisal of the evidence and develops or revises clinical recommendations based on the current evidence. Each regional representative then presents the draft guideline recommendations to key experts and champions in their regions for critical review and support to improve the likelihood of implementation once the guideline is published.

How Often Are Guidelines Reviewed and Revised?

To keep current with changing medical practices, all guidelines are reviewed, and, if appropriate, revised at least every two years. To develop the Coronary Artery Disease (CAD) Guideline, released in December 2010, a multidisciplinary, interregional GDT first met in December 2009 to define the scope of the guideline. The Project Management Team then performed systematic reviews of the medical literature on each of the clinical questions identified by the GDT, assembled the evidence, and developed draft recommendations for review by the GDT. All of the recommendations and supporting evidence were reviewed in depth by the GDT in a series of meetings from August through October 2010. The GQ Committee reviewed and approved the guideline in February 2011. In 2010, only those recommendations for which there was new literature were reviewed (see recommendations 6, 8C, 10A-G, 11A, and 23).

What Does It Mean for a Guideline to Be Evidence-based?

Each clinical recommendation within a guideline is labeled as “evidence-based” or “consensus-based.” A recommendation is considered “evidence-based” if there has been a systematic review of the evidence, the evidence is sufficient, and the recommendation is consistent with the evidence. A recommendation can also be considered “evidence-based” if there is insufficient evidence but either no particular intervention is recommended or options are recommended without favoring one of the options over others. A recommendation is considered “consensus-based” if there has been a systematic review of the evidence, the evidence is insufficient to support an evidence-based recommendation, and the GDT decides to make a consensus recommendation.



What Does It Mean for a Guideline to Be Approved and National?

A recommendation that is consistent with the above policies is labeled as “National Guideline Directors Approved.” A National Guideline Directors Approved guideline for which at least 90% of the recommendations are approved by at least six of the eight KP regions is a "National Guideline." On the topics for which they exist, National Guidelines are the preferred evidence source for KP HealthConnect content. Contact information:

John Golden, MD CAD Clinical Lead Care Management Institute E-mail: [email protected]

Angela Chen, MPH Care Management Consultant Care Management Institute E-mail: [email protected]

Acknowledgments The Kaiser Permanente (KP) Coronary Artery Disease (CAD) Clinical Practice Guideline is the result of the extensive clinical expertise, collaborative efforts, and outstanding personal contributions of the following participants:

KP CAD Guideline Project Management Team John Golden, MD Clinical Lead Care Management Institute Angela Chen, MPH Project Manager Care Management Institute Gladys I. Tom, MS Senior Manager Care Management Institute Qiana R. Amos, MPH Analyst KP-Southern California Jessica A. Lam, MPH Analyst KP-Southern California Wiley Chan, MD EBM Methodologist Care Management Institute Tabitha Pousson Staff Assistant Care Management Institute



KP CAD Guideline Development Team The following GDT members declared a Conflict of Interest: Joel Handler, MD – KP Southern California. Served on JNC8 Expert Panel. Wiley Chan, MD – KP Northwest. Served on JNC8 Expert Panel. Colorado John Merenich, MD – Endocrinology Don Lamprecht, PharmD – Clinical Pharmacy Specialist Georgia George Kawamura, MD – Internal Medicine Hawaii Sue Lim, MD – Hospitalist Stanley Tillinghast, MD – Cardiology Mid-Atlantic States John Golden, MD – Cardiology Northern California Marc Jaffe, MD – Endocrinology and Internal Medicine Eleanor Levin, MD – Cardiology T James Lawrence, MD – Internal Medicine Northwest Lisa J Nakashimada, PharmD – Clinical Pharmacy Services Neil Blair, MD – Internal Medicine Ohio Maan Fares, MD – Cardiology Southern California Joel Handler, MD – Internal Medicine Kathleen S Ryman, MD – Cardiology Gary M Besinque, PharmD – Pharmacy Ronald D Scott, MD – CVD Lead, Family Medicine



Guideline Summary

1. Depression in CAD

Mental Health Outcomes: 1.A. The GDT recommends that the treatment of depression in CAD patients should be based

on the patients’ mental health condition(s), for the purpose of improving mental health outcomes. Consensus-based

Cardiovascular Outcomes: 1.B. The GDT recommends against treating depression in patients who are post-MI with

cognitive behavioral therapy in order to improve cardiovascular outcomes. Evidence-based: D

1.C. The GDT makes no recommendation for or against treating depression in patients with CAD, who are not post-MI, with cognitive behavioral therapy in order to improve cardiovascular outcomes. Evidence-based: I

1.D. The GDT makes no recommendation for or against treating depression in patients with CAD with antidepressant medications in order to improve cardiovascular outcomes. Evidence-based: I

2. Screening for CAD

2. Exercise stress testing, CT angiography, and coronary artery calcium scoring are not recommended for screening asymptomatic individuals for CAD. Consensus-based





ACEI and ARB Therapy

3. ACEI Therapy

3. For patients with CAD, with or without LVSD, angiotensin-converting enzyme (ACE) inhibitor therapy is recommended for long-term use,* unless contraindicated. Evidence-based: B

4. ARB Therapy

4.A. Angiotensin II Receptor Blocker (ARB) therapy is recommended for the following patients with CAD with or without hypertension who are intolerant to ACE Inhibitors:

Patients with CAD and diabetes with hypertension and microalbuminuria (or albuminuria)

Patients with CAD and left ventricular systolic dysfunction (LVSD)

Consensus-based

4.B. For patients with CAD and hypertension (without LVSD, or diabetes with microalbuminuria) who are intolerant to ACE Inhibitors, ARB therapy is an option equal to other antihypertensive medications. Evidence-based

4.C. For all other patients with CAD who are intolerant to ACE Inhibitors, there is insufficient evidence to recommend for or against ARB therapy. Evidence-based

Oral Anticoagulant Therapy

5. Aspirin versus Oral Anticoagulant Therapy

5. In CAD patients who are not at increased embolic risk and who tolerate aspirin, aspirin is recommended in preference to both oral anticoagulant therapy and the combination of aspirin and oral anticoagulant therapy. Evidence-based

6. Aspirin plus Oral Anticoagulant Therapy

6. Low-dose aspirin (81 mg/day) is conditionally recommended for most patients with established CAD receiving warfarin for thromboembolic prophylaxis.

Note: The balance between benefits and harms requires individualized assessment and should be tailored to the individual patient’s preferences and clinical circumstances. Low-dose aspirin (81 mg/day) is recommended because the risk of bleeding increases with higher aspirin dose.

* For patients on concomitant aspirin, low-dose aspirin (81 mg) is recommended to preserve ACE inhibitor benefit.



7. Anticoagulation Post-MI

7.A. Warfarin is recommended for post-MI patients with left ventricular thrombus, unless otherwise indicated. Consensus-based

7.B. Long-term warfarin therapy may be used in consultation with cardiology for post-MI patients with large transmural anterior infarctions. Consensus-based

8. Aspirin

8.A. For all patients with CAD, daily aspirin is recommended indefinitely, unless there is clear contraindication such as active bleeding, major coagulopathy, or true aspirin allergy. Evidence-based: B

8.B. For CAD patients low-dose aspirin (81 mg) is generally recommended. Consensus-based

9. Clopidogrel Use in Stable Patients

9.A. In stable CAD patients who tolerate aspirin well (and who are not post-procedure), clopidogrel is not recommended as either a substitute for or in addition to aspirin. Consensus-based

9.B. In stable CAD patients with contraindications to aspirin, clopidogrel is recommended. Consensus-based

10. Antiplatelet Therapy Post Stent Placement The following recommendations refer to patients withoutactive pathological bleeding. 10.A. All patients with CAD should take aspirin therapy indefinitely regardless of stenting

status.

10.B. Dual antiplatelet therapy with a P2Y12 inhibitor plus aspirin is strongly recommended for patients following coronary stent placement. The preferred P2Y12 inhibitors are as follows: first-line - clopidogrel; acceptable alternative – prasugrel or ticagrelor; least-preferred – ticlopidine.

For patients who suffer stent thrombosiswhile on a combination of clopidogrel plus aspirin, or at high risk for stent thrombosis, prasugrelor ticagrelor plus aspirin is an option.

Prasugrel is not recommended in patients with active pathological bleeding, with a history of stroke or transient ischemic attack (TIA), or in patients ≥ 75 years of age, because of risk of fatal and intracranial hemorrhage and uncertain benefit, except in high risk patients (e.g., diabetes or prior myocardial infarction).

Ticagrelor is not recommended in patients with a history of intracranial hemorrhage (ICH), active pathological bleeding, or severe hepatic insufficiency.

Ticlopidine is the least preferred agent. It is generally reserved who are unable to use prasugrel due to high bleeding risk and are intolerant or allergic to clopidogrel.



10.C. For patients with ACS and a coronary artery bare metal stent (BMS) or drug eluting stent (DES) post-placement treatment with a P2Y12 inhibitor plus aspirin is strongly recommended for at least 12 months.

In patients with a high risk of bleeding, who also have a high risk of discontinuation, BMS placement with a shorter duration of dual antiplatelet therapy (less than 12 months) is an option.

10.D. For patients with stable angina and a drug-eluting stents (DES), uninterrupted dual antiplatelet treatment with a P2Y12 inhibitor and aspirin is strongly recommended for at least 12 months.

Delay of any elective procedures which would require stopping or interrupting this therapy is strongly recommended until after one year (12 consecutive months) of dual antiplatelet therapy is completed.

Prior to stopping dual antiplatelet therapy in patients with coronary DES, consultation with the patient's treating cardiologist is strongly recommended.*

For patients with a drug-eluting stent and who must have procedures that mandate stopping dual antiplatelet therapy, it is strongly recommended that aspirin be continued if at all possible, and dual antiplatelet therapy be restarted as soon as possible after the procedure.

10.E. For patients with stable angina and a bare metal stent (BMS), uninterrupted dual antiplatelet treatment with a P2Y12inhibitor and aspirin for at least 1 month is strongly recommended.

* Healthcare providers who perform invasive or surgical procedures and are concerned about peri-procedural and

post-procedural bleeding should be made aware that the premature discontinuation of dual antiplatelet therapy in the first year following coronary DES placement carries a significant risk for the development of acute DES thrombosis, which in turn carries a high mortality rate (i.e., upwards of 50%).



Beta-Blocker Therapy in the Secondary Prevention of CAD

11. Beta-Blocker Therapy

Secondary Prevention of CAD 11.A. For CAD patients, non-intrinsic sympathomimetic activity (non-ISA) beta-blocker

therapy is recommended, unless contraindicated. Consensus-based

Peri-Operative Beta-Blockers The following recommendations refer to patients with no contraindications to beta-blocker use.*

Currently taking beta-blockers:

11.B. For patients undergoing non-cardiac surgery, clinicians should continue beta-blocker therapy in the peri-operative period for patients with CAD currently taking beta-blockers.

For patients with CAD undergoing non-cardiac surgery and not currently taking beta blockers:

11.C. Clinicians should initiate beta-blockers at least 1 week before surgery. 11.D. In the absence of compelling indications for urgent beta-blocker therapy (e.g.

tachyarrhythmias or uncontrolled hypertension), there is insufficient evidence to make a recommendation for or against initiating beta-blockers 24 hours to 1 week before surgery.

11.E. In the absence of compelling indications for urgent beta-blocker initiation (e.g.,

tachyarrhythmias, uncontrolled hypertension), clinicians should not initiate beta-blockers less than 24 hours before surgery.

11.F. If beta-blockers are not initiated in the pre-operative period, they should be initiated once

the patient is stable in the postoperative period.

* Contraindications and Cautions

Beta-blockers are not recommended for patients with severe reversible airway disease, high degree heart block, or other contraindications to their use. Initiating beta blockade should be approached with caution in patients with resting heart rates < 55.



12. CAD plus Mild to Moderate Reversible Airway Disease or COPD

12.A. For CAD patients with concomitant mild to moderate reversible airway disease or chronic obstructive pulmonary disease (COPD) cardioselective beta-blockers are recommended. Evidence-based

12.B. Discuss the risks and benefits of treatment with the patient and instruct the patient to report any increase in airway symptoms. Consensus-based

12.C. Initiating beta-blocker therapy is NOT recommended:

For patients with severe airway disease requiring frequent hospitalization or intubation.

During acute exacerbation of airway disease.

When airway disease is unstable or poorly controlled.

Consensus-based

13. CAD plus Heart Failure

13.A. For CAD patients with either left ventricular systolic dysfunction (LVSD) (NYHA Class II-IV) or asymptomatic LVSD (NYHA Class I), beta-blockers are strongly recommended. Evidence-based

13.B. For CAD patients with left ventricular systolic dysfunction carvedilol, metoprolol succinate, or bisoprolol is the recommended choice of beta-blocker therapy. Evidence-based



Calcium Channel Blocker Therapy

14. CAD with Normal Ventricular Systolic Function

14.A. Calcium channel blockers (CCBs) are NOT recommended to reduce morbidity or mortality from CAD. Evidence-based

14.B. In CAD patients with normal ventricular systolic function, calcium channel blockers (CCBs) may be used for the treatment of angina pectoris or hypertension when beta-blockers and ACE inhibitors are ineffective or contraindicated. Consensus-based

14.C. In patients with CAD, immediate release formulations of nifedipine are NOT recommended due to the increased risk of cardiovascular mortality. Evidence-based

15. CAD with LVSD

15.A. Amlodipine* and felodipine* (second generation dihydropyridine calcium channel blockers) are options for the treatment of angina pectoris or hypertension in patients with LVSD. Evidence-based

15.B. The GDT recommends against the use of calcium channel blockers (CCBs) other than amlodipine* and felodipine* in patients with LVSD. Evidence-based

Lifestyle Modification

16. Diet Therapy

16. For all patients with CAD, a diet rich in fruits, vegetables, legumes, nuts, whole grains, and n-3 (omega-3) polyunsaturated fatty acids is recommended. Evidence-based

17. Dietary Fat Modification

17. For all patients with CAD consuming a usual Western diet, the following modifications in dietary fat are recommended:

Increase intake of n-3 (omega-3) polyunsaturated fatty acids to a level of ~ 1 g/day from a variety of sources (flaxseed, canola, and soybean oils, nuts, fish, and fish oil supplements).

Replace saturated fatty acids with polyunsaturated and monounsaturated fatty acids.

Reduce or eliminate intake of trans-fatty acids.

Consensus-based

* Not FDA-approved for heart failure.



18. Dietary Supplement Therapy

18.A. For patients with CAD, supplemental vitamins C, E, and beta carotene are not recommended for prevention of cardiovascular mortality or subsequent coronary events. Evidence-based: D

18.B. For patients with CAD, supplemental folic acid, vitamin B6, and vitamin B12 are not recommended. Evidence-based: D

19. Smoking Cessation

19. For all patients with CAD who smoke, complete smoking cessation is strongly recommended. Evidence-based: A

20. Exercise

20.A. For all patients with CAD, 30 to 60 minutes of exercise (walking, jogging, cycling, or other aerobic activity) at least three to four times weekly is recommended. Evidence-based: B

20.B. Either supervised or non-supervised exercise is recommended. Consensus-based

21. Hormone Therapy

21.A. For postmenopausal women with CAD, unopposed estrogen therapy and estrogen and progestin combination therapy are not recommended for the prevention of cardiovascular events. Women taking these therapies solely to prevent cardiovascular events are strongly recommended to discontinue these therapies. Evidence-based

21.B. Women currently taking hormone therapy solely for the prevention of cardiovascular events are advised to discontinue use either all at once or by tapering the dose. Consensus-based

Comorbid Conditions

22. Hypertension: Target Blood Pressure

22.A. The optimal goal blood pressure for patients with CAD or CAD risk equivalents (AAA, peripheral arterial disease, or carotid arterial disease) is < 140/90 mm Hg. Consensus-based

22.B. The optimal goal blood pressure for patients with CAD and diabetes or renal disease is < 140/90 mm Hg. Consensus-based



23. Lipid Management - Choice of Drug*

23.A. A statin (simvastatin, lovastatin, atorvastatin, or pravastatin) is recommended as drug therapy for prevention of a future cardiovascular event in patients with established atherosclerotic disease. Evidence-based: A

23.B. Simvastatin is recommended as first-line therapy whenever statins are indicated. Consensus-based

23.C. There is insufficient evidence to determine which lipid-lowering therapy is superior, due to the lack of direct head-to-head trials. Evidence-based: I

24. Lipid Management - Treatment Strategy*

24.A. Initiate statins at a dose sufficient to reduce LDL-C to < 100 mg/dL and by at least 30 - 40%. Treatment is recommended even if baseline LDL-C is < 100 mg/dL. Evidence-based: B

24.B. In people with established CAD, an LDL-C goal of < 70 mg/dL is optional.† Consensus-based

25. Acute Management – Statin Initiation

In patients with acute coronary syndrome, it is strongly recommended that treatment with a high-dose, high-potency statin, such as simvastatin 40 - 80mg, be initiated as soon as possible regardless of baseline LDL-C.

Note: Risk factors for rhabdomyolysis (e.g., advanced age, frailty, multiple comorbidities, impaired renal function, potentially interacting drugs) favor the lower end of this dose range.‡

* Excerpted from the KP National Dyslipidemia Guidelines.

† One study among patients with acute coronary syndrome supports an LDL-C goal of < 70 mg/dL, while another

study suggests that an LDL-C goal of < 80 mg/dL may be appropriate for patients with stable CAD. However, based on the balance of costs/harms vs. benefits, the LDL-C goal is optional.

‡ For details, please refer to the link for Table 3. Lipid-Lowering Medications from the Dysplidemia Guideline: http://cl.kp.org/pkc/national/cmi/programs/dyslipidemia/guideline/files/DyslipidemiaMgmtinAdults2008.pdf#page=8



Rationale Statements

1. Depression in CAD

Mental Health Outcomes: 1.A. The GDT recommends that the treatment of depression in CAD patients should be based

on the patients’ mental health condition(s), for the purpose of improving mental health outcomes. Consensus-based

Cardiovascular Outcomes: 1.B. The GDT recommends against treating depression in patients who are post-MI with

cognitive behavioral therapy in order to improve cardiovascular outcomes. Evidence-based: D

1.C. The GDT makes no recommendation for or against treating depression in patients with CAD, who are not post-MI, with cognitive behavioral therapy in order to improve cardiovascular outcomes. Evidence-based: I

1.D. The GDT makes no recommendation for or against treating depression in patients with CAD with antidepressant medications in order to improve cardiovascular outcomes. Evidence-based: I

Rationale:

Evidence Grade: Recommendation 1A – Good (See KP National Depression Guideline) Recommendation 1B – Fair Recommendations 1C, D – Insufficient

Search Strategy Only RCTs or meta-analyses were included that studied people with persistent asthma in head-to-head comparisons of any of the following asthma medications: inhaled corticosteroids, leukotriene antagonist, cromolyn, nedocromil, theophylline, long-acting beta-agonist, short-acting beta-agonist (regular use or as needed), or placebo. Searches refined from 2001 to be more sensitive in identifying steroids, other anti-inflammatory agents, and bronchodilators. See Appendix B for more information on the search strategy.

2008 Guideline

Because of the good evidence for the effectiveness of treating MDD in the general population, the treatment of MDD in patients with CAD should be the same as for patients without CAD.



One relevant RCT was identified in the peer-reviewed literature that evaluated the treatment of MDD in CAD patients in order to improve cardiovascular outcomes. The Enhancing Recovery in Coronary Heart Disease Patients (ENRICHD) randomized trial

evaluated the effects of treating depression and low perceived social support (LPSS) on clinical events after MI Berkman et al., 2003.(1)

The trial included 2481 MI patients, enrolled from eight clinical centers. Major and minor depression was diagnosed by modified Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria and severity by the 17-item HAM-D score; LPSS was determined by the enhancing Recovery in Coronary Heart Disease (ENRICHD) Social Support Instrument (ESSI). Random allocation was to usual medical care or cognitive behavior therapy (CBT)-based psychosocial intervention.

The aim of the trial was to determine whether mortality and recurrent infarction were reduced by treatment of depression and LPSS with CBT, supplemented with a selective serotonin reuptake inhibitor (SSRI) antidepressant when indicated, in patients enrolled within 28 days after MI. CBT was initiated at a median of 17 days after the index MI for a median of 11 individual sessions during six months, plus group therapy when feasible, with SSRIs for patients scoring > 24 on the HAM-D, or having < 50% reduction in Beck Depression Inventory (BDI) scores after five weeks. SSRI treatment was initiated at 50 mg/day and adjusted to a maximum of 200 mg/day. The main outcome measure was a composite primary end point of death or recurrent MI; secondary outcomes included change in HAM-D-17 score or ESSI scores for LPSS at 6 months.

Improvement in psychosocial outcomes at six months favored treatment: the mean change in HAM-D-17 score was -10.1 7.8 in the depression and psychosocial intervention group versus -8.4 7.7 in the depression and usual care group (p < 0.001); the mean change in ESSI score was 5.1 5.9 in the LPSS and psychosocial intervention group versus 3.4 6.0 in the LPSS and usual care group (p < 0.001).

After an average of 29 months, there was no significant difference in event-free survival between patients receiving usual care (75.9%) and those receiving psychosocial intervention (75.8%). There were also no differences in survival between the psychosocial intervention and usual care arms among patients in any of the three psychosocial risk groups (depression, LPSS, and depression plus LPSS).

The intervention of CBT and SSRI in depressed post-MI patients did not increase event-free survival. The intervention alleviated depression and social isolation, although the relative improvement in the psychosocial intervention group compared with the usual care group was less than expected due to substantial improvement in patients receiving usual care.

Conclusion There is fair evidence that treating depression in post-MI patients with cognitive behavioral therapy does not improve cardiovascular outcomes. The GDT therefore recommends against its use in post-MI depressed patients to improve cardiovascular outcomes. Treatment of depression in CAD patients should be based on the patient’s mental health condition(s), for the purpose of improving mental health outcomes (see the KP National Depression Guideline).



There is insufficient evidence that treating depression in patients with CAD with antidepressant medications improves cardiovascular outcomes. The GDT therefore makes no recommendation for or against treating depressed patients with CAD to improve cardiovascular outcomes. Treatment of depression in CAD patients should be based on the patient’s mental health condition(s), for the purpose of improving mental health outcomes (see the KP National Depression Guideline). There is insufficient evidence that treating depression with cognitive behavioral therapy in patients with CAD who are not post-MI improves cardiovascular outcomes. The GDT therefore makes no recommendation for or against treating depressed patients with CAD who are not post-MI to improve cardiovascular outcomes. Treatment of depression in CAD patients should be based on the patient’s mental health condition(s); for the purpose of improving mental health outcomes (see the KP National Depression Guideline). There is insufficient evidence that treating depression in patients with CAD with antidepressant medications improves cardiovascular outcomes. The GDT therefore makes no recommendation for or against treating depressed patients with CAD to improve cardiovascular outcomes. Treatment of depression in CAD patients should be based on the patient’s mental health condition(s), for the purpose of improving mental health outcomes (see the KP National Depression Guideline).

2. Screening for CAD

2. Exercise stress testing, CT angiography, and coronary artery calcium scoring are not recommended for screening asymptomatic individuals for CAD. Consensus-based

Rationale:

Evidence Grade: Recommendation 2 – Insufficient

2008 Guideline

No relevant studies were identified in the peer-reviewed medical literature that evaluated exercise stress testing or CT angiography in screening for CAD for any of the outcomes specified for this problem formulation. Three prospective cohort studies were identified that evaluated electron-beam CT with calcium scoring against a gold standard of long-term follow-up for the presence of MI or CAD death. Kondos et al.(2) performed electron-beam CT with calcium scoring on a group of asymptomatic low-to-intermediate risk adults, reporting the number of deaths, myocardial infarctions, and revascularization procedures over a three-year period for a group of 5,635 persons. A positive calcium score was defined as any detectable level of coronary artery calcium. There were 58 outcome events seen in this group, with 53 occurring in the group that demonstrated any coronary artery calcium. The presence of coronary artery calcium had a positive predictive value of 0.01 in this study.



In a study of the predictive value of high calcium scores on the risk of MI or death due to coronary heart disease, a group of 1,461 asymptomatic individuals who underwent electron-beam CT with calcium scoring were observed for seven years (Greenland et al., 2004).(3) Calcium scoring of greater than or equal to 301 was reported in 221 persons, and a positive predictive value of 0.15 was demonstrated. LaMonte et al., 2005(4) followed a group of 10,746 asymptomatic persons who were screened with electron beam CT with calcium scoring, reporting 34 instances of death or myocardial infarction in 1,380 individuals whose score was 250 or greater. This study demonstrated a positive predictive value of 0.03.

Other Considerations The U.S. Preventive Services Task Force (USPSTF) recommends against routine screening with resting electrocardiography (ECG), exercise treadmill test (ETT), or electron-beam computerized tomography (EBCT) scanning for coronary calcium for either the presence of severe coronary artery stenosis (CAS) or the prediction of coronary heart disease (CHD) events in adults at low risk for CHD events (USPSTF, 2004).(5)

Conclusion No relevant studies were identified in the peer-reviewed medical literature that evaluated exercise stress testing or CT angiography in screening for CAD for any of the outcomes specified for this problem formulation. We found no randomized screening trials with calcium scoring during our search of the literature. The prospective cohort studies that were found show that electron-beam CT with calcium scoring may provide some useful information, but the low positive predictive values suggest that it is not useful for screening asymptomatic individuals. Although the results of calcium scoring have been shown to correlate with the presence of coronary disease on angiography, there are no studies (1) demonstrating that the results significantly supplement the information gained from standard risk factor analysis, or (2) establishing the validity of using calcium scoring findings to guide patient management. Based on the absence of quality evidence on the benefits and harms of resting electro-cardiography (ECG) or exercise treadmill testing (ETT) as screening tests for coronary artery disease, the GDT recommends against the use of ETT or ECG as screening tests for CAD. The GDT finds that the costs of routine screening for CAD with electron-beam computerized tomography (EBCT) scanning for coronary calcium for either the presence of severe coronary artery stenosis (CAS) or the prediction of coronary heart disease (CHD) events in adults at low risk for CHD events exceed the benefits and therefore recommends against such screening. The GDT finds that the costs of routine screening for CAD with electron-beam computerized tomography (EBCT) scanning for coronary calcium for either the presence of severe coronary artery stenosis (CAS) or the prediction of coronary heart disease (CHD) events in adults at low risk for CHD events exceed the benefits and therefore recommends against such screening.



ACEI and ARB Therapy

3. ACEI Therapy

3. For patients with CAD, with or without LVSD, angiotensin-converting enzyme (ACE) inhibitor therapy is recommended for long term use,* unless contraindicated. Evidence-based: B

Rationale:

Evidence Grade: Recommendation 3 – Good

2008 Guideline

Two relevant meta-analyses of RCTs were identified in the peer-reviewed medical literature that addressed ACE inhibitor treatment of CAD patients without LVSD. No new evidence was found for ACE inhibitor treatment of CAD patients with LVSD. A systematic review and meta-analysis(6) of RCTs on angiotensin-converting enzyme

inhibitors in coronary artery disease (CAD) with preserved left ventricular systolic function was performed, including HOPE (2000),(7) EUROPA (2003),(8) PEACE (2004),(9) QUIET (2001),(10) PART-2 (2000),(11) and CAMELOT (2004).(12) The main outcomes were cardiovascular mortality, nonfatal MI, all-cause mortality, and revascularization rates. The mean follow-up was 4.4 years. ● There were 16,772 patients randomized to ACE inhibitor and 16,728 patients to placebo.

● Use of ACE inhibitor therapy was associated with a decrease in cardiovascular mortality (RR = 0.83, 95% CI: 0.72 to 0.96, p = 0.01), nonfatal MI (RR = 0.84, 95% CI: 0.75 to 0.94, p = 0.003), all-cause mortality (RR = 0.87, 95% CI: 0.81 to 0.94, p = 0.0003), and coronary revascularization rates (RR = 0.93, 95% CI: 0.87 to 1.00, p = 0.04).

● The number needed to treat with ACE inhibitors to prevent one death, or one nonfatal MI, or one cardiovascular death or one coronary revascularization procedure for an average of 4.4 years was 100.

● The test for heterogeneity showed no difference in effect among studies as evident by I2 estimates for different outcomes.

● The cumulative evidence provided by this meta-analysis showed a modest favorable effect of ACE inhibitors on the outcome of patients with CAD and preserved left ventricular function.

* For patients on concomitant aspirin, low-dose aspirin (81 mg) is recommended to preserve ACE inhibitor benefit.



A second meta-analysis(13) of the use of ACE inhibitors in patients with CAD and without heart failure or left ventricular systolic dysfunction (LVSD) included seven RCTs: HOPE (2000),(7) EUROPA (2003),(8) PEACE (2004),(9) QUIET (2001),(10) PART-2 (2000),(11) CAMELOT (2004)(12) and SCAT (2000).(14) The principal outcomes were all-cause mortality, cardiovascular death, and MI. Secondary outcomes included stroke, cardiac arrest, myocardial revascularization, hospitalization because of heart failure, and onset of diabetes mellitus. The mean follow-up was 4.4 years (ranging from two to five years). ● A total of 33,960 patients were randomized to the ACE inhibitor or placebo groups.

● All-cause mortality was lower in the treatment arms than in the placebo arms of all trials except one (CAMELOT), and the reduction was statistically significant in HOPE. Overall mortality was significantly reduced (Odds Ratio = 0.86, 95% CI: 0.79 to 0.93, p < 0.001) in the meta-analysis.

● Cardiovascular mortality was consistently reduced by treatment with ACE inhibitors in all trials except CAMELOT, and the reduction was significant in HOPE. In the meta-analysis, cardiovascular mortality was significantly reduced by treatment with ACE inhibitors (Odds Ratio = 0.81, 95% CI: 0.73 to 0.90, p < 0.001).

● In addition, MI and stroke were reduced after ACE inhibitor treatment (OR = 0.82, 95% CI: 0.75 to 0.89, p < 0.001 for MI; Odds Ratio = 0.77, 95% CI: 0.66 to 0.88, p < 0.001 for stroke).

● Myocardial revascularization and hospitalization were also reduced after ACE inhibitor treatment by 8%, and 23%, respectively.

● ACE inhibitors reduced all-cause mortality and major cardiovascular end points in patients who had CAD and no LVSD or heart failure.

Conclusion There is good evidence that treatment with ACE inhibitors, when added to conventional therapy, reduces all-cause mortality, cardiovascular mortality, nonfatal MI, and subsequent revascularization in patients with CAD without LVSD. The drugs in the conventional therapy comparison groups were not the same in all of the studies included in the evidence summary. For the purposes of the analysis, conventional therapy is assumed to consist of aspirin, a beta-blocker, and a statin. Based on the meta-analyses discussed above, the GDT finds that the benefits of ACE inhibitors outweigh their harms and costs and therefore recommends long-term use of ACE inhibitors in patients with CAD. The GDT decided to delete the footnote in the 2006 version of this recommendation that said “In the PEACE Trial, patients with stable coronary artery disease and preserved left ventricular systolic function had no benefit on the composite endpoint of cardiovascular death, MI, and coronary revascularization with the addition of an ACE Inhibitor to standard medical therapy. ACE inhibition is, therefore, not required in such patients.”

2006 Guideline

No change to the 2004 recommendations has been made as a result of this systematic review (no new evidence).



2004 Guideline

Supporting Evidence for ACE Inhibitor Therapy versus Placebo In the PERSUADE(15) substudy of EUROPA, non-q-wave infarction was lower in patients on perindopril (5.1%) than those on placebo (7.7%). Relative risk reduction was 34% (95% CI: 0.1 to 56). The EUROPA Study, (8) conducted in a broad range of patients with CAD and no evidence of heart failure or notable hypertension (n = 12,218), found perindopril to reduce the combined frequency of CV death, MI and cardiac arrest by 20% (95% CI: 9 to 2, p = 0.0003; Absolute Risk = 8.0% for perindopril-treated and 9.9% for placebo group; ARR = 0.0188). The investigators report that 50 patients need to be treated for four years to prevent one major CV event. These findings were consistent in most subgroups and benefits were achieved against a background of high usage of aspirin, beta-blockers, and lipid-lowering drugs. Consistent with this finding, the previously reported HOPE study(7) of 9,000 patients with vascular disease or diabetes and another risk factor, found ramipril, another long-acting ACE Inhibitor, to reduce the combined frequency of cardiovascular death, MI, and stroke by 22% (from 17.8% to 14%, p < 0.001). The PEACE Trial,(9) a study of ACE inhibition with trandolapril in patients with stable coronary artery disease and preserved LV systolic function on standard medical therapy (n = 8,290), demonstrated no treatment effect on the primary composite endpoint of cardiovascular death, MI, and coronary revascularization (HR = 0.96; 95% CI: 0.88 to 1.06). However, this study did demonstrate a non-statistically significant favorable effect on overall mortality similar in magnitude to that reported in the EUROPA Trial (HR = 0.89; 95% CI: 0.76 to 1.04). Moreover, active treatment resulted in statistically significant reductions in hospitalizations for heart failure (HR = 0.75; 95% CI: 0.59 to 0.95) and in the development of new-onset diabetes (HR = 0.83; 95% CI: 0.72 to 0.96) consistent with those demonstrated in several prior ACE Inhibitor trials. The PERSUADE substudy of EUROPA did not change the weight of the evidence regarding the use of ACE Inhibitors in patients with CAD. For patients with CAD and left ventricular systolic dysfunction, see the 2006 KP National Heart Failure Guidelines. Professional Group Recommendations Reviewed ACC/AHA Guidelines for Preventing Heart Attack and Death in Patients with

Atherosclerotic Cardiovascular Disease: 2001 Update ACC/AHA 2002 Guideline Update for the Management of Patients with Unstable Angina

and Non-ST-Segment Elevation Myocardial Infarction ACC/AHA 2002 Guideline Update for the Management of Patients with Chronic Stable

Angina AHA Scientific Statement: Secondary Prevention of Coronary Artery Disease in the

Elderly (with emphasis on Patients > 75 Years of Age.



Other Considerations The ACC/AHA 2002 Practice Guidelines for Secondary Prevention in Patients with Coronary and Other Vascular Disease states:

“Treat all patients indefinitely post-MI; start early in stable high-risk patients (anterior MI, previous MI, Killip class II [S3 gallop, rales, radiographic HF]). Consider chronic therapy for all other patients with coronary or other vascular disease unless contraindicated. Use as needed to manage blood pressure or symptoms in all other patients.”

This evidence on the use of ACE Inhibitors in patients with CAD is consistent with and strengthens that presented in the 2002 CMI CAD Guidelines in support of ACE Inhibitor use. The GDT concurs with the PEACE investigators’ hypothesis that the PEACE Trial does not demonstrate the magnitude of benefit from ACE inhibition shown by HOPE and EUROPA primarily because the patients enrolled in the PEACE Trial were at lower baseline risk for cardiovascular events. This is attributable in part to baseline characteristics (the documented absence of clinically significant left ventricular dysfunction and a high incidence of prior coronary revascularization) and in part to intensive concomitant medical management. Supporting this interpretation is the fact that event rates in the placebo group in the PEACE Trial were not only lower than those in the placebo groups in HOPE and EUROPA, but also lower than those in the active treatment arms of the two previous trials. Given these observations, the GDT believes that ACE Inhibitor therapy is still recommended for most CAD patients.

2002 Guideline

One large RCT(7) of ramipril versus placebo provides evidence that ACE inhibitors protect a broad range of high-risk patients over the age of 55 from the risk of MI, stroke and cardiovascular death. Relative Risk Reduction was 22% (RR = 0.78; 95% CI: 0.70 to 0.86) and Absolute Risk Reduction was 3.7%; Numbers Needed to Treat = 27.



4. ARB Therapy

4.A. Angiotensin II Receptor Blocker (ARB) therapy is recommended for the following patients with CAD with or without hypertension who are intolerant to ACE Inhibitors:

Patients with CAD and diabetes with hypertension and microalbuminuria (or albuminuria)

Patients with CAD and left ventricular systolic dysfunction (LVSD)

Consensus-based

4.B. For patients with CAD and hypertension (without LVSD, or diabetes with microalbuminuria) who are intolerant to ACE Inhibitors, ARB therapy is an option equal to other antihypertensive medications. Evidence-based

4.C. For all other patients with CAD who are intolerant to ACE Inhibitors, there is insufficient evidence to recommend for or against ARB therapy. Evidence-based

Rationale:

2008 Guideline

No relevant RCTs or meta-analyses were identified in the peer-reviewed literature that evaluated ARB therapy in patients with CAD.

2006 Guideline

No change in the 2004 recommendations has been made as a result of this systematic review (no new evidence).

2004 Guideline

Supporting Evidence for Angiotensin II Receptor Blockers (ARB) Therapy in CAD Patients Who Are Intolerant to Angiotensin-Converting Enzyme (ACE) Inhibitor Therapy No studies were found that evaluated the use of ARBs in CAD patients who were intolerant to ACE Inhibitors. For patients with CAD and diabetes with hypertension and micro-albuminuria (or albuminuria) the 2004 KP National Diabetes Guidelines recommendation on the use of ARBs was adopted. For patients with CAD and left ventricular dysfunction the 2004 KP National Heart Failure Guidelines recommendation on ARBs was adopted.



For patients with CAD and hypertension (without either LVSD or diabetes), and for those with CAD alone, the GDT examined the following evidence comparing ARBs to ACE Inhibitors: The OPTIMAAL Study(16) compared losartan with captopril in patients with acute MI and

signs or symptoms of heart failure during the acute phase (n = 5,477). Over 50% of study subjects had ischemic heart disease and 36% had hypertension, equally distributed between intervention groups. Although there were small differences in total mortality (18.2% in Losartan; 16.4% in Captopril; RR = 1.13; 95% CI: 0.99 to 1.28, p = 0.069), and in CV mortality (15.3% in losartan and 13.3% in captopril; RR = 1.17; 95% CI: 1.01 to 1.34, p = 0.032) in favor of captopril (ACE Inhibitor), losartan (ARB) was better tolerated and associated with significantly fewer discontinuations than captopril. Because of this, the study investigators concluded that losartan can be considered in patients intolerant of ACE inhibition even though the role of losartan in patients intolerant of ACE inhibition was not clearly defined in this study.

The VALIANT trial(17) compared the effect of valsartan (ARB), captopril (ACE Inhibitor) and the combination of the two on mortality in patients with MI complicated by left ventricular systolic dysfunction, heart failure or both (n = 14,703). Over 50% of study subjects, equally distributed among intervention groups, had hypertension. After 24.7 months of follow-up, all-cause and cause-specific mortality were similar in the three treatment groups (valsartan-treated = 19.9%; captopril-treated = 19.3%; valsartan plus captopril-treated = 19.5%). Combining valsartan with captopril increased the rate of adverse events without improving survival. The study investigators concluded that valsartan met the trial criterion of noninferiority and thus may be considered a clinically effective alternative to ACE Inhibitor therapy.

Professional Group Recommendations Reviewed ACC/AHA 2002 Guideline Update for the Management of Patients with Unstable Angina


Angina ACC/AHA 2005 Guideline update for the Diagnosis and Management of Chronic Heart

Failure in the Adult.



Oral Anticoagulant Therapy

5. Aspirin versus Oral Anticoagulant Therapy

5. In CAD patients who are not at increased embolic risk and who tolerate aspirin, aspirin is recommended in preference to both oral anticoagulant therapy and the combination of aspirin and oral anticoagulant therapy. Evidence-based

Rationale:

2008 Guideline

No relevant RCTs or meta-analyses were identified in the peer-reviewed medical literature published since the previous update of this guideline that addressed the use of aspirin versus oral anticoagulant therapy in patients with CAD.

2006 Guideline

In July 2004, Clinical Evidence reported one systematic review that found that moderate or high-intensity oral anticoagulant therapy reduced the risk of cardiovascular events in people with CAD but substantially increased the risks of hemorrhage as compared with placebo or aspirin. This same review found that when added to aspirin, moderate or high-intensity anticoagulant therapy reduced the risk of serious cardiovascular events as compared with aspirin alone, but also increased the risk of major hemorrhage.(18) One subsequent RCT found that adding fixed, low-dose warfarin to aspirin had no effect on cardiovascular outcomes as compared with the use of aspirin alone (N = 2,300 with CAD in the (LoWASA Study; event rate = 28.1% with warfarin plus aspirin vs. 28.8% with aspirin alone; p = 0.67).(19) The recommendation remains unchanged.

2004 Guideline

Supporting Evidence for Oral Anticoagulant Therapy in the Absence of Antiplatelet Therapy According to Clinical Evidence,(20) the results of two RCTs have been published: “One subsequent RCT (3,630 people with previous acute myocardial infarction) compared three treatments: warfarin alone (to target INR 2.8 to 4.2); aspirin 160 mg daily; and warfarin (to target INR 2.0 to 2.5) plus aspirin 75 mg daily.(21) After four years, it found that warfarin alone significantly reduced cardiovascular events (death, myocardial infarction, or cerebral infarction) compared with aspirin alone (cardiovascular event rate 203/1216 [16.7%] with warfarin vs. 241/1206 [20%] with aspirin alone; RR = 0.81; 95% CI: 0.69 to 0.83).” However, “warfarin significantly increased major nonfatal bleeding compared with aspirin (0.68% a year with warfarin vs. 0.17% a year with aspirin; RR = 4.00; 95% CI: 1.67 to 10.00)”.



“A second subsequent RCT (999 people after acute coronary syndrome) similarly compared three treatments: aspirin 80 mg daily; oral anticoagulants (to target INR 3.0 to 4.0); and aspirin 80 mg daily plus oral anticoagulants (to target INR 2.0 to 2.5).(22) It found that oral anti-coagulants reduced cardiovascular events compared with aspirin, although the result was of borderline significance (17/325 [5%] with anticoagulants vs. 31/336 [9%] with aspirin; HR = 0.55; 95% CI: 0.30 to 1.00). [This] RCT found no significant difference in major bleeding between aspirin and combination treatment, although the study may have lacked power to detect a clinically important difference (1% with combination vs. 1% with aspirin; HR 1.03; 95% CI: 0.21 to 5.08).” Supporting Evidence for Oral Anticoagulant Therapy in Addition to Antiplatelet Therapy According to Clinical Evidence,(23) the results of four RCTs have been published:

“The first subsequent RCT (3,712 people with unstable angina) compared five months’ oral anticoagulant treatment (target INR 2.0 to 2.5) plus standard treatment (usually including aspirin) versus standard treatment alone.(24) When this trial was included in a meta-analysis with the previous trials assessing the addition of moderate intensity oral anticoagulation to aspirin, oral anticoagulation was associated with a nonsignificant reduction in mortality, myocardial infarction, or stroke (OR = 0.83; 95% CI: 0.66 to 1.03).”(25) [There was also evidence of] “clear excess of major haemorrhage in people allocated oral anticoagulation (OR = 1.95; 95% CI: 1.27 to 2.98).”(24) “The second subsequent RCT (5,059 people with myocardial infarction in the previous 14 days; unblinded) compared warfarin (target INR 1.5 to 2.5) plus aspirin 81 mg daily versus aspirin 162 mg daily alone. It found no significant differences between treatments in mortality, recurrent myocardial infarction, or stroke after a median of 2.7 years (mortality 17.6% with warfarin plus aspirin vs. 17.3% with aspirin alone, p = 0.8; AR for recurrent myocardial infarction: 13.3% with warfarin plus aspirin vs. 13.1% with aspirin alone, p = 0.8; AR for stroke 3.1% with warfarin plus aspirin vs. 3.5% with aspirin alone, p = 0.5) The addition of moderate intensity anticoagulation to aspirin also found that combined treatment increased risk of major haemorrhage (RR = 1.78; 95% CI: 1.27 to 2.72).”(26) “The third subsequent RCT (3,630 people with previous acute myocardial infarction) compared three treatments: warfarin alone (target INR 2.8 to 4.2); aspirin 160 mg daily; and warfarin (target INR 2.0 to 2.5) plus aspirin 75 mg daily. After four years, it found that warfarin plus aspirin significantly reduced cardiovascular events (death, myocardial infarction, or cerebral infarction) compared with aspirin alone (cardiovascular event rate 181/1208 [15%] with warfarin plus aspirin vs. 241/1206 [20%] with aspirin alone; RR = 0.71; 95% CI: 0.60 to 0.83). However, warfarin plus aspirin was associated with increased bleeding compared with aspirin alone (“…nonfatal major bleeding: 0.57% a year with warfarin plus aspirin vs. 0.17% a year with aspirin; RR, CI, and significance not stated).”(21)



The fourth subsequent RCT (999 people after acute coronary syndrome) similarly compared three treatments: aspirin 80 mg daily; oral anticoagulants (to target INR 3.0 to 4.0); and aspirin 80 mg daily plus oral anticoagulants (to target INR 2.0 to 2.5). It found that combination treatment significantly reduced cardiovascular events compared with aspirin alone (16/332 [5%] with combination vs. 31/336 [9%] with aspirin; HR = 0.50; 95% CI: 0.27 to 0.92)… and no significant difference in major bleeding between aspirin and combination treatment, although the study may have lacked power to detect a clinically important difference (2% with combination vs. 1% with aspirin alone; HR = 2.35; 95% CI: 0.61 to 9.10).” (21) “One RCT (135 people with unstable angina or nonST-segment myocardial infarction, with prior coronary artery bypass grafting) compared three treatments: aspirin 80 mg daily alone plus placebo; warfarin (target INR 2.0 to 2.5) plus placebo; and aspirin plus warfarin. It found no significant difference among treatments for rates of primary end point (death or myocardial infarction or unstable angina requiring admission to hospital at one year; AR = 14.6% with warfarin alone vs. 11.5% with aspirin alone vs. 11.3% with combination, p = 0.76). However, it found no significant difference for major haemorrhage among people taking warfarin compared with those who were not. Event rates were low and the study may have lacked power to detect a clinically important difference for adverse effects.”(27)

Professional Group Recommendations Reviewed AHA/ACC Foundation Guide to Warfarin Therapy, 2003

Other Considerations The ACC/AHA also recommends aspirin in preference to oral anticoagulants for CAD patients who tolerate aspirin.

Overall Conclusions Although the evidence shows that oral anticoagulants provide protection against vascular events in the absence of antiplatelet treatment, the risks of serious hemorrhage are higher than for antiplatelet treatment and regular monitoring is required. Aspirin provides similar protection and is safer and easier to use. The addition of a moderately intense oral anticoagulant regimen to aspirin may provide additional net benefit to people at high risk of ischemic cardiac events although such evidence is inconsistent and the risk of hemorrhage is reportedly increased in several studies. This update from Clinical Evidence on the use of oral anticoagulant agents by patients with CAD adds additional RCTs to the evidence from a meta-analysis presented in the 2002 CAD Guidelines for anticoagulant use. The recommendation remains unchanged.

Summary of 2002 Rationale:

Although there is evidence that high or moderate intensity oral anticoagulant therapy significantly improves outcomes for CAD patients when compared with placebo, no significant evidence was found that oral anticoagulant therapy alone is more beneficial than aspirin alone in this population. Furthermore, there is strong evidence that oral anticoagulant therapy when compared with aspirin significantly increases the risk of major bleeding.



6. Aspirin Plus Oral Anticoagulant Therapy

6. Low-dose aspirin (81 mg/day) is conditionally recommended for most patients with established CAD receiving warfarin for thromboembolic prophylaxis.

Note: The balance between benefits and harms requires individualized assessment and should be tailored to the individual patient’s preferences and clinical circumstances. Low-dose aspirin (81 mg/day) is recommended because the risk of bleeding increases with higher aspirin dose.

Rationale:

2010 Update

Search Strategy A comprehensive search was conducted in January 2010 to identify RCTs relevant to this problem formulation. See Search Strategy (located in Appendix B for more information on specific search terms). RCTs were included if they compared aspirin plus an oral anticoagulant (warfarin) to oral anticoagulant (warfarin) alone in patients with CAD. Patients with CAD include adult patients with a history of ischemic heart disease, myocardial infarction (MI), coronary artery bypass graft (CABG), and/or percutaneous coronary intervention (PCI) or documented CAD (by angiography or noninvasive testing). A total of three studies were identified and included. No relevant RCTs were identified that evaluated the use of aspirin plus oral anticoagulant therapy for patients with established CAD using oral anticoagulant for thromboembolic prophylaxis. Studies included for this problem formulation compared combination aspirin plus oral anticoagulant therapy to oral anticoagulant alone in patients not requiring baseline oral anticoagulant therapy.

Evidence Summary A total of three studies were identified that compared combination aspirin plus oral anticoagulant therapy to oral anticoagulant alone in patients with acute coronary syndrome (ACS) not requiring baseline oral anticoagulant therapy. No studies were identified that evaluated the use of aspirin plus oral anticoagulant therapy in CAD patients requiring oral anticoagulant for thromboembolic prophylaxis. The GRADE system was used for assessing the quality of evidence.

Summary of Evidence on Efficacy of Aspirin Aspirin has been shown to be effective in treating patients with CAD. In the Antithrombotic Trialists Collaborative meta-analysis(28) of 195 trials, antiplatelet therapy reduced the incidence of serious vascular events by ~25% in high risk patients (those with AMI or ischemic stroke, unstable or stable angina, previous MI, stroke or cerebral ischemia, peripheral artery disease or atrial fibrillation). Although this analysis did not identify subjects on warfarin, such patients were not systematically excluded from the studies reviewed.



Summary of Evidence on Efficacy of Aspirin plus Oral Anticoagulant Therapy Overall, the quality of evidence for efficacy outcomes among the three identified RCTs was low due to the imprecision in effect size estimates and the indirectness of the included populations (ACS patients not requiring baseline oral anticoagulant may not be generalizable to CAD patients on oral anticoagulant therapy for thromboembolic prophylaxis). There are no studies that address (concomitant) use of aspirin in CAD populations requiring oral anticoagulant. But, there is no reason to suspect that the efficacy of aspirin for preventing death and myocardial infarction would differ in CAD patients requiring oral anticoagulants (typically atrial fibrillation or venous thromboembolism), as compared to CAD patients not requiring oral anticoagulant. The critical outcomes for efficacy identified by the GDT were all-cause mortality, myocardial infarction, stroke, and coronary revascularization. Among the efficacy outcomes of myocardial infarction, stroke, and coronary revascularization, aspirin plus oral anticoagulant therapy showed no indication of increased harm as compared to oral anticoagulant therapy alone over one to four years follow-up. Although there was a slight increase in risk for all-cause mortality, the pooled estimate was not statistically significant. Furthermore, aspirin plus oral anticoagulant therapy demonstrated moderate benefit, although not significant, towards decreased risks for myocardial infarction and coronary revascularization procedures compared to oral anticoagulant therapy alone. For the efficacy outcomes of myocardial infarction, stroke, and coronary revascularization, Hurlen et al. (2002) could not be pooled with other studies reporting the same outcomes. Hurlen et al. (2002) reported myocardial infarction, stroke, and coronary revascularization as number of events, as opposed to number of patients, and therefore, the results from this study could not be pooled into a meta-analysis with results from other studies. In regard to myocardial infarction (MI), Hurlen et al. (2002) reported 69 MI events among 1,208 patients in the aspirin plus warfarin therapy group as compared to 90 MI events among 1,216 patients in the warfarin alone group over a follow-up time of four years. No statistical comparison was provided between these two groups for this outcome, but the result appears to be consistent with the other two studies. In regard to stroke, Hurlen et al. (2002) reported 17 stroke events among 1,208 patients on aspirin and warfarin therapy compared to 17 stroke events among 1,216 patients on warfarin alone over a follow-up time of four years. Both studies evaluating stroke (21, 22) show similar results indicating the risk for stroke is not increased with aspirin plus oral anticoagulant therapy as compared to oral anticoagulant alone. In regard to coronary revascularization, Hurlen et al. (2002) reported 430 coronary revascularization procedures among 1,208 aspirin plus warfarin patients compared to 416 coronary revascularization procedures among 1,216 warfarin only patients. The rates of coronary revascularization procedures were similar in both groups over a follow-up time of four years.



Summary of Evidence on Safety of Aspirin plus Oral Anticoagulant Therapy The important safety outcomes assessed in the three RCTs were major and minor bleeding. Overall, the quality of evidence for major and minor bleeding was very low due to the risk of bias of open-label study designs in two of three of the studies, the imprecision of effect size estimates across studies, and the indirectness of included populations. Definitions of major bleeding varied among the three studies. Major bleeding was defined in the Hurlen et al. (2002) study as nonfatal cerebral hemorrhage or bleeding necessitating surgical intervention or blood transfusion. Huynh et al. (2001) defined major bleeding as fatal bleeding, intracranial hemorrhage, or any bleeding requiring admission, irrespective of interventions, and van Es et al. (2002) defined major bleeding as a fall in hemoglobin of 2 g/L or requiring blood product transfusion. Minor bleeding was defined as all other bleeding events outside of the definition of major bleeding. Although definitions of major bleeding varied, the rates of major bleeding events were similar overall between patients taking aspirin plus oral anticoagulant and patients taking oral anticoagulant alone. There was a slight increased risk for major bleeding events in patients taking aspirin plus oral anticoagulant, but the pooled estimate was not statistically significant. However, the studies showed a significant increased risk for minor bleeding in patients taking aspirin plus oral anticoagulant therapy as compared to those on oral anticoagulant alone. In addition, a previous update of this guideline identified an RCT, SPAF III,(29) which studied the efficacy and safety of combination aspirin and fixed dose warfarin therapy for stroke prevention in patients with atrial fibrillation. SPAF III detected no significant differences in the rates of bleeding between treatment groups. (Combination therapy: 2.4% per year; 95% CI: 1.4 to 4.1; Adjusted dose warfarin, 2.1% per year; 95% CI: 1.2 to 3.7). Although SPAF III patients were randomized to warfarin alone versus aspirin plus warfarin, not all patients had CAD.

Professional Society Recommendations: The ACC/AHA 2006 Guideline on Secondary Prevention for Patients with Coronary and Other Atherosclerotic Vascular Disease and the 2007 ACC/AHA Chronic Stable Angina Guideline both say: “Use of warfarin in conjunction with aspirin and/or clopidogrel is associated with increased risk of bleeding and should be monitored closely.”

Evidence Synthesis

There is no direct evidence evaluating the use of aspirin plus oral anticoagulant therapy for patients with established CAD using oral anticoagulant for thromboembolic prophylaxis.

However, there is strong evidence of the benefit of aspirin in preventing CVD events and mortality in patients with CAD.

The overall quality of evidence was low due to the imprecision in effect size estimates and the indirectness of the included populations (ACS patients not requiring baseline oral anticoagulant may not be generalizable to CAD patients on oral anticoagulant therapy for thromboembolic prophylaxis).

Given the low quality of available evidence, further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.



There is a statistically significant increased risk for minor bleeding, but not major bleeding, with combination aspirin and oral anticoagulant therapy.

While the efficacy of aspirin with oral anticoagulant is not significantly greater than the efficacy of oral anticoagulant alone, there is no evidence suggesting increased harm or risk for death or cardiovascular events with combination aspirin plus oral anticoagulant therapy. The strong pathophysiologic rationale for the efficacy of aspirin and the demonstrated safety of combination therapy support a conditional recommendation for the use of aspirin in patients with established CAD requiring warfarin for thromboembolic prophylaxis. However, the balance between benefits and harms requires individualized assessment and should be tailored to the individual patient’s preferences and clinical circumstances. Low-dose aspirin (81 mg/day) is recommended because the Antithrombotic Trialists Collaborative meta-analysis(28) demonstrated that there is no increased benefit with higher dose, and it is generally accepted that the risk of bleeding increases with higher aspirin doses, although this was not explicitly explored.

Although the level of certainty is low, there are important trade-offs between the benefits of reduced risk for thromboembolic events, myocardial infarction, and coronary revascularization procedures and the harms of increased minor bleeding risk with the use of aspirin plus anticoagulant therapy in patients with established CAD. Although bleeding risk calculators exist for some patients with CAD,(30-32) none specifically address the risk of bleeding from adding aspirin to oral anticoagulants in patients with CAD who otherwise require oral anticoagulant therapy.



Meta-analyses of Critical and Important Outcomes











GRADE System of Evidence Rating The overall quality of evidence for outcomes was assessed using a method developed by the GRADE Working Group, which classified the grade of evidence across outcomes according to the following criteria: High = Further research is very unlikely to change our confidence on the estimate of effect. Moderate = Further research is likely to have an important impact on our confidence in the

estimate of effect and may change the estimate. Low = Further research is very likely to have an important impact on our confidence in the

estimate of effect and is likely to change the estimate. Very Low = Any estimate of effect is very uncertain.

GRADE also suggests using the following scheme for assigning the “grade” or strength of evidence:

Reference: Atkins D, Best D, Briss PA, Eccles M, Falck-Ytter Y, Flottorp S, Guyatt GH, Harbour RT, Haugh MC, Henry D, Hill S, Jaeschke R, Leng G, Liberati A, Magrini N, Mason J, Middleton P, Mrukowicz J, O'Connell D, Oxman AD, Phillips B, Schünemann HJ, Edejer TT, Varonen H, Vist GE, Williams JW Jr, Zaza S; GRADE Working Group. Grading quality of evidence and strength of recommendations. BMJ. 2004 Jun 19;328(7454):1490.



GRADE Evidence Profile

Aspirin + Oral Anticoagulant vs. Oral Anticoagulant Alone

Quality assessment No of patients Effect

No of studies Design Limitations Inconsistency Indirectness Imprecision

Other considerations

Aspirin therapy plus

anticoagulants Anticoagulant

alone Relative (95% CI) Absolute Quality Importance

Mortality, All-Cause (follow-up 1-4 years) 32 randomised

trials no serious limitations3

no serious inconsistency4

serious5 serious6 none

106/1584 (6.7%) 101/1586 (6.4%)RR 1.05 (0.80 to 1.36)

3 more per 1000 (from 12 fewer to 24 more)

LOW

CRITICAL

Myocardial Infarction7 (follow-up 1 years) 27 randomised


no serious inconsistency


12/376 (3.2%) 17/370 (4.6%)RR 0.70 (0.34 to 1.44)

14 fewer per 1000 (from 30 fewer to 20

more)

LOW

CRITICAL

Stroke (follow-up 1 years) 111 randomised

trials no serious limitations


serious12 serious13 none 1/332 (0.3%) 0/325 (0%)

Not estimable

Not estimable

LOW

CRITICAL

Coronary Revascularization7 (follow-up 1 years) 27 randomised




35/376 (9.3%) 40/370 (10.8%)

RR 0.87 (0.56 to 1.33)


more)

LOW

CRITICAL

Bleeding, Major (follow-up 1-4 years) 32 randomised

trials serious15 no serious

inconsistency4 serious5 serious16 none

37/1584 (2.3%) 37/1586 (2.3%) RR 1.05 (0.60 to 1.83)

0 fewer per 1000 (from 8 fewer to 13 more)

VERY LOW

IMPORTANT

Bleeding, Minor (follow-up 1-4 years) 32 randomised


inconsistency4 serious5 no serious

imprecision17 none

192/1584 (12.1%) 139/1586 (8.8%)RR 1.39 (1.03 to 1.89)

33 more per 1000 (from 11 more to 61 more)

LOW

IMPORTANT



1 CAD is defined as a history of ischemic heart disease, MI, CABG, and/or PCI or documented CAD (by angiography or noninvasive testing). 2 Hurlen 2002; Huynh 2001; van Es 2002. 3 No serious limitations. Although 2 of the 3 studies are open-label, outcomes were adjudicated by an independent group blinded to treatment in both of these studies. 4 One study (Hurlen 2002; N = 3630) reported outcomes at 4 years, while the remaining 2 studies (van Es 2002 and Huynh 2001; N = 1134 combined) reported outcomes at 1 year. Although all 3 studies are consistent in regard to intervention, comparison, and outcome measured, the follow-up time, treatment effect, and effect sizes differ between the larger study and the other 2 smaller studies. However, confidence intervals do all overlap with each other as well as with the point estimate, suggesting that the heterogeneity did not strongly affect the estimate of effect. All 3 studies looked at populations with acute coronary syndrome, but the larger study also required that patients have a prior CABG in addition to ACS. 5 All 3 studies evaluated populations with acute coronary syndromes (ACS), but not the broader diagnosis of CAD. Patients with ACS are a subset of patients of CAD, but given that the patients included in these studies are ACS patients, results are not necessarily generalizable to all CAD patients. Furthermore, two of the studies (Huynh 2001; van Es 2002) excluded patients with established indications for oral anticoagulants, and Huynh 2001 also excluded patients with conditions mandating treatment with aspirin. 6 The number of events is small (<300), and 2 of the 3 studies have wide confidence intervals including. The confidence interval of the point estimate includes negligible effect and appreciable harm. 7 Huynh 2001 and van Es 2002 8 No serious limitations. Although van Es 2002 is open-label, outcomes were adjudicated by an independent group blinded to treatment. Huynh 2001 was double-blind. 9 Both studies evaluated populations with acute coronary syndromes (ACS), but not the broader diagnosis of CAD. Patients with ACS are a subset of patients of CAD, but given that the patients included in these studies are ACS patients, results are not necessarily generalizable to all CAD patients. Furthermore, both studies excluded patients with established indications for oral anticoagulants, and Huynh 2001 also excluded patients with conditions mandating treatment with aspirin. 10 The sample sizes and number of events is very small, as illustrated by the wide confidence intervals, suggesting imprecision. Furthermore, the 95% confidence interval around the estimate of effect includes negligible effect as well as appreciable harm and benefit. 11 van Es 2002 12 This study evaluated a population with acute coronary syndromes (ACS), but not the broader diagnosis of CAD. Furthermore, patients with established indications for treatment with oral anticoagulants were excluded from this study. Patients with ACS are a subset of patients of CAD, but given that the patients included in these studies are ACS patients, results are not necessarily generalizable to all CAD patients. 13 The number of events is very low (only 1 event), suggesting that imprecision is highly likely. 14 The confidence intervals of the studies include no effect. The number of events is low (75), suggesting imprecision. The 95% confidence interval around the pooled estimate of effect includes negligible effect and appreciable benefit and harm. 15 Two studies (Hurlen 2002 and van Es 2002) were open-label study designs. It is possible that knowledge of drug allocation affected reporting of bleeding or assessment of bleeding outcome. 16 The number of events is very low (74), suggesting imprecision in the estimate of effect. All confidence intervals include no effect. The 95% confidence interval around the pooled estimate of effect includes negligible effect and appreciable benefit and harm.17 Although one of the studies is small with a wide confidence interval including no effect, the point estimate has a narrow confidence interval showing appreciable harm. The other studies which were both larger and more precise are consistent with the point estimate and estimate of effect.



7. Anticoagulation Post-MI

7.A. Warfarin is recommended for post-MI patients with left ventricular thrombus, unless otherwise indicated. Consensus-based

7.B. Long term warfarin therapy may be used in consultation with cardiology for post-MI patients with large transmural anterior infarctions. Consensus-based

Rationale:

2008 Guideline

No relevant RCTs or meta-analyses were identified in the peer-reviewed medical literature published since the previous update of this guideline that addressed oral anticoagulant therapy in patients with CAD and either left ventricular thrombus or large transmural anterior infarction.

2006 & 2004 Guideline

No additional evidence was found to supplement the rationale in the 2002 CAD Guidelines. Therefore, the recommendations remain unchanged.

2002 Guideline

Insufficient evidence was found to link anticoagulation in post-MI patients with anterior infarction or LV thrombus to decreased risk of stroke. In fact, there has been recent dispute over the importance of anterior location of the infarction (and therefore a left ventricular thrombus) as a risk factor for stroke. Nevertheless, there have been a number of small observational studies demonstrating a higher risk of embolic stroke for patients with large anterior infarction and demonstration of LV mural thrombus by echocardiography. Given these observations and the concern over the incidence of systemic embolism in patients who have experienced anterior MIs, oral anticoagulants may be given for patients with large anterior infarction or demonstration of LV mural thrombus. However, benefit of stroke prevention should be weighed against the risk of bleeding.



8. Aspirin

8.A. For all patients with CAD, daily aspirin is recommended indefinitely, unless there is clear contraindication such as active bleeding, major coagulopathy, or true aspirin allergy. Evidence-based: B

8.B. For CAD patients low-dose aspirin (81 mg) is generally recommended. Consensus-based

Rationale:

Evidence Grade: Recommendation A: Good Recommendation B: Insufficient

2010 Update

Only the evidence for recommendation 8C was reviewed in 2010. No change in the recommendations was made as a result of this systematic review.

2008 Guideline

Supporting Evidence for Thienopyridine plus Aspirin Therapy versus Aspirin Alone One relevant RCT was identified in the peer-reviewed medical literature that assessed the use of antiplatelet therapy in patients with chronic stable CAD. The CHARISMA trial (Bhatt et al., 2006)(33) included 15,603 patients aged 45 years and older who were randomly assigned to treatment with clopidogrel plus aspirin or aspirin plus placebo and followed for a median of 28 months. The primary efficacy endpoint was a composite of myocardial infarction, stroke, or death from cardiovascular causes. Combination therapy was not reported to be significantly more effective than aspirin therapy alone.

Conclusion Recent evidence regarding the use of clopidogrel with aspirin in CAD patients does not clearly document a substantial additional therapeutic benefit for patients with stable CAD. It remains an appropriate therapeutic choice for patients who cannot tolerate aspirin. Previous good evidence documented reductions in vascular events for CAD patients using aspirin. The GDT therefore recommends aspirin alone for patients with CAD without a clear contraindication to aspirin use.



The GDT added recommendations C and D in the 2008 update of the guidelines: Rationale for C: The dosage for aspirin in the first six months after stent placement is taken from doses used in short-term studies of dual therapy. Mueller(34) used 100 mg of aspirin. Two studies in the Bhatt meta-analysis, Bertrand (Bertrend et al., 2000)(35) and Taniuchi (Taniuchi et al., 2001)(36) used 325 mg of aspirin. After stent placement, the GDT recommends the lower, long-term dose of aspirin because of concerns about patient safety with higher doses. Rationale for D: Because of concerns about the risks of bleeding with higher doses of aspirin, the GDT recommends starting aspirin therapy at 81 to 162 mg of aspirin. The GDT did not believe that patients who are doing well on the higher doses of aspirin needed to be switched to the lower dose range.

Other Considerations The 2007 Chronic Angina Focused Update of the ACC/AHA 2002 Guidelines for the Management of Patients with Chronic Stable Angina states “Aspirin should be started at 75 to 162 mg per day and continued indefinitely in all patients unless contraindicated.”

2006 Guideline

No change in the 2004 recommendations has been made as a result of this systematic review.

2004 Guideline

Supporting Evidence for Antiplatelet therapy versus Placebo The Antithrombotic Trialists’ Collaborative (ATC) meta-analysis(28) of 195 trials of antiplatelet therapy versus controls reported that aspirin, or another antiplatelet drug, reduced the combined outcome of any serious vascular event by ~25% in high risk patients including those with an AMI or ischemic stroke, unstable or stable angina, previous MI, stroke or cerebral ischemia, peripheral arterial disease, or atrial fibrillation. In each of these categories of patients, the absolute benefits substantially outweighed the absolute risks of major extra-cranial bleeding. Some differences were reported in proportional risk reductions by subcategory of disease.

Supporting Evidence for Aspirin versus Placebo (Including Dose) When compared to placebo, the ATC meta-analysis(28) found aspirin to be an effective antiplatelet agent in the prevention of serious vascular events in high risk patients. Among the trials of higher daily doses of aspirin versus no aspirin, doses of 75 to 150 mg daily were at least as effective as higher doses for long-term prevention. No evidence was cited to support aspirin doses > 1,000 mg for stroke prevention. In those trials reported by the ATC comparing aspirin with control, the proportional increase in the risk of a major extracranial bleed was similar with all daily aspirin doses < 325 mg, with odds ratios in the range of 1.4 to 1.7. In a separate meta-analysis evaluating the benefits and risks of low-dose (50 to 325 mg) aspirin compared to placebo in secondary prevention trials, Weisman(37) reported aspirin to confer a statistically significant reduction in all-cause mortality as well as vascular events and MI. NNT calculations suggest that 1.5 lives are saved for every GI bleed event attributed to aspirin.



Supporting Evidence for Aspirin versus Thienopyridine Therapy When any aspirin dose was compared with any other antiplatelet drug the ATC meta-analysis(28) reported a nonsignificant test result for heterogeneity in support of the finding that there were no differences among antiplatelet agents in their effects on serious vascular events (81,731 patients in 166 trials, excluding acute stroke). Among the 19,185 patients with a history of MI, stroke or peripheral artery disease, in the CAPRIE Trial cited by the ATC, (28) a statistically significant reduction of 10% (standard error = 4%) in serious vascular events was found for clopidogrel compared with aspirin. In a separate analysis of the 19,185 CAPRIE Trial participants, Cannon(38) reports clopidogrel significantly reduced the relative risk of AMI (by 19.2%, p = 0.008) compared to aspirin among those patients with ischemic stroke, AMI, or peripheral artery disease.

Supporting Evidence for Thienopyridine plus Aspirin Therapy versus Aspirin Alone The CURE trial,(39) a large randomized, controlled trial of 12,562 patients with acute coronary syndrome, without ST-segment elevation, found that clopidogrel plus aspirin reduces the risk of cardiovascular death, MI and stroke, with benefits emerging within 24 hours of initiation of treatment and continuing throughout the three to 12 months (mean was nine months) of the study (RR = 0.82; 95% CI: 0.70 to 0.95, p = 0.009).

Supporting Evidence for Low-Dose Aspirin in Patients on ACE Inhibitors See 2004 KP National Heart Failure Guidelines for complete discussion of evidence. These guidelines cite a study(40) which evaluated the effect of aspirin dose in the coadministration of ACE Inhibitors and aspirin in heart failure patients (31% of whom had had an MI) and reported that at low doses (≤ 160 mg) aspirin did not result in increased mortality (HR = 1.02, p = 0.18).

Professional Group Recommendations Reviewed ACC/AHA Guidelines for Preventing Heart Attack and Death in Patients with

Atherosclerotic Cardiovascular Disease: 2001 Update ACC/AHA 2002 Guideline Update for the Management of Patients with Unstable Angina


Angina AHA Scientific Statement: Secondary Prevention of Coronary Heart Disease in the Elderly

(With Emphasis on Patients > 75 Years of Age)

Other Considerations This updated evidence on the use of antiplatelet agents by patients with CAD is consistent with that presented in the 2002 CMI CAD Guidelines in support of aspirin use. Since July 2001, additional evidence available on multiple dose ranges strengthens the recommendation in 2004 for low-dose aspirin (at 75 to 150 mg) in those who tolerate aspirin. The recommendation remains unchanged to permit use of aspirin in units commonly available. A second recommendation for preferential low-dose aspirin is added for persons taking ACE Inhibitors to address reports of decreased efficacy of ACE Inhibitors with concomitant use of aspirin.



The ACC/AHA 2002 Practice Guidelines for secondary prevention in patients with coronary and other vascular disease states: “Start and continue indefinitely 75 to 325 mg/day of aspirin if not contraindicated.”

Overall Conclusion from Evidence Because of the reliability and homogeneity of these findings across studies, extrapolation of the evidence to a wide range of high-risk CAD patients is appropriate. Although there is evidence presented which supports the use of thienopyridine therapy (clopidogrel) alone in preference to aspirin as a first line antiplatelet treatment in persons at high risk of vascular events, an analysis of quality adjusted years of life saved (QALY) renders the choice of clopidogrel (in those who tolerate aspirin) prohibitive ($11,000/QALY for aspirin vs. > $130,000/QALY for clopidogrel).(41)

Summary of 2002 Rationale: One extensive meta-analysis(7) demonstrated the protective effect of daily aspirin in reducing the odds of a vascular event (nonfatal MI, nonfatal stroke, or vascular death) for patients at high risk of ischemic cardiac events. This meta-analysis showed further benefits from longer treatment periods, but no further benefit from an aspirin dose greater than 325 mg. Two additional clinical trials(8, 9) further support that low-dose aspirin can significantly reduce the incidence of cardiac events.

9. Clopidogrel Use in Stable Patients

9.A. In stable CAD patients who tolerate aspirin well (and who are not post-procedure), clopidogrel is not recommended as either a substitute for or in addition to aspirin. Consensus-based

9.B. In stable CAD patients with contraindications to aspirin, clopidogrel is recommended. Consensus-based

Rationale:

Evidence Grade: Recommendation 9A, B – Insufficient

2008 Guideline

One relevant RCT was identified in the peer-reviewed medical literature that assessed the use of antiplatelet therapy in patients with chronic stable CAD. The CHARISMA trial (Bhatt et al., 2006)(33) included 15,603 patients aged 45 years and older who were randomly assigned to treatment with clopidogrel plus aspirin or with aspirin plus placebo and followed for a median of 28 months. The primary efficacy endpoint was a composite of myocardial infarction, stroke, or death from cardiovascular causes. Combination therapy was not reported to be significantly more effective than aspirin therapy alone.



Conclusion Recent evidence regarding the use of clopidogrel with aspirin in CAD patients does not clearly document a substantial net therapeutic benefit for patients with stable CAD. Clopidogrel remains an appropriate therapeutic choice for patients who cannot tolerate aspirin based on equivalent effect/noninferiority in general populations with CAD. Direct evidence is lacking since aspirin-intolerant patients are usually excluded from relevant trials. The GDT therefore recommends continuing the recommendation for the use of clopidogrel in aspirin-intolerant patients with CAD.

2006 Guideline

No change in the 2004 recommendations has been made as a result of this systematic review (no new evidence).

2004 Guideline

Supporting Evidence for use of Antiplatelet Agents Other Than Aspirin in the Treatment of Persons with Contraindications to Aspirin Because persons with contraindications to aspirin have been excluded from large trials of antiplatelet use, there is no direct evidence to support a recommendation in this group. Evidence for use of clopidogrel as the antiplatelet agent of choice is based upon the proven effectiveness of the thienopyridines when compared to aspirin.(28) Clopidogrel is recommended in preference to ticlopidine because ticlopidine is associated with greater incidences of skin rash, diarrhea, thrombocytopenia, and thrombotic thrombocytopenia.(42)

Professional Group Recommendations Reviewed ACC/AHA Guidelines for Preventing Heart Attack and Death in Patients with

Atherosclerotic Cardiovascular Disease: 2001 Update

ACC/AHA 2002 Guideline Update for the Management of Patients with Unstable Angina and Non-ST-Segment Elevation Myocardial Infarction

ACC/AHA 2002 Guideline Update for the Management of Patients with Chronic Stable Angina

AHA Scientific Statement: Secondary Prevention of Coronary Heart Disease in the Elderly (With Emphasis on Patients > 75 Years of Age)

Other Considerations This updated evidence on the use of antiplatelet agents by patients with CAD is consistent with that presented in the 2002 CMI CAD Guidelines recommendation in support of antiplatelet use for those CAD patients with contraindications to aspirin. The ACC/AHA 2002 Practice Guidelines for secondary prevention in patients with coronary and other vascular disease state: “Consider clopidogrel as an alternative if aspirin is contraindicated.”



2002 Guideline

Daily clopidogrel appears to be as effective as daily aspirin in reducing morbidity and mortality in patients with coronary artery disease. At this point, the magnitude of these benefits is not convincing enough to override the high cost of clopidogrel treatment. Therefore, clopidogrel cannot be recommended as the first line treatment for patients who tolerate aspirin. In addition to the comparatively higher cost of clopidogrel, when compared to aspirin, clopidogrel increased the risk of minor and major bleeding episodes when added to aspirin therapy.(43) Clopidogrel is also associated with a 30% excess of skin rash and diarrhea when compared to aspirin.(44) The CURE trial(43) showed that combination of aspirin and clopidogrel compared to aspirin and placebo significantly reduced the risk of primary events (death from CV causes, nonfatal MI, or stroke) for patients with acute coronary syndrome. However, there was a significant increase in bleeding (RR = 1.13; 95% CI: 1.13 to 1.67) in the clopidogrel group. This included a statistically significant increase in life-threatening bleeding episodes.



10. Antiplatelet Therapy Post Stent Placement The following recommendations refer to patients without active pathological bleeding 10.A. All patients with CAD should take aspirin therapy indefinitely regardless of stenting

status.

10.B. Dual antiplatelet therapy with a P2Y12 inhibitor plus aspirin is strongly recommended for patients following coronary stent placement. The preferred P2Y12 inhibitors are as follows: first-line - clopidogrel; acceptable alternative – prasugrel or ticagrelor; least-preferred – ticlopidine.

For patients who suffer stent thrombosiswhile on a combination of clopidogrel plus aspirin, or at high risk for stent thrombosis, prasugrelor ticagrelor plus aspirin is an option.

Prasugrel is not recommended in patients with active pathological bleeding, with a history of stroke or transient ischemic attack (TIA), or in patients ≥ 75 years of age, because of risk of fatal and intracranial hemorrhage and uncertain benefit, except in high risk patients (e.g., diabetes or prior myocardial infarction).

Ticagrelor is not recommended in patients with a history of intracranial hemorrhage (ICH), active pathological bleeding, or severe hepatic insufficiency.

Ticlopidine is the least preferred agent. It is generally reserved who are unable to use prasugrel due to high bleeding risk and are intolerant or allergic to clopidogrel.

10.C. For patients with ACS and a coronary artery bare metal stent (BMS) or drug eluting stent (DES) post-placement treatment with a P2Y12 inhibitor plus aspirin is strongly recommended for at least 12 months.

In patients with a high risk of bleeding, who also have a high risk of discontinuation, BMS placement with a shorter duration of dual antiplatelet therapy (less than 12 months) is an option.

10.D. For patients with stable angina and a drug-eluting stents (DES), uninterrupted dual antiplatelet treatment with a P2Y12 inhibitor and aspirin is strongly recommended for at least 12 months.

Delay of any elective procedures which would require stopping or interrupting this therapy is strongly recommended until after one year (12 consecutive months) of dual antiplatelet therapy is completed.

Prior to stopping dual antiplatelet therapy in patients with coronary DES, consultation with the patient's treating cardiologist is strongly recommended.*

For patients with a drug-eluting stent and who must have procedures that mandate stopping dual antiplatelet therapy, it is strongly recommended that aspirin be continued if at all possible, and dual antiplatelet therapy be restarted as soon as possible after the procedure.

* Healthcare providers who perform invasive or surgical procedures and are concerned about peri-procedural and

post-procedural bleeding should be made aware that the premature discontinuation of dual antiplatelet therapy in the first year following coronary DES placement carries a significant risk for the development of acute DES thrombosis, which in turn carries a high mortality rate (i.e., upwards of 50%).



10.E. For patients with stable angina and a bare metal stent (BMS), uninterrupted dual antiplatelet treatment with a P2Y12inhibitor and aspirin for at least 1 month is strongly recommended.

Rationale:

There is good direct evidence that dual antiplatelet therapy (DAPT) after stent reduces CVD events and mortality. Active pathological bleeding is a contraindication common to all DAPT regimens.

Clopidogrel is recommended as the first-line P2Y12 inhibitor for use in combination with aspirin for DAPT after stent placement, for the following reasons:

Ticlopidine and clopidogrel appear to be equally efficacious as to rates of mortality and major cardiac events, but ticlopidine is associated with significantly higher rates of gastrointestinal intolerance, neutropenia and thrombotic thrombocytopenic purpura (TTP). As a result, ticlopidine is the least preferred agent and is generally reserved for patients at high bleeding risk who are intolerant or allergic to clopidogrel.

Compared to clopidogrel, the use of prasugrel or ticagrelor is associated with slightly lower rates of mortality and major cardiac events, but with higher rates of major bleeding; and are much more costly than clopidogrel which is available as a generic product

In patients with low bleeding risk who are at high risk of an atherothrombotic event, both prasugrel plus aspirin and ticagrelor plus aspirin are considered to be reasonable alternatives to clopidogrel plus aspirin for dual antiplatelet therapy.

There is good direct evidence that not continuing DAPT for at least 12 months after DES results in higher mortality compared to less than 12 months.

No studies were identified that directly answered the posed clinical questions as they related to bare metal stents and drug-eluting stents separately. Studies included for this problem formulation contained patients who received either a drug eluting or bare metal stent; no subgroup analyses was performed in these studies to distinguish between the effects of antiplatelet therapy post-stent in each respective group separately. Evidence Summary Clopidogrel vs. Prasugrel or Ticagrelor There is more clinical experience with clopidogrel, and generic clopidogrel is much less

expensive than prasugrel and ticagrelor. Based on results from one study (TRITON), prasugrel was more effective than clopidogrel in

reducing the composite endpoint of CV mortality, non-fatal MI, and non-fatal stroke; this was at the expense of more incidents of bleeding.

In patients with low bleeding risk who are at high risk of an atherothrombotic event, either prasugrel plus aspirin or ticagrelor plus aspirin are considered to be reasonable alternatives to clopidogrel plus aspirin for dual antiplatelet therapy.



In the rare cases of patients experiencing stent thrombosis while on uninterrupted clopidogrel plus aspirin, switching to prasugrel plus aspirin or ticagrelor plus aspirin may be considered. However, no direct evidence suggests that patients who suffer stent thrombosis on clopidogrel plus aspirin are less likely to suffer recurrent stent thrombosis on prasugrel plus aspirin or ticagrelor plus aspirin.

Unlike prasugrel and clopidogrel, ticagrelor binds to P2Y12 reversibly, has a faster onset and a faster offset of action, and must be dosed twice daily, introducing suboptimal medication adherence as a potential barrier to optimized DAPT efficacy.

Prasugrel is not recommended in patients with active pathological bleeding, with a history of stroke or transient ischemic attack (TIA), or in patients = 75 years of age, because of risk of fatal and intracranial hemorrhage and uncertain benefit, except in high risk patients (e.g., diabetes or prior myocardial infarction).

Ticagrelor is not recommended in patients with a history of intracranial hemorrhage (ICH), active pathological bleeding, or severe hepatic insufficiency. Additionally, in the pivotal registration trial, ticagrelor demonstrated an increase in spontaneous hemorrhagic events, dyspnea, bradycardia, uric acid, and serum creatinine, compared to clopidogrel.

Clopidogrel vs. Ticlopidine Ticlopidine is currently used only in patients who are intolerant to clopidogrel who are at

high risk of bleeding and therefore are not good candidates for prasugrel or ticagrelor. Clopidogrel is safer than ticlopidine; there are concerns regarding neutropenia and thrombotic thrombocytopenic purpura (TTP).

Meta-analysis of registry data shows that clopidogrel is more effective in reducing mortality and major adverse cardiac events based on registry data compared to ticlopidine.

Based on the CREDO(46) trial, treatment with dual antiplatelet therapy for at least one year in patients with DES is recommended as it results in a reduction of cardiac events.Thus, elective procedures which would require stopping or interrupting this therapy should be delayed until after one year (12 consecutive months) of dual antiplatelet therapy is completed. Furthermore, providers must be aware of the risks involved with discontinuation and patients should consult with their treating cardiologist before stopping medication. If medication is stopped, it should be restarted as soon as possible after elective procedures. Due to the lack of evidence the level of certainty is low with regard to these statements; however, the magnitude of net benefit is high considering that there is a decrease in major cardiac adverse events when dual antiplatelet therapy is continued for one year in patients with DES. One month duration for antiplatelets with BMS was based on pathophysiologic studies that suggest that stent endothelialization is complete within two to three weeks. Therefore, there would be little rationale to treating longer. There are no formal recommendations about specific surgical and dental procedures that can be done safely in the presence of dual antiplatelet therapy. However, such recommendations have been developed for patients on warfarin alone. Clinicians can use these as a guide to assess whether the procedures can be done without discontinuation of dual antiplatelet therapy. Bleeding risks associated with certain procedures, adapted from CHEST/ACCP, are found at the end of this rationale in the tables labeled “Bleeding Risk Associated with Different Types of Procedures” and “Procedure Risk of Outpatient Dental Treatments”.These tables are adapted



from the American Dental Association, and they include dental procedures, as well as their judgments about relative safety of performing those procedures at various levels of anticoagulation with warfarin.

Search Strategy: A comprehensive search was conducted to identify RCTS published up to January 2010; a limited update search was conducted in 2012 with the addition of the study drug ticagrelor. (See Search Strategy section for more information on specific search terms).In addition, websites from leading professional organizations in the cardiac field were screened for relevant publications. RCTs were included if they compared aspirin plus one type of P2Y12inhibitor (clopidogrel, ticlopidine, prasugrel, or ticagrelor) to another aspirin plus aP2Y12 inhibitor combination. A total of six studies were identified and included.

Prasugrel + Aspirin vs. Clopidogrel + Aspirin A total of one study was identified (Wiviott, 2007). Results for this study can be found in Appendix B. The critical outcomes for efficacy identified by the GDT were all-cause mortality, cardiovascular mortality, myocardial infarction, stroke, and coronary revascularization. There is high quality evidence from one study that demonstrates a significant decrease in myocardial infarction, coronary revascularization, and stent thrombosis when comparing prasugrel plus aspirin to clopidogrel plus aspirin while there is an increase in TIMI majorbleeding. Rates of all-cause mortality and cardiovascular mortality were lower in the group receiving prasugrel although the reductions were not significant. Rates of stroke were similar for both comparison groups.

Ticagrelor + Aspirin vs. Clopidogrel + Aspirin A total of one study (PLATO) was identified (Wallentin, 2009) in a minimal literature review. Results from these studies can be found in the study characteristics section. The critical outcomes for efficacy identified by the GDT were all-cause mortality, cardiovascular mortality, myocardial infarction, stroke, stent thrombosis, and major bleeding. There is high quality evidence from one study that demonstrates a significant decrease in mortality (all-cause and cardiovascular), myocardial infarction, and stent thrombosis when comparing ticagrelor to clopidogrel. There were slight increases in bleeding and similar rates of stroke among both groups. The following information regarding ticagrelor was excerpted from a drug monograph created by the Kaiser Permanente Drug Information Services, California Regions (10/2011): The PLATO study showed a greater reduction of death from vascular causes, myocardial

infarction (MI), and stroke combined for ticagrelor when compared to clopidogrel. According to the boxed warning, ticagrelor can cause significant, sometimes fatal,

bleeding. Maintenance doses of aspirin above 81 mg reduce the effectiveness of ticagrelor and should

be avoided. The use of ticagrelor is not recommended in patients with a history of intracranial

hemorrhage (ICH), active pathological bleeding, or severe hepatic insufficiency.



Based on the Ticagrelor versus Clopidogrel in Patients with Acute Coronary Syndromes (PLATO) results, an increased risk of spontaneous hemorrhagic events, (e.g., gastrointestinal and fatal intracranial bleeding) was seen with ticagrelor compared to clopidogrel, (4.5% vs. 3.8%, respectively; HR, 1.19; 95% CI, 1.02-1.38; p=0.03). Major bleeding did not significantly differ between treatment arms (11.6% vs. 11.2%; HR, 1.04; 95% CI, 0.95-1.13; p=0.43).

Higher rates of dyspnea were observed with ticagrelor compared to clopidogrel (13.8% vs. 7.8%, respectively; HR, 1.84; 95% CI, 1.68-2.02; p<0.001). Most episodes lasted less than a week and few required therapy discontinuation (0.9% vs. 0.1%, respectively; HR, 6.12; 95% CI, 3.41-11.01; p<0.001). The ticagrelor arm demonstrated increased cases of bradycardia (4.4% vs. 4.0%, respectively; p=0.21), increased uric acid (15 ± 52 vs. 7 ± 31 percent increase from baseline at 12 months, respectively; p<0.001), and increased serum creatinine (11 ± 22 vs. 9 ± 22 percent increase from baseline at 12 months, respectively; p<0.001).

When compared to clopidogrel, ticagrelor did have a reduction in CV events (PLATO). However, ticagrelor also had an increased rate of spontaneous hemorrhagic events and cases of dyspnea, all of which may lead to hospitalizations or greater lengths of stay.

Clopidogrel + Aspirin vs. Ticlopidine + Aspirin A total of four studies were identified (Taniuchi, 2001; Muller, 2000; Mueller, 2003; Bertrand, 2000). Results from these studies can be found in Appendix B. The critical outcomes for efficacy identified by the GDT were all-cause mortality, cardiovascular mortality, myocardial infarction, cardiac event, and coronary revascularization. Pooled results from these four studies are not significant, across all outcomes.However, there is low quality evidence from one study (Mueller, 2003)(34)which demonstrates that clopidogrel plus aspirin compared to ticlopidine plus aspirin substantially increases all-cause mortality, long-term cardiovascular mortality (at 28 months), and myocardial infarction. On the other hand, the other 3 studies (Taniuchi, 2001; Muller, 2000; Bertrand, 2000) reported cardiovascular mortality at one month and showed a non-significant reductionwith clopidogrel plus aspirin, compared to ticlopidine plus aspirin. Rates of stent thrombosis and major bleeding were similar for both comparison groups.

Supporting Evidence on Clopidogrel plus Aspirin versus Ticlopidine plus Aspirin In a meta-analysis of ten randomized and registry comparisons of clopidogrel plus aspirin versus ticlopidine plus aspirin after stenting(45) reductions in mortality and major adverse cardiac events observed with clopidogrel treatment (OR = 0.44; 95% CI: 0.29 to 0.67,p = 0.001) were only significant in registry data, not in results from three RCTs. Thus, the overall evidence from RCTs and registry comparisons does not clearly favor either clopidogrel plus aspirin or ticlopidine plus aspirin.

Supporting Evidence for Duration of Post Stent treatment In patients with CAD/ischemia, referred for planned PCI or coronary angiogram (CREDO(46) trial, n = 2,116), clopidogrel plus aspirin for at least one year post procedure compared to four weeks post-procedure reduced major thrombotic events (RRR = 26.9%; 95% CI: 3.9 to 44.4, p = 0.02].(46)



Supporting Evidence for Uninterrupted Treatment with Dual Antiplatelet Therapy. A retrospective cohort of 2,017 patients with ACS receiving clopidogrelat hospital discharge was conducted to determine the rate of all-cause mortality or acute myocardial infarction within one year after stopping treatment among patients who did not have an event before stopping clopidogrel(Ho et al., 2010).Rates were calculated for each 90-day interval after stopping clopidogrel. A reduction in all-cause mortality or myocardial infarction was seen at later time points (2.3% at 0 to 90 days; 1.4% at 91 to 180 days). The incidence rate of death/MI per 10 000 patient-days after stopping clopidogrel decreased at each 90-day interval. Multivariate analysis (adjusted for duration of clopidogrel treatment) showed that there was a significant increase risk of death/MI at 0 to 90 days compared to 91 to 360 days (IRR: 2.74; 95% CI: 1.69 to 4.44). Among patients with a DES, the IRR of death or MI was slightly higher than among patients with a BMS (2.46 vs. 1.70; IRR not significant for either group). An additional study (Ho et al., 2010) examined the effect of prescription refill delays on adverse events. A total of 7402 patients receiving a DES were included. Patients with a delay in refilling their clopidogrel prescription had a higher risk of death/MI (14.3% vs. 7.9%; p < 0.0001). Multivariate analysis also showed an increased risk of death/MI (HR: 1.54; 95% CI: 1.24 to 1.91) and death alone (HR: 1.45; 95% CI: 1.06 to 1.97) with refill delay.

Professional Society Recommendations The ACC/AHA/SCAI 2011 Guideline for PCI Recommendations state:

(statements on- duration). Class I In patients receiving a stent (BMS or DES) during PCI for ACS, P2Y12 inhibitor therapy should be given for at least 12 months. Options include clopidogrel 75 mg daily,570prasugrel 10 mg daily,567 and ticagrelor 90 mg twice daily.568(Level of Evidence: B)

Because the risk of stent thrombosis with BMS is greatest in the first 14 to 30 days, this is the generally recommended minimum duration of DAPT therapy for these individuals. Consensus in clinical practice is to treat DES patients for at least 12 months with DAPT to avoid late (after 30 days) stent thrombosis.208,212 Therefore, the ability of the patient to tolerate and comply with at least 30 days of DAPT with BMS treatment and at least 12 months of DAPT with DES treatment is an important consideration in deciding whether to use PCI to treat patients with CAD. Class I 1. After PCI, use of aspirin should be continued indefinitely.560–563(Level of Evidence: A)

2. The duration of P2Y12 inhibitor therapy after stent implantation should generally be as follows:

a. In patients receiving a stent (BMS or DES) during PCI for ACS, P2Y12 inhibitor therapy should be given for at least 12 months. Options include clopidogrel 75 mg daily,570prasugrel 10 mg daily,567 and ticagrelor 90 mg twice daily.568(Level of Evidence: B)

b. In patients receiving DES for a non-ACS indication, clopidogrel 75 mg daily should be given for at least 12 months if the patient is not at high risk of bleeding.208,212,571(Level of Evidence: B)



c. In patients receiving BMS for a non-ACS indication, clopidogrel should be given for a minimum of 1 month and ideally up to 12 months (unless the patient is at increased risk of bleeding; then it should be given for a minimum of 2 weeks).572(Level of Evidence: B)

Class IIb 1. Continuation of clopidogrel, prasugrel, or ticagrelor beyond 12 months may be

considered in patients undergoing placement of DES.567,568(Level of Evidence: C)

(statement on- high bleeding risk).

Class IIa If the risk of morbidity from bleeding outweighs the anticipated benefit afforded by a recommended duration of P2Y12 inhibitor therapy after stent implantation, earlier discontinuation (e.g., <12 months) of P2Y12 inhibitor therapy is reasonable. (Level of Evidence: C)

(statement on- adherence).

3. Patients should be counseled on the importance of compliance with DAPT and that therapy should not be discontinued before discussion with their cardiologist. 208(Level of Evidence: C)

(statements on- aspirin dose).

Class IIa 1. After PCI, it is reasonable to use aspirin 81 mg per day in preference to higher

maintenance doses.302,573–576(Level of Evidence: B)

Class IIa 2. If the risk of morbidity from bleeding outweighs the anticipated benefit afforded by a

recommended duration of P2Y12 inhibitor therapy after stent implantation, earlier discontinuation (eg, <12 months) of P2Y12 inhibitor therapy is reasonable. (Level of Evidence: C)




*Note: Meta-analyses were only performed on those outcomes for where more than one study was available.











estimate of effect and is likely to change the estimate. Very Low = Any estimate of effect is very uncertain. GRADE also suggests using the following scheme for assigning the “grade” or strength of evidence:




GRADE Evidence Profiles

Clopidogrel + Aspirin vs. Ticlopidine + Aspirin Summary of findings

Quality assessment No of patients Effect No of

studies Design Limitations Inconsistency Indirectness Imprecision Other

considerations Aspirin +

Clopidogrel Asprin +

Ticlopidine Relative (95% CI) Absolute Quality Importance

Mortality, All-Cause (follow-up median 28 months) 11 randomised


inconsistency no serious indirectness

serious3 none 29/355 (8.2%) 9/345 (2.6%)

RR 3.04 (1.49 to

6.07)

53 more per 1000 (from 13 more to

132 more)

LOW

CRITICAL

Mortality, Cardiovascular (1 month) (follow-up 1 months) 24 randomised

trials serious5 serious6 no serious

indirectness serious7 none

4/840 (0.5%) 8/863 (0.9%) RR 0.55 (0.18 to

1.73)


more)

VERY LOW

CRITICAL

Mortality, Cardiovascular (28 months) (follow-up median 28 months) 11 randomised



serious3 none 26/355 (7.3%) 8/345 (2.3%)

RR 3.16 (1.45 to

6.88)


136 more)

LOW

CRITICAL

Myocardial Infarction (follow-up 1-28 months) 28 randomised


inconsistency10 no serious indirectness

serious7 none 20/700 (2.9%) 14/685 (2%)

RR 1.39 (0.71 to

2.72)

8 more per 1000 (from 6 fewer to

35 more)

LOW

CRITICAL

Cardiac Event (follow-up 1 months) 311 randomised



34/1194 (2.8%) 33/1207 (2.7%)RR 1.06

(0.66 to 1.7)


19 more)

VERY LOW

CRITICAL

Coronary Revascularization (follow-up 1 months) 311 randomised



18/1195 (1.5%) 16/1208 (1.3%)RR 1.16

(0.6 to 2.23)


16 more)

VERY LOW

CRITICAL16

Stent Thrombosis (sub-acute) (follow-up 1 months) 117 randomised



serious3 none 1/494 (0.2%) 1/522 (0.2%)

RR 0 (0 to 0)


fewer)

LOW

CRITICAL

Bleeding, Major (follow-up 1 months) 117 randomised



serious3 none 1/494 (0.2%) 1/522 (0.2%)

RR 0 (0 to 0)


LOW

CRITICAL



Summary of findings Quality assessment No of patients Effect



Aspirin + Clopidogrel

Asprin + Ticlopidine

Relative (95% CI) Absolute Quality Importance

fewer) 1 Mueller, 2003 2 Treatment was not blinded but all endpoints were adjudicated by a clinical events committee whose members were unaware of the assignments. 3 RR based on one study with fewer than 300 total events. 4Taniuchi, 2001; Bertrand, 2000 5 Treatment was not blinded in 1 study (Taniuchi, 2001). 6 1 study (Taniuchi, 2001) favored aspirin + clopidogrel (RR: 0.4; 0.11-1.49; NS) while the remaining study (Bertrand, 2000) favored aspirin + ticlopidine (RR: 2.96; 0.12-72.32; NS) 7 RR based on 2 studies with less than 300 total events. 8 Mueller, 2003 and Bertrand, 2000 9 In 1 study (Mueller, 2003) tx was not blinded but all end points were adjudicated by a clinical events committee; also study had a risk of outcome classification as outcome may be assessed by patient self-report. 10 All studies showed similar results in favor of aspirin + ticlopidine 11Taniuchi, 2001; Muller, 2000; Bertrand, 2000 12 Treatment was not blinded in 2 studies (Taniuchi, 2001 and Muller, 2000) 13 Results varied across studies. One study (Taniuchi, 2000) favored aspirin + clopidogrel (RR: 0.84; 0.46-1.51; NS) with regard to cardiac event. The remaining 2 studies favored aspirin + ticlopidine (p=NS) 14 RR based on 3 studies with fewer than 300 total events. 15 Results varied across studies. One study (Bertrand, 2000) favored aspirin + clopidogrel (RR: 0.2; 0.01-4.09; NS) with regard to coronary revascularization. The remaining 2 studies favored aspirin + ticlopidine (p=NS) 16 Outcome was comprised of target vessel revascularization, Any AND target vessel revascularization, Urgent 17Taniuchi, 2001 18 Treatment not blinded.



Prasugrel + Aspirin vs. Clopidogrel + Aspirin Summary of findings

Quality assessment No of patients Effect No of

studies Design Limitations Inconsistency Indirectness Imprecision Other

considerations Aspirin + Prasugrel

Aspirin vs. Clopidogrel


Mortality, All-Cause (follow-up median 15 months) 11 randomised



no serious indirectness

no serious imprecision2

none 188/6813

(2.8%) 197/6795 (2.9%)

HR 0.95 (0.78 to

1.16)


fewer)

HIGH

CRITICAL

Mortality, Cardiovascular (follow-up median 15 months) 11 randomised





none 133/6813

(2%) 150/6795 (2.2%)

HR 0.89 (0.7 to 1.12)


more)

HIGH

CRITICAL

Myocardial Infarction (follow-up median 15 months) 11 randomised





none 475/6813

(7%) 620/6795 (9.1%)

HR 0.76 (0.67 to

0.85)

21 fewer per 1000 (from 13 fewer to

29 fewer)

HIGH

CRITICAL3

Stroke (follow-up median 15 months) 11 randomised





none 61/6813 (0.9%)

60/6795 (0.9%) HR 1.02 (0.71 to

1.45)

0 more per 1000 (from 3 fewer to 4

more)

HIGH

CRITICAL

Coronary Revascularization (follow-up median 15 months) 11 randomised





none 156/6813

(2.3%) 233/6795 (3.4%)

HR 0.66 (0.54 to

0.81)


16 fewer)

HIGH

CRITICAL4

Stent Thrombosis (follow-up median 15 months) 11 randomised





none 68/6813 (1%) 142/6795 (2.1%)

HR 0.48 (0.36 to

0.64)


13 fewer)

HIGH

CRITICAL5

Bleeding, Major, TIMI (follow-up median 15 months) 11 randomised





none 146/6741

(2.2%) 111/6716 (1.7%)

HR 1.32 (1.03 to

1.68)


11 more)

HIGH

CRITICAL

1Wiviott, 2007 2 Confidence intervals around estimate were small. 3 Myocardial infarction was reported as Nonfatal MI in study. 4 Reported as urgent target vessel revascularization in study. 5 Stent thrombosis was defined as probable/definite based on criteria set by the Academic Research Consortium.



Ticagrelor + Aspirin vs. Clopidogrel + Aspirin


No of studies Design Risk of bias Inconsistency Indirectness ImprecisionOther

considerationsAspirin + Ticagrelor

Aspirin + Clopidogrel

Relative(95% CI)

Absolute

Quality Importance

Mortality, All-Cause (follow-up mean 12 months)

1 randomised trials

no serious risk of bias1




none 399/9333 (4.3%)

506/9291 (5.4%)

HR 0.78 (0.69 to

0.89)

12 fewer per 1000 (from 6 fewer to 17 fewer)

High CRITICAL

Mortality, Cardiovascular (follow-up mean 12 months)

1 randomised trials





none 353/9333 (3.8%)

442/9291 (4.8%)

HR 0.79 (0.69 to

0.91)


High CRITICAL

Myocardial Infarction (follow-up mean 12 months)

1 randomised trials





none 504/9333 (5.4%)

593/9291 (6.4%)

HR 0.84 (0.75 to

0.95)


High CRITICAL

Stroke (follow-up mean 12 months)

1 randomised trials





none 125/9333 (1.3%)

106/9291 (1.1%)

HR 1.17 (0.91 to

1.52)


High CRITICAL

Stent Thrombosis (follow-up mean 12 months)

1 randomised trials





none 71/5640 (1.3%)

106/5649 (1.9%)

HR 0.67 (0.5 to 0.91)


High CRITICAL

Bleeding, Major, Study Criteria (follow-up mean 12 months)

1 randomised trials





none 961/9235 (10.4%)

929/9186 (10.1%)

HR 1.04 (0.95 to

1.13)


High CRITICAL3

Bleeding, Major, TIMI (follow-up mean 12 months)

1 randomised trials





none 657/9235 (7.1%)

638/9186 (6.9%)

HR 1.03 (0.93 to

1.15)


High CRITICAL

1 Double blind however it was unclear if outcome assessors were blinded to treatment also; An independent data and safety monitoring board had access to unblinded data 2 Confidence intervals around estimates were small. 3 Study criteria defined major bleeding as fatal or intracranial or intrapericardial with cardiac tampanade or hypovalemic shock or severe hypotension requiring pressors or surgery



Bleeding Risk Associated with Different Types of Procedures

From Kaiser Permanente Northern California, adapted from CHEST/ACCP (Douketis et al., 2008).



Procedure Risk of Outpatient Dental Treatments

From Kaiser Permanente Northern California, adapted from the Journal of the American Dental Association (Herman et al., 1997).



ACC/AHA Classification of Recommendations and Level of Evidence Grading

(taken from the ACC/AHA/SCAI 2009 Joint STEMI/PCI Focused Update)



11. Beta-Blocker Therapy

Beta-Blocker Therapy in the Secondary Prevention of CAD

11.A. For CAD patients, non-intrinsic sympathomimetic activity (non-ISA) beta-blocker therapy is recommended, unless contraindicated. Consensus-based

Peri-Operative Beta-Blockers

The following recommendations refer to patients with no contraindications to beta-blocker use.*

Currently taking beta-blockers:

11.B. For patients undergoing non-cardiac surgery, clinicians should continue beta-blocker therapy in the peri-operative period for patients with CAD currently taking beta-blockers.

For patients with CAD undergoing non-cardiac surgery and not currently taking beta blockers:

11.C. Clinicians should initiate beta-blockers at least 1 week before surgery. 11.D. In the absence of compelling indications for urgent beta-blocker therapy (e.g.

tachyarrhythmias or uncontrolled hypertension), there is insufficient evidence to make a recommendation for or against initiating beta-blockers 24 hours to 1 week before surgery.

11.E. In the absence of compelling indications for urgent beta-blocker initiation (e.g.,

tachyarrhythmias, uncontrolled hypertension), clinicians should not initiate beta-blockers less than 24 hours before surgery.

11.F. If beta-blockers are not initiated in the pre-operative period, they should be initiated once

the patient is stable in the postoperative period.

* Contraindications and Cautions

Beta-blockers are not recommended for patients with severe reversible airway disease, high degree heart block, or other contraindications to their use. Initiating beta blockade should be approached with caution in patients with resting heart rates < 55.



Rationale:

2012 Update Subgroup Recommendation Basis of

Recommendation Balance of desirable and

undesirable effects Quality of Evidence

Values and Preferences

Resource implications

A1. Patients with Coronary Artery Disease (CAD) or Left Ventricular Systolic Dysfunction (LVSD) currently on beta-blockers

A1. For patients undergoing non-cardiac surgery, clinicians should continue beta-blocker therapy in the peri-operative period for patients with CAD or LVSD currently taking beta-blockers. (Strong Recommendation) .

The strong recommendation to continue on beta-blockers in the peri-operative period is based on the high risk associated with abrupt beta-blocker withdrawal.

Beta-blockers reduce mortality and cardiovascular events in people with CAD or LVSD Abrupt withdrawal of beta-blockers is associated with beta-blocker withdrawal syndrome, marked by a beta-adrenergic hyper-responsiveness. The GDT believes the benefits of continuing beta-blockers far outweigh the harms

Very low [study design, serious indirectness] Evidence for benefit of beta-blockers is moderate to good, but evidence for harms of beta-blocker is based on observational studies, therefore low quality, and further downgraded because studies do not directly address CAD/LVSD

The GDT believes that patients with CAD or LVSD would likely value the continuation of an existing therapy over the risks associated with abrupt withdrawal of beta-blockers, and believes that variation in patient acceptance of peri-operative beta-blocker therapy is likely to be low.

Low

A2. Patients with CAD or LVSD not currently on beta-blockers*

A2. For patients with CAD or LVSD undergoing non-cardiac surgery and not currently taking beta-blockers:

Beta-blockers reduce mortality and cardiovascular events in people with CAD or LVSD. In the current analyses, patients initiating beta-blockers within 24 hours of surgery have increased stroke, but decreased rates of myocardial infarctions. However, in the two studies that initiated beta-blockers >=1 week prior to surgery, there was reduced risk of cardiovascular mortality and non-fatal MI and no increase in adverse outcomes.

Low

a. Clinicians should initiate beta-blockers at least 1 week before surgery.

a. The strong recommendation to initiate beta-

a. Low (Risk of bias, imprecision)

a. The GDT believes that patients with CAD or LVSD would



(Strong Recommendation)

blockers at least one week prior to surgery is based on evidence of long-term benefit in reducing CVD events, patient values and preferences, low risk of harm, and low cost.

likely value the benefits of initiating beta-blockers at least one week prior to surgery in order to avoid the risk of serious adverse events over the potential decreased mortality and increased cardiovascular benefit. The GDT also believes that variation in patient acceptance of peri-operative beta-blocker therapy is likely to be low.

b. In the absence of compelling indications for urgent beta-blocker therapy (e.g. tachyarrhythmias or uncontrolled hypertension), there is insufficient evidence to make a recommendation for or against initiating beta-blockers 24 hours to 1 week before surgery.

b. There are no studies evaluating initiation of beta-blockers >24 hours and within one week of surgery.

b Very low [no evidence exists]

b. Considering patients’ perspectives and values, because no evidence exists, the GDT believes that patients with CAD or LVSD would likely show significant variation in acceptance to initiating beta-blockers 24 hours to one week prior to surgery in the peri-operative period.

c. In the absence of compelling indications for urgent beta-blocker initiation (e.g., tachyarrhythmias, uncontrolled hypertension), clinicians

c. This strong recommendation is based on evidence suggesting that the harms of initiating beta-

c. Moderate [imprecision]

c. Considering patients’ perspectives and values the GDT believes that patients with CAD or LVSD would likely value



should not initiate beta-blockers less than 24 hours before surgery. (Strong Recommendation)

blockers within 24 hours prior to surgery exceed the benefits.

the benefits of initiating beta-blockers within 24 hours prior to surgery in order to avoid the risk of serious adverse events over the potential decreased mortality and increased cardiovascular benefit. Variation in patient preference to decline peri-operative beta-blocker therapy initiated within one day of surgery is likely to be low.

d. If beta-blockers are not initiated in the pre-operative period, they should be initiated once the patient is stable in the postoperative period. (Strong Recommendation)

d. The strong recommendation to initiate beta-blockers once the patient is stable in the postoperative period is based on evidence of long-term benefit in reducing CVD events, patient values and preferences, low risk of harm, and low cost.

d. very low (consensus-based)

d. The GDT believes that patients with CAD or LVSD would likely value the benefits of initiating beta-blockers in the postoperative period in order to avoid the risk of serious adverse events over the potential decreased mortality and increased cardiovascular benefit. The GDT also believes that variation in patient acceptance of postoperative beta-blocker therapy is likely to be low.



Evidence Summary

Non-cardiac surgery is hypothesized to be associated with an increase in risk of cardiovascular complications, which may in part be attributed to an increase in catecholamines, resulting in an increase in heart rate and blood pressure. Beta-blockers may prevent peri-operative cardiovascular complications by attenuating the effects of increased catecholamine levels. The evidence for benefit of beta-blockers in patients with coronary artery disease (CAD) and left ventricular systolic dysfunction (LVSD) is well documented in the Kaiser Permanente National CAD and Heart Failure guidelines (2, 3).

No existing studies examine beta-blocker initiation from 24 hours to one week before surgery. Clinicians may prescribe beta-blockers in the 24 hour to one week pre-op period provided there is sufficient medical surveillance and opportunity for adequate titration. For example, a hospitalized patient or a patient followed closely in a cardiology clinic may meet these criteria. Patients seen on a limited basis in a primary care setting, or in a pre-operative medical evaluation, may not meet these criteria. Clinicians probably should not prescribe beta-blockers in the one week pre-op period when there is not sufficient medical surveillance available.

The use of peri-operative beta-blockers in patients already on beta-blockers for the treatment of hypertension and other conditions was not examined in this clinical question. However, serious adverse effects associated with the abrupt withdrawal of beta-blockers are well documented. In hypertensive patients, the abrupt withdrawal of beta-blockers may lead to rebound blood pressure elevation, as well as an exacerbation of angina, and increased risk for MI and mortality (4-6). In patients on chronic beta-blocker therapy for other conditions, abrupt withdrawal can lead to a physiological beta-blocker withdrawal syndrome, marked by a beta-adrenergic hyper-responsiveness, typically manifested as an increased heart rate. (7, 8) Therefore, patients currently on beta-blockers should continue therapy when undergoing non-cardiac surgery.



Studies with beta-blocker initiation <24 hrs pre-op to post-op


No of studies

Design Risk of bias Inconsistency Indirectness Imprecision Other

considerations Beta-

blockers Control

Relative (95% CI)

Absolute

Quality Importance

mortality, all-cause

8 randomised trials




serious2 none 228/5212 (4.4%)

208/5211 (4%)

RR 0.99 (0.74 to 1.34)


MODERATE

CRITICAL

mortality, cardiovascular

5 randomised trials

no serious risk of bias



serious3 none 16/10184 (0.16%)

130/10194 (1.3%)

RR 1.24 (0.89 to 1.71)


MODERATE

CRITICAL

MI, nonfatal

3 randomised trials




no serious imprecision

none 346/9060 (3.8%)

474/9072 (5.2%)

RR 0.73 (0.6 to 0.89)


fewer)

HIGH

CRITICAL

stroke, any

5 randomised trials




serious3 none 50/4900 (1%)

22/4892 (0.45%)

RR 2.18 (1.33 to 3.57)

5 more per 1000 (from 1 more to 12 more)

MODERATE

CRITICAL

1 Overall, low RoB, however 1 study (Neary) high RoB due to imbalance in treatment groups, lack of details 2 95% CI contains both appreciable benefit and appreciable harm, >25% on both sides. 3 Low event rates - total < 300



Studies with beta-blocker initiation ≥ 1 week pre-op


No of studies

Design Risk of

bias Inconsistency Indirectness Imprecision


Beta-blockers

ControlRelative (95% CI)

Absolute

Quality Importance

mortality, all-cause

1 randomised trials

serious1 no serious inconsistency2


serious3 none 10/533 (1.9%)

16/533 (3%)

RR 0.62 (0.29 to 1.36)


LOW

CRITICAL

mortality, cardiovascular

2 randomised trials

serious1 no serious inconsistency


serious3 none 4/1184 (0.34%)

28/1172 (2.4%)

RR 0.17 (0.05 to 0.65)


LOW

CRITICAL

MI, nonfatal

2 randomised trials

serious1 no serious inconsistency


serious3 none 22/1186 (1.9%)

72/1174 (6.1%)

RR 0.22 (0.03 to 1.48)


LOW

CRITICAL

1 Open-label study; may result in treatment bias, reporting bias. Also lack of other methodological details 2 NA - only one study 3 Very low event rate - total <300



2010 Update

Only the evidence for recommendation 11A was reviewed in 2010. No change to the recommendation was made.

2008 Guideline

No relevant RCTs or meta-analyses were identified in the peer-reviewed medical literature published since the previous update of this guideline that addressed beta-blocker therapy in patients with CAD. Previously, this guideline identified evidence to support recommendations for the use of beta-blockers in six different subgroups of patients with CAD. This was done in an effort to distinguish subtleties in the level of evidence support for treatment in various patient subsets. However, the GDT is concerned that the resultant complexity of this recommendation may have contributed to both confusion and under treatment. In an effort to simplify decision-making around the use of this important therapy, the GDT has opted for a broad-based consensus recommendation for the use of beta-blockers in all patients with CAD. These are the recommendations that were consolidated into recommendation A:

“Beta-blocker therapy is recommended for CAD patients unless contraindicated; specifically: For post-MI patients, non-intrinsic sympathomimetic activity (non-ISA) beta-blocker

therapy is recommended. For post-MI patients, non-ISA beta-blocker therapy is recommended to be initiated within

hours after MI and continued long term. For CAD patients with unstable angina, long term non-ISA beta-blocker therapy is

recommended. For CAD patients with chronic stable angina, long term non-ISA beta-blocker therapy is

recommended for treatment of symptoms. For CAD patients with silent ischemia, non-ISA beta-blocker therapy is recommended. For patients with CAD, beta-blocker therapy is recommended perioperatively for vascular

surgery or noncardiac surgery with general anesthesia.”



2006 Guideline

No change in the previous recommendations has been made as a result of this systematic review. Findings from COMMIT(48) provided further evidence that early beta-blocker treatment decreased the risk of reinfarction (OR = 0.82; 95% CI: 0.72 to 0.92; p < 0/001).

2004 Guideline

The only additional evidence that was found to supplement the evidence presented in the previous guidelines was one systematic review(49) of treatment side effects. In RCTs of patients with previous MI, heart failure or hypertension, (n > 35,000) there was no significant difference between groups treated with beta-blockers and placebo groups in depressive symptoms (RR = 1.12; 95% CI: 0.89 to 1.41) or sexual dysfunction (RR = 1.10; 95% CI: 0.96 to 1.25). A small but significant increase in fatigue was reported for groups of patients taking beta-blockers (RR = 1.15; 95% CI: 1.05 to 1.25).

Professional Group Recommendations Reviewed ACC/AHA 2002 Guideline Update for the Management of Patients with Chronic Stable

Angina ACC/AHA 2002 Guideline Update for the Management of Patients with Unstable Angina

and Non-ST-Segment Elevation Myocardial Infarction Colorado Region Coronary Artery Disease Secondary Prevention Practice Guideline,

December, 2001 Group Health Cooperative Secondary Prevention of ASCVD, Beta-blockers Guideline,

October, 2002 Southern California Region Clinical Practice Guideline for Coronary Artery Disease,

March, 2002

Other Considerations The ACC/AHA recommends that beta-blocker therapy: Be initiated and continued indefinitely in all post-MI and acute ischemic syndrome

patients, Used as needed to manage angina, rhythm, or blood pressure in all other patients.

In their 2002 Guidelines on unstable angina, ACC/AHA concludes: “The rationale for beta-blocker use in all forms of CAD, including UA, is very compelling and in the absence of contraindications is sufficient to make beta-blockers a routine part of care, especially in patients who are to undergo cardiac or non-cardiac surgery…The duration of benefit with long-term oral therapy is uncertain.” The previous recommendations remain unchanged. A definition of CAD risk(50) was added in 2004.



2002 Guideline

Post-MI Two meta-analyses(51, 52) demonstrated the protective effect of long-term beta blockade after myocardial infarction. The long-term use of beta-blockers reduced the odds of total mortality and reinfarction with no indication of life threatening side effects. Although there are no good data regarding the initiation and treatment duration of beta-blocker therapy post-MI, the evidence does suggest that routine long-term use of beta-blockers, even if broadly defined, does significantly reduce mortality and reinfarction. The GDT believes strongly that beta-blocker therapy should be initiated within hours after MI, based on evidence supporting early initiation of beta-blockers for patients with acute MI and continued long-term.

Unstable Angina The well-known benefits of beta-blockers in coronary disease support their long-term use in patients with unstable angina, even in the absence of major, randomized beta-blocker trials. A strong pathogenic link between unstable angina and acute myocardial infarction has led to the recommendation that these medications be used as first-line agents in unstable angina, non-ST elevation MI, and ST elevation MI.

Chronic Stable Angina Beta-blockers are effective at relieving the symptoms of angina, and are the recommended therapy for this purpose. However, there is insufficient evidence regarding cardiovascular events or mortality for the treatment of patients with chronic stable angina and who have not had an MI.

Silent Ischemia Insufficient evidence was found (following the criteria of randomized, controlled trials) showing cardiovascular events or mortality was reduced in patients whose only cardiac symptom was the finding of silent ischemia. In the few studies conducted, beta-blockers have been shown to reduce the frequency of ischemic episodes but not MI or death in patients with silent ischemia. These studies have been too small to demonstrate statistically significant benefit on long-term outcome, however most GDT members favored the use of beta-blocker therapy for patients with known silent ischemia.

Peri-Operative Two RCTs(50, 53) support the use of beta-blocker therapy peri-operatively to reduce mortality and cardiovascular events for cardiac and noncardiac surgery in patients who have or are at high risk for CAD.

Note: Beta-blockers with ISA vs. beta-blockers without ISA Two studies(51, 52) conclude that beta-blockers with ISA confer less benefit than beta-blockers without ISA.



12. CAD plus Mild to Moderate Reversible Airway Disease or COPD

12.A. For CAD patients with concomitant mild to moderate reversible airway disease or chronic obstructive pulmonary disease (COPD) cardioselective beta-blockers are recommended. Evidence-based

12.B. Discuss the risks and benefits of treatment with the patient and instruct the patient to report any increase in airway symptoms. Consensus-based

12.C. Initiating beta-blocker therapy is NOT recommended:

For patients with severe airway disease requiring frequent hospitalization or intubation.

During acute exacerbation of airway disease.

When airway disease is unstable or poorly controlled.

Consensus-based

Rationale:

2008 Guideline

No relevant RCTs or meta-analyses were identified in the peer-reviewed medical literature published since the previous update of this guideline that addressed beta-blocker therapy in patients with CAD and mild to moderate reversible airway disease or chronic obstructive pulmonary disease (COPD).

2006 Guideline

See 2006 KP National Heart Failure Guidelines. See 2005 KP National Asthma Guidelines. No additional evidence was found in either 2004 or 2006 to supplement that presented in the 2002 CMI CAD Guidelines. The recommendations in the previous guidelines were expanded in 2004 to include COPD, consistent with evidence presented in the 2004 CMI Heart Failure Guidelines. Reference to specific cardioselective non-ISA beta-blockers was removed, due to the lack of comparison data for this subgroup of CAD patients.

2002 Guideline

See KP National Adult Asthma Guidelines.



13. CAD plus Heart Failure

13.A. For CAD patients with either left ventricular systolic dysfunction (LVSD) (NYHA Class II-IV) or asymptomatic LVSD (NYHA Class I), beta-blockers are strongly recommended. Evidence-based

13.B. For CAD patients with left ventricular systolic dysfunction carvedilol, metoprolol succinate, or bisoprolol is the recommended choice of beta-blocker therapy. Evidence-based

Rationale:

2008 Guideline

No relevant RCTs or meta-analyses were identified in the peer-reviewed medical literature published since the previous update of this guideline that addressed beta-blocker therapy in patients with CAD and heart failure. The availability of generic carvedilol has eliminated economic issues addressed in previous versions of this guideline. Thus the previous recommendation stating “Metoprolol tartrate (short-acting formulation) titrated to maximum tolerated dosage, is an acceptable but less well-established alternative to carvedilol, metoprolol CR/XL, or bisoprolol.” has been removed. Also, metoprolol CR/XL has been changed to metoprolol succinate.

2006 Guideline

See the 2006 KP National Heart Failure Guidelines for discussion of beta-blocker use in patients with LVSD. Because patients with CAD comprised a subset of subjects in the meta-analyses and randomized, controlled trials cited in the Heart Failure Guidelines, these study findings were considered by the GDT to be generalizable to the population of patients with CAD plus Heart Failure. On the basis of the evidence of reduced mortality and hospitalization in patients with NYHA Class II-IV LVSD presented in the 2006 Heart Failure Guidelines and the evidence of the benefits to CAD patients of beta-blocker use presented in the 2002 CAD Guidelines (summarized in the rationale for Beta-Blocker Therapy) the GDT recommends use of beta-blockers in patients with CAD plus LVSD, including those with asymptomatic (NYHA Class I) LVSD.

2002 Guideline

See the KP National Heart Failure Guidelines.



Calcium Channel Blocker Therapy

14. CAD with Normal Ventricular Systolic Function

14.A. Calcium channel blockers (CCBs) are NOT recommended to reduce morbidity or mortality from CAD. Evidence-based

14.B. In CAD patients with normal ventricular systolic function, calcium channel blockers (CCBs) may be used for the treatment of angina pectoris or hypertension when beta-blockers and ACE inhibitors are ineffective or contraindicated. Consensus-based

14.C. In patients with CAD, immediate release formulations of nifedipine are NOT recommended due to the increased risk of cardiovascular mortality. Evidence-based

Rationale:

2008 Guideline

No relevant RCTs or meta-analyses were identified in the peer-reviewed medical literature published since the previous update of this guideline that evaluated calcium channel blocker therapy for CAD patients with normal left ventricular function and contraindications to beta-blockers. The GDT decided to delete the consensus-based recommendation D because it was redundant and listed all drugs in the formulary:

“Unless contraindicated, the recommended calcium channel blockers for CAD patients are sustained-release nifedipine, second-generation dihydropyridine calcium channel blockers (amlodipine, felodipine), or nondihydropyridine calcium channel blockers (verapamil, diltiazem).”

The GDT made a correction and added “and ACE inhibitors” to recommendation B to clarify that CCBs should be used when both beta-blockers and ACE inhibitors are ineffective.

2006 Guideline

In July 2004, Clinical Evidence reported one systematic review (Teo, 1993, 24 RCTs),(54) which found no significant difference in mortality in people after myocardial infarction or with coronary heart disease treated with calcium channel blockers and those treated with placebo. However, subgroup analysis by drug type found that diltiazem and verapamil reduced the rates of refractory angina in people without heart failure after myocardial infarction. The review found nonsignificantly higher mortality with dihydropyridines than with placebo.



Two RCTs were published subsequent to this systematic review. The CAMELOT(12) RCT (N = 1,997) on the effect of amlodipine (10 mg) or enalapril

(20 mg) vs. placebo in patients with CAD found that cardiovascular events were reduced with the use of amlodipine vs. placebo (HR = 0.69; 95% CI: 0.54 to 0.88), amlodipine vs. enalapril (HR = 0.81; 95% CI: 0.63 to 1.04), and enalapril vs. placebo (HR = 0.85; 95% CI: 0.67 to 1.07). The study was limited in sample size, resulting in wide confidence intervals around the study endpoints. Although the CAMELOT study findings are suggestive of an enhanced protective effect for patients with CAD when amlodipine is added to the standard regimen of statin and aspirin use, larger, longer-term studies are required to confirm this finding before changes in recommendations are adopted.

The ACTION(55) RCT (N = 3,825) on the effect of nifedipine on the long term-outcome of patients with stable angina found that the rate of death, cardiovascular event, or cardio-vascular procedure was 9.32 per 100 patient-years in the treated group vs. 10.50 per 100 patient-years in controls (0.89; 95% CI: 0.83 to 0.95). Nifedipine had no effect on the rate of myocardial infarction.

No change to the previous recommendations has been made a result of this systematic review.

Other Considerations The ACC/AHA recommends: CCBs for ischemic symptoms when beta-blockers are not successful or contraindicated or

cause unacceptable side effects. Avoidance of short-acting dihydropyridine antagonists. Verapamil or diltiazem for patients with asthma or chronic obstructive pulmonary disease

(COPD). See the 2005 KP National Hypertension Guidelines: Step-Care Therapy for Uncomplicated Hypertension.

2004 Guideline

No additional evidence was found to supplement that presented in the previous guidelines. Therefore, Recommendations A, B, and C remained unchanged in 2004. Recommendation D was added to clarify the calcium channel blockers available for use with patients with CAD.

Professional Group Recommendations Reviewed in 2004 ACC/AHA 2002 Guideline Update for the Management of Patients with Chronic Stable

Angina ACC/AHA 2002 Guideline Update for the Management of Patients with Unstable Angina

and NonST-Segment Elevation Myocardial Infarction

Colorado Region Coronary Artery Disease Secondary Prevention Practice Guideline, December, 2001

Group Health Cooperative Secondary Prevention of ASCVD, Calcium Channel Blockers Guideline, October, 2002

Southern California Region Clinical Practice Guideline for Coronary Artery Disease, March, 2002



2002 Guideline

CCBs are NOT recommended to reduce morbidity or mortality from CAD Calcium channel blockers have been studied extensively to determine their effectiveness in reducing morbidity and mortality in patients with cardiovascular diseases. For the purpose of these guidelines, we sought to determine the role of calcium channel blockers compared to placebo or beta-blockers in reducing cardiovascular events and mortality in patients with CAD. Generally, the data from six meta-analyses; one randomized, controlled trial; and one case controlled study of calcium channel blockers found no significant improvement in cardiovascular morbidity and mortality for patients in the CCB group compared to placebo or other active treatment. However, one meta-analysis(56) of verapamil compared to placebo or other active treatment showed significant reductions in nonfatal MI (RR = 0.79; 95% CI: 0.65 to 0.97) or MI or death (RR = 0.82; 95% CI: 0.70 to 0.94). Overall, the weight of the evidence does not support the use of CCBs as monotherapy in CAD patients.

CCBs for the treatment of angina pectoris or hypertension In a meta-analysis of 16 randomized, controlled trials, verapamil was more effective than placebo in preventing nonfatal MI (RR = 0.79; 95% CI: 0.65 to 0.97, p = 0.024) and the composite endpoint of MI or death (RR = 0.82; 95% CI: 0.70 to 0.94, p = 0.016).(56)

Nifedipine A meta-analysis(57) found the risk of death, stroke, MI, or revascularization to be significantly increased in patients treated with immediate release (IR) nifedipine.



15. CAD with LVSD

15.A. Amlodipine* and felodipine* (second generation dihydropyridine calcium channel blockers) are options for the treatment of angina pectoris or hypertension in patients with LVSD. Evidence-based

15.B. The GDT recommends against the use of calcium channel blockers (CCBs) other than amlodipine* and felodipine* in patients with LVSD. Evidence-based

Rationale:

2008 Guideline

No relevant RCTs or meta-analyses were identified in the peer-reviewed medical literature published since the previous update of this guideline that evaluated calcium channel blocker therapy for CAD patients with left ventricular systolic dysfunction.

2006 Guideline

In July 2004, Clinical Evidence reported that three RCTs(58-60) of diltiazem or verapamil compared with placebo found a trend toward harm for people with clinical manifestations of heart failure that were taken into account in the 2006 update of the KP National Heart Failure Guidelines. See the 2006 KP National Heart Failure Guidelines for recommendations for patients with LVSD. Consistent with the recommendations from the Heart Failure Guidelines, nondihydropyridine CCBs or first-generation dihydropyridine (e.g., nifedipine) calcium channel blockers are not recommended for CAD patients with heart failure due to LVSD. No additional evidence was found as a result of systematic reviews in 2004 and 2006 to supplement that presented in the 2002 CAD Guidelines. Therefore, the recommendations remain unchanged.

Other Considerations The ACC/AHA recommends: Amlodipine or felodipine in patients with moderate to severe LVSD Avoidance of verapamil, diltiazem in patients with moderate to severe LVSD

2002 Guideline

See KP National Heart Failure Guidelines.

* Not FDA-approved for heart failure.



Lifestyle Modification

16. Diet Therapy

16. For all patients with CAD, a diet rich in fruits, vegetables, legumes, nuts, whole grains, and n-3 (omega-3) polyunsaturated fatty acids is recommended. Evidence-based

Rationale:

2008 Guideline

No relevant RCTs or meta-analyses were identified in the peer-reviewed medical literature that evaluated diet therapy for patients with coronary artery disease.

2006 Guideline

No change has been made in the 2004 recommendations as a result of this systematic review (no new evidence).

Supporting Evidence on Diet Modification Three RCTs found substantial survival benefit to persons with coronary heart disease or CAD risk factors advised to consume a Mediterranean type diet which differed from the usual Western Diet. In the largest of the three trials (n = 1,000) patients with one or more risk factors for CAD (hypertension, hypercholesterolemia, diabetes, angina, or previous MI) consuming an Indo-Mediterranean diet were compared to those consuming a Step 1 NCEP (National Cholesterol Education Program) diet. The treated group consumed more fruits, vegetables, legumes, walnuts, almonds, whole grains, and mustard seed or soybean oil (for α-linolenic acid, an n-3 polyunsaturated fatty acid source). Consumption of an Indo-Mediterranean diet resulted in statistically significant reductions in nonfatal MI (Adj RR = 0.47; 95% CI: 0.28 to 0.79), sudden cardiac death (Adj RR = 0.33; 95% CI: 0.13 to 0.86), and total cardiac endpoints (Adj RR = 0.48; 95% CI: 0.33 to 0.71; NNT is 14 in two years).(61) In the Indian Heart Study (n = 204) post-MI patients who consumed a diet high in fruits, vegetables, legumes, nuts and fish had a statistically significant reduction in cardiac events (RR = 0.60; 95% CI: 0.31 to 0.75; NNT is six in one year) and total cardiac mortality (RR = 0.58; 95% CI: 0.34 to 0.83) when compared with patients who consumed a “prudent diet.”(62) In the Lyon Heart Study (n = 605) survivors of a first MI assigned to a Mediterranean-type diet had a reduced rate of major cardiac endpoints (RR = 0.28; 95%, CI: 0.15 to 0.53; NNT is 10 in 46 months), cardiovascular death (RR = 0.35; 95% CI: 0.15 to 0.83), and overall mortality (RR = 0.44; 95% CI: 0.21 to 0.94), compared to those consuming a “prudent diet.” The concordance in results at 27 and 46 months of follow-up supports the efficacy of long term dietary change.(63, 64)



Other Non-RCT Evidence Prospective Cohort Studies: In a population-based prospective cohort study of 22,043 healthy adults, adherence to the Mediterranean diet was associated with a reduction in both total mortality (adjusted hazard ratio for death associated with a two-point increment in Mediterranean diet score = 0.75, 95% CI: 0.64 to 0.87), and death due to coronary heart disease (adjusted hazard ratio = 0.67; 95% CI: 0.47 to 0.94) at 44 months of follow-up.(65) In a nested cohort study within the GISSI randomized, controlled trial (n = 11,323) of post-MI patients, all food groups (vegetables, fruit, fish, and olive oil) in the Mediterranean diet were associated with a significant reduction in risk of death at 6.5 years of follow-up. Compared with those in the lowest quartile on consumption of the diet, the odds ratio in those with the highest quartile was 0.51 (95% CI: 0.44 to 0.59). Additionally, the total diet was protective in subgroups defined by age, sex, smoking status, randomized treatment regimen, and concomitant drug therapy. The study investigators concluded that post-MI patients can respond positively to simple dietary advice.(66)

Professional Group Recommendations Reviewed American Heart Association (AHA) Dietary Guidelines, 2000 AHA Scientific Statement on Fish Consumption, Fish Oil, Omega-3 Fatty Acids, and

Cardiovascular Disease, 2002 AHA Conference Proceedings on Dietary Fatty Acids and Cardiovascular Health, 2001 AHA Science Advisory on Lyon Diet Heart Study, 2001 AHA Science Advisory on Monounsaturated Fatty Acids and Risk of Cardiovascular

Disease NCEP (National Cholesterol Education Program) ATP (Adult Treatment Panel) III

Guidelines 2004 EPA Advisories on Environmental Contaminants in Fish FDA Health Claims for Prevention of Cardiovascular Disease

Other Considerations The 2002 CMI CAD Guidelines did not include a dietary recommendation. This 2004 CMI CAD recommendation on diet is consistent with the AHA Dietary Guidelines which recommend a dietary pattern that emphasizes fruits, vegetables, and low-fat dairy products and is reduced in fat.

Overall Conclusions Findings from both clinical trials of secondary prevention and prospective cohort studies of primary prevention are congruent on the benefit of a total diet which includes high consumption of fruits, vegetables, nuts, legumes, whole grains and a source of n-3 poly-unsaturated fatty acids. Cohort study evidence suggests that the combination of multiple dietary factors is more powerful than any single factor alone. Persistence of results over years in study populations suggests that dietary advice can lead to a change in diet and to modest, sustained cardiovascular risk reduction.



17. Dietary Fat Modification

17. For all patients with CAD consuming a usual Western diet, the following modifications in dietary fat are recommended:

Increase intake of n-3 (omega-3) polyunsaturated fatty acids to a level of ~ 1 g/day from a variety of sources (flaxseed, canola, and soybean oils, nuts, fish, and fish oil supplements).

Replace saturated fatty acids with polyunsaturated and monounsaturated fatty acids.

Reduce or eliminate intake of trans-fatty acids.

Consensus-based

Rationale:

2008 Guideline

No relevant RCTs or meta-analyses were identified in the peer-reviewed medical literature that evaluated dietary fat modification for patients with coronary artery disease. However, the recommendation was changed. The GDT decided to take out the footnote after the first bullet that said "To limit the bio-accumulation of methyl mercury, polychlorinated biphenols (PCBs), dioxins, and other environmental contaminants, intake of certain fish (e.g. swordfish, tuna, and farmed salmon) is recommended not to exceed two servings per week." The list of fish mentioned was outdated and inaccurate (for example, farmed salmon should not be included and other fish, such as king mackerel, shark, and tilefish, should be included). The KP National Dyslipidemia Guidelines does not mention specific types of fish, and were no systematic reviews of the literature the GDT could use to substantiate a change. Thus, the GDT decided to follow the Dyslipidemia Guidelines and take out this footnote.

2006 Guideline

No change has been made to the recommendations as a result of this systematic review (no new evidence).

Supporting Evidence on Dietary Fat Modification Reduction in total fat intake. One systematic review found no evidence that allocation to a low-fat diet reduced mortality from coronary heart disease.(67) Two secondary prevention trials of total fat reduction included in the review (MRC, n = 123; DART, n = 1,015) did not find a significant reduction in serum cholesterol or CHD events among male patients, post-MI.(68, 69)



Increased polyunsaturated fatty acids (PUFA)/Decreased saturated fat. In two secondary prevention trials (Oslo Diet Heart Study, n = 206, post-MI patients; MRC, n = 199 post-MI patients) comparing a reduced saturated fat/increased polyunsaturated fat diet against a control diet both serum cholesterol and coronary event rates were reduced in the low saturated/high polyunsaturated diet group.(70-72) Increased n-3-polyunsaturated fatty acids (PUFA). Plant-derived source is α-linolenic acid from flaxseed oil, canola oil, soybean oil, walnut oil, and mustard seed oil (not generally available in the US). Marine-derived sources are eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) from fish and fish oils. In a meta-analysis of 11 RCTs (n = 15,806 CHD patients) n-3 PUFA intake resulted

in a reduction in fatal MI (RR = 0.7; 95% CI: 0.6 to 0.8, p < 0.001), sudden death (RR = 0.7; 95% CI: 0.6 to 0.9, p < 0.01) and overall death (RR = 0.8; 95% CI: 0.7 to 0.9, p < 0.001).(73) In one study included in the meta-analysis, post-MI patients (n = 360) were randomized to fish oil, mustard oil or placebo. After one year, cardiac events were lower in both the fish oil (RR = 0.7; 95% CI: 0.29 to 0.90; NNT = 10) and mustard seed oil groups (RR = 0.81; 95% CI: 0.30 to 1.12; NNT = 15) than in the placebo group.(74)

Since this meta-analysis of studies was published through 1999, the GISSI Study Investigators published an additional analysis of findings citing a significant reduction in mortality (RR = 0.59; 95% CI: 0.36 to 0.97) among post-MI patients consuming low-dose supplemental n-3 PUFA’s (n = 11,323).(75) Investigators concluded that these results, appearing in the first three months, were accounted for by a decrease in sudden death which assumes statistical significance by month four (RR = 0.467; 95% CI: 0.219 to 0.995). Findings are consistent with the hypothesis of antiarrhythmic /antifibrillatory effect for n-3 PUFA’s.

A meta-analysis of seven trials of n-3 PUFA intake on rates of restenosis post PCI concluded that the rate of restenosis was 5.1% lower in treated compared to control groups (95% CI: -3.8 to 13.9%).(76)

Several trials reported no benefit from n-3 PUFA’s on restenosis rates. The EMPAR Trial (n = 814) reported a rate of restenosis for the treated group of 46.5%

compared to a control group of 44.7%.(77) The CART Study of restenosis following PCI (n = 500) found supplementation with 5.1 g/d

of n-3 PUFA’s for six months did not reduce the incidence of restenosis when compared to placebo (OR = 1.25; 95% CI: 0.87 to 1.80, p = 0.21).(78)

To address this conflicting evidence, the ESPRIT (n = 257) found n-3 poly-unsaturated fatty acids (in the form of supplemental fish oil) to produce a small reduction in restenosis of marginal statistical and questionable clinical significance (31.2% in treated compared to 40.9% in control group).(79)



Other Non-RCT Evidence A systematic review of 11 prospective cohort studies published before 2000(80) concluded that the inverse association between fish intake and coronary heart disease was stronger for fatal CHD than for nonfatal MI, and the benefit was most evident in populations with higher than average risk of CHD. In the aggregate, these studies suggest that fish consumption of 40 to 60 g/d is associated with reductions in mortality of 40 to 60%. Since 1999, four additional published prospective cohort studies further support the protective effects of marine n-3 PUFA’s against CHD in diverse populations.(81-84)

Decreased Trans-Fatty Acids Trans-fatty acids are unsaturated fatty acids, formed primarily through the hydrogenation of PUFA’s. Selected sources include stick margarine, vegetable shortenings, and the commercially prepared food products containing them (e.g., pastries, fried foods, crackers, and cookies). In addition, dairy fat and meats contain trans-fatty acids. No RCTs have been conducted. However, both the Food and Nutrition Board of the Institute of Medicine, National Academy of Sciences and the AHA recommend that trans-fatty acid consumption be restricted to as low a level as possible while consuming a nutritionally adequate diet. Evidence in support of the tentative conclusion that trans-fatty acids may be more responsible than saturated fat (on a per-gram basis) for the elevated cholesterol and coronary event rates attributed to dietary fat intake, includes: Three feeding studies showing a positive linear trend between trans-fatty acid intake and

LDL cholesterol concentrations.(85-87) Five prospective cohort studies showing an increased risk of MI, CHD and major coronary

events in those consuming higher intakes of trans-fats.(83, 88-91)

Other Considerations The 2002 CMI CAD Guidelines recommended that CAD patients be encouraged to increase the uptake of n-3 polyunsaturated fatty acids (1 g daily) found in fatty fish. To increase n-3 polyunsaturated fatty acid intake, the AHA Dietary Guidelines recommend that patients with documented CHD consume ~ 1 g of EHA plus DHA per day, preferably from oily fish. The recommendation further states that EPA plus DHA dietary supplements be considered in consultation with the physician for patients with documented coronary heart disease (CHD). The FDA has approved a qualified health claim for EPA and DHA n-3 PUFA’s in dietary supplements(92) stating that:

“Consumption of omega-3 fatty acids [AKA n-3 polyunsaturated fatty acids] may reduce the risk of coronary heart disease. FDA evaluated the data and determined that, although there is scientific evidence supporting the claim, the evidence is not conclusive.”

Nutritional labeling of food products for trans-fatty acids began in 2006. Dosing information on n-3 polyunsaturated fatty acids in plant and marine forms is available on the Natural Standard Database (http://cl.kp.org).



Safety Considerations in Increasing Fish Consumption The Food and Drug Administration (FDA) has ruled that intakes of up to 3 g/d of marine omega-3 fatty acids are GRAS (Generally Recognized as Safe) for inclusion in the diet. The ruling considered effects on glycemic control in patients with diabetes, bleeding, and LDL cholesterol.(93) Fish and seafood are major sources of methylmercury, polychlorinated biphenyl’s (PCB’s), dioxins, and other environmental contaminants. The removal of skin and fat from fish can reduce exposure to PCBs but not to methylmercury. The FDA has concluded that persons (other than pregnant women, women who may become pregnant as well as nursing mothers and children) can consume up to seven ounces per week of fish with methylmercury levels around one PPM* (e.g., shark, swordfish, king mackerel, tilefish) and 14 ounces per week of fish with methylmercury levels averaging 0.5 PPM (e.g., fresh tuna, orange marlin, and red snapper).(94) Methylmercury levels of fish are available at the FDA web site: http://www.cfsan.fda.gov/~frf/sea-mehg.html The National Listing of Fish and Wildlife Advisories are available at the EPA web site: http://www.epa.gov/waterscience/fish

Professional Group Recommendations Reviewed American Heart Association (AHA) Dietary Guidelines, 2000 AHA Scientific Statement on Fish Consumption, Fish Oil, Omega-3 Fatty Acids, and

Cardiovascular Disease, 2002 AHA Conference Proceedings on Dietary Fatty Acids and Cardiovascular Health, 2001 AHA Science Advisory on Monounsaturated Fatty Acids and Risk of Cardiovascular

Disease NCEP ATP III Guidelines, 2004 Update Letter Report on Dietary Reference Intakes for Trans-Fatty Acids by the Food and

Nutrition Board, Institute of Medicine, National Academy of Sciences, 2002.

Overall Conclusions Findings from RCTs of secondary prevention and prospective cohort studies of primary prevention are congruent on the following as effective dietary strategies for prevention of coronary events, including mortality: Substitution of polyunsaturated and monounsaturated for saturated fats and trans-fats. Increased consumption of n-3 PUFA’s, including both EPA plus DHA (marine sources)

and a-linolenic acid (plant sources). RCTs of n-3 PUFA’s for restenosis prevention after PCI have yielded conflicting results.

The optimal amount of unsaturated (monounsaturated and polyunsaturated) fatty acid intake remains unclear.

* Parts per million.



18. Dietary Supplement Therapy

18.A. For patients with CAD, supplemental vitamins C, E, and beta carotene are not recommended for prevention of cardiovascular mortality or subsequent coronary events. Evidence-based: D

18.B. For patients with CAD, supplemental folic acid, vitamin B6, and vitamin B12 are not recommended. Evidence-based: D

Rationale:

Evidence Grade: Recommendation A – Fair Recommendation B – Good

2008 Guideline

One meta-analysis was identified in the peer-reviewed medical literature. In a meta-analysis of RCTs (Bazzano, et al, 2006)(95) the effect of folic acid supplementation on the risk of cardiovascular diseases and all-cause mortality among persons with preexisting cardiovascular or renal disease was evaluated. Twelve trials were selected (January 1966 to July 2006), randomly assigning a total of 16,958 participants. The trials compared folic acid supplementation with either placebo or usual care for a minimum duration of six months; clinical cardiovascular disease events were reported as an end point. The trials were analyzed with the use of a random-effects model. The overall relative risks of outcomes for patients treated with folic acid supplementation compared with controls were 0.95 (95% CI: 0.88 to 1.03) for cardiovascular diseases, 1.04 (95% CI: 0.92 to 1.17) for coronary heart disease, 0.86 (95% CI: 0.71 to 1.04) for stroke, and 0.96 (95% CI: 0.88 to 1.04) for all-cause mortality. The relative risk was consistent among participants with preexisting cardiovascular or renal disease. Folic acid supplementation did not reduce the risk of cardiovascular diseases or all-cause mortality among participants with a prior history of vascular disease.

Conclusion The results reported by this study are inadequate to establish a protective role of folic acid in reduction of cardiovascular risk. There is fair evidence that beta carotene can increase mortality and conflicting heterogenous evidence that vitamin E has an effect on cardiovascular mortality in secondary prevention. There is some evidence that adding antioxidants to simvastatin and niacin reduce the benefit of the treatment. On this basis, the GDT maintains the recommendation that antioxidants not be used for prevention of CVD or subsequent coronary events. Based on a well-conducted meta-analysis and clinical trials which did not show an effect of folic acid or B vitamin supplementation on the risks of CAD, stroke, or CVD and earlier trials showing adverse effects, the GDT does not recommend folic acid supplementation for patients with CAD.



The GDT decided to delete the following recommendation because it is duplicative of recommendation A, which already says that beta carotene is not recommended for CAD patients regardless of smoking status:

“For CAD patients who are current or former smokers, supplemental beta carotene is not recommended due to a small but significant excess in all-cause mortality reported in this group.”

2006 Guideline

No change has been made in 2004 recommendations on vitamins C, E, and beta carotene as a result of this systematic review. The recommendation on B vitamin supplementation has been strengthened to recommend against supplemental folic acid, vitamin B6, and B12 as a result of publication of findings from the following trials: The Heart Outcomes Prevention Evaluation (HOPE 2(96) (n = 5,522) in which supplements

combining folic acid, B6, and B12 did not reduce the risk of major cardiovascular events or secondary outcomes in patients with vascular disease (RR = 0.95; 95% CI: 0.84 to 1.07).

The Norwegian Vitamin Intervention Trial (NORVIT(97) (n = 3,749) in which treatment with folic acid plus B12 (RR = 1.08; 95% CI: 0.93 to 1.25) and vitamin B6 alone (RR = 1.14, 95% CI: 0.98 to 1.32) did not lower the risk of recurrent cardiovascular disease after acute myocardial infarction. The results of the combined treatment with folic acid plus B12 plus B6 (RR = 1.22; 95% CI: 1.00 to 1.50) was suggestive of a harmful effect.

Supporting Evidence on Antioxidant Supplementation In one meta-analysis of antioxidant vitamin supplementation for the prevention of cardio-vascular disease,(98) four trials of CAD patients (n = 69,788) found all-cause mortality to be slightly elevated in the beta carotene treated groups. In two of these four trials (of former/ active smokers or asbestos-exposed only patients), the increased mortality reached statistical significance: ATBC (Alpha-Tocopherol Beta Carotene Cancer Prevention Study) (n = 29,133) Absolute

Event Rate for Treated (AERT) = 12.7%, for Controls = 11.8%, p = 0.02 CARET (The Beta Carotene and Retinol Efficacy Trial) (n = 18,314) AERT = 4.9%,

for Controls = 4.1%, p = 0.02 HPS (The Heart Protection Study) (n = 20,536) AERT = 14.1%, for Controls = 13.5%,

p = 0.25 SCP (The Skin Cancer Prevention Study) (n = 1,805) AERT = 8.7%, for Controls = 8.1%,

p = 0.66



In the five trials of CAD patients cited in the same meta-analysis (n = 72,536) all-cause mortality in the vitamin E-treated groups was nonsignificantly elevated in three of the five trials. In one trial mortality was nonsignificantly reduced and in another there was no difference in mortality between the vitamin E-treated and nontreated groups: ATBC (n = 29,133) AERT = 12.3%, for Controls = 12.1%, p = 0.58 CHAOS (Cambridge Heart Antioxidant Study) (n = 2,002) AERT = 3.5%,

for Controls = 2.7%, p = 0.31 GISSI (Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico)

(n = 11,324) AERT = 8.6%, for Controls = 9.3%, p = 0.18 HOPE (Heart Outcomes Prevention Evaluation)(n = 9,541) AERT = 11.2%,

for Controls = 11.2%, p = 1.00 HPS (n = 20,536) AERT = 11.3%, for Controls = 11.1%, p = 0.42

Treatment with vitamin E had no effect on the combined endpoint of cardiovascular death and nonfatal MI in two of the three secondary prevention trials in which these outcomes were reported. In the smallest of the three trials there was a statistically significant increase in cardiovascular death and nonfatal MI observed in the vitamin E-treated group: CHAOS (n = 2,002) AERT = 4.0%, for Controls = 6.6%, p = 0.01 GISSI (n = 11,324) AERT = 8.0%, for Controls = 8.0%, p = 1.00 HPS (n = 20,536) AERT = 13.1%, for Controls = 12.7%, p = 0.47 One RCT of postmenopausal women (n = 423) with coronary stenosis failed to demonstrate

that antioxidant vitamins C and E reduce either all-cause mortality (Hazard Ratio = 2.8; 95% CI: 1.1 to 7.2, p = 0.047) or death/nonfatal MI (Hazard Ratio = 2.1; 95% CI: 0.99 to 4.5, p = 0.09).(99)

A second RCT of patients with coronary disease and low HDL and normal LDL cholesterol (HATS Trial n = 160) found the addition of antioxidant vitamins (vitamins C and E, beta carotene, and selenium) to simvastatin and niacin treatment to diminish the arterial benefit of this treatment (+0.7% increase in proximal stenosis in antioxidant group, compared to -0.4% in the simvastatin-niacin treatment alone group). In addition, the frequency of clinical benefits was reduced when antioxidants were added to the treatment (14% cardiovascular events, with antioxidants added, compared to 3% in the simvastatin-niacin treatment alone group).(100) The combined results of three additional small RCTs in older patients(101) comparing vitamin C supplementation with placebo provided no evidence of any substantial reduction in mortality with vitamin C supplementation (RR = 1.08; 95% CI: 0.93 to 1.26).



Other Considerations The 2002 CMI CAD Guidelines recommend against the use of antioxidant supplements (vitamins C and E and beta carotene) for CAD patients. No recommendation was made regarding the use of B vitamin supplements. The AHA (American Heart Association) recommends that a balanced diet with emphasis on antioxidant-rich fruits and vegetables and whole grains be consumed. Supplemental antioxidants are not recommended. “The U.S. Preventive Services Task Force (USPSTF) concludes that the evidence is insufficient to recommend for or against the use of supplements of vitamins A, C, E; multivitamins with folic acid; or antioxidant combinations for the prevention of [cancer or] cardiovascular disease.”(102) Professional Group Recommendations Reviewed American Heart Association (AHA) Dietary Guidelines, 2000 American Heart Association (AHA) Science Advisory: Antioxidant Consumption and

Risk of Coronary Heart Disease: Emphasis on Vitamin C, Vitamin E, and B-Carotene American Heart Association (AHA) Science Advisory: Homocysteine, Diet, and

Cardiovascular Diseases Routine Vitamin Supplementation to Prevent Cardiovascular Disease: A summary of the

Evidence for the U.S. Preventive Services Task Force

2004 Guideline

Overall Conclusions on Antioxidant Supplementation Evidence from RCTs of secondary prevention fails to demonstrate that the antioxidant vitamins C, E, and beta carotene in supplemental form benefit patients with CAD. Beta carotene may increase risk of mortality in former/active smokers and those exposed to asbestos. Three RCTs currently underway may further inform recommendations on antioxidant supplementation within the next two years. Until then, increases in antioxidant intake may be achieved through dietary increases in whole grains, nuts, seeds, fruits and vegetables.

Supporting Evidence on Supplementation with Vitamins B6, B12, and/or Folic Acid In one RCT of low-dose (0.5 mg/d) folic acid supplementation in patients with stable CAD (n = 593) followed for 24 months, the folic acid-treated group did not experience a reduction in recurrence of cardiovascular events (RR = 1.05; 95% CI: 0.63 to 1.75) in spite of an 18% reduction (p < 0.001) in plasma homocysteine levels in the treated group compared to controls.(103) In an RCT of high-dose (5.0 mg/d) folic acid supplementation in a comparable population with ischemic heart disease (n = 1,882) followed for 1.7 years, the folic acid–treated group did not experience a reduction in risk of the composite endpoint of nonfatal MI, cardio-vascular death or unplanned revascularization (RR = 0.97; 95% CI: 0.72 to 1.29) in spite of reductions in plasma homocysteine levels (from 11.2 ±6.9 mmol/l to 9.7 ±5.3 mmol/l).(104)



The Swiss Heart Study RCT (n = 553) examined the effect of homocysteine-lowering therapy with moderate levels of supplementation of folic acid (1 mg/d), vitamin B6 (10 mg/d), and vitamin B12 (400 mcg/d) on clinical outcomes, including coronary restenosis one year post-PCI. In the treated compared to the placebo group the risk of a major adverse coronary event was lower (RR = 0.68; 95% CI: 0.48 to 0.96, p = 0.03). The risk of restenosis was also lower in the treated compared to placebo group (RR = 0.70; 95% CI: 0.49 to 1.01, p = 0.06).(105) In a subset analysis of the Swiss Heart Study homocysteine-lowering therapy was also shown to significantly decrease binary restenosis rates (15% in the treated group compared to 42% in the placebo group, p = 0.002) thus reducing the need for target lesion revascularization in patients undergoing PCI of small coronary arteries.(106) Early results have been released from the FACIT (Folate after Coronary Intervention Trial) RCT (n = 636) in which a slightly higher combination dose of folate (1.2 mg/d), vitamin B6 (48 mg/d), and vitamin B12 (600 mcg/d) post-PCI was administered. The treated compared to the placebo group had a higher MACE (death, MI, TLR) rate at 250 days (16.8 in treated compared to 10.9 in placebo group, p = 0.03) and a higher rate of restenosis at six months (34.5% in treated group, 26.5% in placebo group, p = 0.047).(107) The results of HOPE 2(96) and NORVIT(97) clearly shift the weight of the evidence against the use of B vitamin supplements for reduction of cardiovascular events.

Other Considerations Non-RCT Evidence Meta-analyses of prospective and observational epidemiological studies as well as genetic studies suggest that the relationship between serum homocysteine and cardiovascular disease risk may be causal.(108, 109) If so, then lowering concentrations of serum homocysteine from current levels through B vitamin supplementation could reduce ischemic heart disease and stroke.

Future Studies of Efficacy of B Vitamin Supplementation in the CAD Population There are four major on-going clinical trials of the effects of supplemental B vitamins on cardiovascular events. They are WENBIT (the Western Norway B Vitamin Intervention Trial), VISP (Vitamin Intervention for Stroke Prevention in the United States), PACIFIC (the Prevention with a Combined Inhibitor and Folate in Coronary Heart Disease in Australia), and SEARCH (the Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine in the United Kingdom).



19. Smoking Cessation

19. For all patients with CAD who smoke, complete smoking cessation is strongly recommended. Evidence-based: A

Rationale:

2008 Guideline

No relevant RCTs or meta-analyses were identified in the peer-reviewed literature that evaluated smoking cessation in patients with CAD.

2006 Guideline

All patients who smoke should be given smoking cessation advice or counseling. Mortality was lower in patients who quit smoking (17%) than in those who continued (27%) in a meta-analysis of 20 cohort studies of patients with coronary heart disease.(110) The relative risk was 64% (95% CI: 58% to 71%). Advise to avoid secondhand smoke.(111) Provide counseling, pharmacologic therapy, and formal smoking cessation programs.

Professional Group Recommendations Reviewed: AHA/ACC Guidelines for Secondary Prevention for Patients with Coronary and Other

Atherosclerotic Vascular Disease: 2006 Update (Endorsed by the National Heart, Lung, and Blood Institute):(112)

SMOKING: Ask about tobacco use status at every visit. I (B)

Goal Advise every tobacco user to quit. I (B)

Assess the tobacco user’s willingness to quit. I (B)

Assist by counseling and developing a plan for quitting. I (B)

Arrange follow-up, referral to special programs, or pharmacotherapy (including nicotine replacement and bupropion). I (B)

Complete cessation. No exposure to environmental tobacco smoke.

Urge avoidance of exposure to environmental tobacco smoke at work and home. I (B)



20. Exercise

20.A. For all patients with CAD, 30 to 60 minutes of exercise (walking, jogging, cycling, or other aerobic activity) at least three to four times weekly is recommended. Evidence-based: B

20.B. Either supervised or non-supervised exercise is recommended. Consensus-based

Rationale:

2008 Guideline

No relevant RCTs or meta-analyses were identified in the peer-reviewed literature that evaluated exercise in patients with CAD. “Either supervised or home-based, nonsupervised exercise” in recommendation B was a little confusing, and the GDT decided to delete “home-based” for clarification purposes.

2006 Guideline

Mortality was lower in patients participating in exercise-based cardiac rehabilitation programs than in control patients in a meta-analysis of eleven RCTs in patients with CAD (RR = 0.85; 95% CI: 0.77 to 0.94).(113) The frequency, duration, and level of supervision of training of the studies included in this meta-analysis varied. Five studies evaluated the effects of supervised training three times per week for periods of three to 12 months. Four studies evaluated the effects of supervised training twice weekly for between one and 12 weeks. One study evaluated the effects of training over six months in a five-days-per-week supervised program of 20-minute intervals for a total of 100 minutes. The published RCT of Kaiser Permanente patients (included in this meta-analysis) compared the effects of home versus group exercise programs. By week 11 of a 26-week evaluation period, home and group training were both found to be safe and equally effective in increasing the functional capacity of low-risk patients after MI.(114) On the basis of this study, the GDT determined that either supervised or home-based exercise is recommended.




Atherosclerotic Vascular Disease: 2006 Update (Endorsed by the National Heart, Lung, and Blood Institute): (112)

PHYSICAL ACTIVITY: For all patients, assess risk with a physical activity history and/or an exercise test, to guide prescription. I (B)

For all patients, encourage 30 to 60 minutes of moderate-intensity aerobic activity, such as brisk walking, on most, preferably all, days of the week, supplemented by an increase in daily lifestyle activities (e.g., walking breaks at work, gardening, household work). I (B)

Encourage resistance training two days per week. IIb (C)

Goal 30 minutes, 7 days per week (min. 5 days per week)

Advise medically supervised programs for high-risk patients (e.g., recent acute coronary syndrome or revascularization, heart failure). I (B)



21. Hormone Therapy

21.A. For postmenopausal women with CAD, unopposed estrogen therapy and estrogen and progestin combination therapy are not recommended for the prevention of cardiovascular events. Women taking these therapies solely to prevent cardiovascular events are strongly recommended to discontinue these therapies. Evidence-based

21.B. Women currently taking hormone therapy solely for the prevention of cardiovascular events are advised to discontinue use either all at once or by tapering the dose. Consensus-based

Rationale:

2008 Guideline

No relevant RCTs or meta-analyses were identified in the peer-reviewed literature that evaluated hormone replacement therapy in patients with CAD. The previous recommendations separated women with and without a uterus. The GDT decided to combine these recommendations, since the recommendation was the same for both groups. The GDT also decided to add the word “solely” to clarify that the recommendation to stop is for women who take hormone therapy for the sole purpose of preventing cardiovascular disease. There are other reasons why women take hormone therapy, and these recommendations allow women to take hormone therapy for other reasons.

2006 Guideline

One additional publication of findings from the Women’s Health Initiative (N = 10,739, aged 50 to 79 years) has been released since the previous recommendations were approved.(115) This analysis concluded that conjugated equine estrogens (CEE) provided no overall protection against myocardial infarction or coronary death in generally healthy postmenopausal women during a 7-year period of use (HR = 0.95; 95% CI: 0.79 to 1.16). However, there was a suggestion of lower coronary heart disease risk with CEE among women aged 50 to 59 years at baseline (HR = 0.63; 95% CI: 0.36 to 1.08). No changes to the previous recommendations have been made as a result of this evidence.

2004 Guideline

Supporting Evidence for Unopposed Estrogen versus Placebo in Women Who Have Had Hysterectomies In February 2004 the National Institutes of Health (NIH) terminated the intervention phase of the WHI estrogen alone study, a large, randomized, double-blind, placebo controlled trial in 10,739 women with hysterectomy. This trial was terminated prior to its planned completion in 2005 in the interest of safety after the finding of an increased risk of stroke and no effect on risk of coronary heart disease in the treated group. Trial participants were aged 50 to 79 years, healthy, and at average risk of CHD, although 441 women (4.1%) with prior MI or coronary revascularization were also enrolled. The treated group received 0.625 mg/d of conjugated equine estrogen (CEE).



In the first published report of this trial no significant effect of CEE was observed on CHD rates compared with placebo (49 vs. 54 per 10,000 person-years; 9% reduction; HR = 0.91; 95% CI: 0.75 to 1.12). The incidence of stroke was increased by 39% in the CEE group (44 vs. 32 per 10,000 person-years, z = -2.72, p = 0.007; HR = 1.39; 95% CI: 1.10 to 1.77). The risk of venous thrombotic disease, including both deep vein thrombosis (DVT) and pulmonary embolism, was increased for women taking CEE (28 vs. 21 per 10,000 person-years; 33% increase; HR = 1.33; 95% CI: 0.99 to 1.79) although only the increased rate of DVT reached statistical significance (p = 0.03). Total cardiovascular disease event rates, including stroke, were 12% higher in women taking CEE (225 vs. 201 per 10,000 person-years, p = 0.02). The global index of health risks and benefits was balanced overall (HR = 1.01; 95% CI: 0.91 to 1.12). Use of CEE did not significantly affect total mortality rates or cause-specific mortality. Deaths attributed to cardiovascular disease were 93 (0.26) in the CEE group compared to 95 (0.26) in the placebo group. Among the 441 women enrolled with prior MI or revascularization procedures, the effect of CEE relative to placebo (33 vs. 31; HR = 1.04; 95% CI: 0.63 to 1.71) did not differ significantly from the CEE effect in women without documented CHD (143 vs. 162; HR = 0.91; 95% CI: 0.73 to 1.14, p = 0.55). Similarly, in 168 women reporting prior stroke, the HR for subsequent stroke (6 vs. 6; HR = 1.67; 95% CI: 0.52 to 5.36) did not differ from the HR in women without a history of stroke (152 vs. 112; HR = 1.39; 95% CI: 1.09 to 1.78, p = 0.77). Removing from the analysis the few participants with a history of pulmonary embolism (PE) did not alter the hazard ratio for PE substantially (47 vs. 37; HR = 1.31; 95% CI: 0.85 to 2.01).(116)

Supporting Evidence for Estrogen and Progestin versus Placebo in Women with Intact Uteri In the final results of the Women’s Health Initiative primary prevention trial(117) of estrogen plus progestin, combined hormone therapy was associated with a hazard ratio for coronary heart disease (CHD) of 1.24 (nominal 95% CI: 1.00 to 1.54; adjusted for sequential monitoring, 95% CI: 0.97 to 1.60). The elevation in risk was most apparent at one year (HR = 1.81; 95% CI: 1.09 to 3.01). Absolute rates of CHD were 39 cases per 10,000 person years in treated women compared with 33 cases per 10,000 person years for women on placebo. In (a priori planned) subgroup analyses, women with preexisting CHD (history of MI, CABG, or PCI) or other cardiovascular disease (history of MI, CABG, stroke, or TIA) did not have a significantly greater risk of subsequent coronary events.



In a small randomized, double blind trial of postmenopausal women (n = 423) with 15 to 75% coronary stenosis at baseline, Waters(99) reported death, nonfatal MI and stroke in 26 HRT-treated patients versus 15 controls (HR = 1.9; 95% CI: 0.97 to 3.6). Coronary progression (primary outcome), measured in mean change (SD), worsened with HRT by 0.047 (0.15) mm/y and by 0.024 (0.15) mm/y in placebo (p = 0.17). In a small randomized trial of transdermal HRT for secondary prevention of ischemic heart disease in postmenopausal women (n = 255) followed for 30.8 months, Clarke(118) reported 53 primary endpoint events (hospital admission for unstable angina, proven MI, cardiac death) among treated women (15.4 events/100 patient years) and 37 events in the control group (11.9 events / 100 patient years), an event rate ratio of 1.29 (95% CI: 0.84 to 1.95, p = 0.11). These nonsignificant results suggest that transdermal HRT does not represent a more cardioprotective alternative for HRT delivery.

Professional Groups Recommendations Reviewed ACC/AHA 2002 Guideline for the Management of Chronic Stable Angina Kaiser Permanente Southern California Clinical Practice Guidelines for Hormone

Replacement Therapy

Other Considerations The ACC/AHA 2002 Guideline for the Management of Chronic Stable Angina states that “… at the present time there is no basis for adding or continuing estrogens in postmenopausal women with clinically evident CAD or cerebrovascular disease in an effort to prevent or retard progression of their underlying disease.” For guidance on counseling women on the benefits and risks of both estrogen and estrogen plus progestin in secondary prevention of cardiovascular disease as well as methods of discontinuing HRT, see Kaiser Permanente Southern California Clinical Practice Guidelines for Hormone Replacement Therapy (http://cl.kp.org/pkc/scal/cpg/cpg/html/Dyslipid.html).

2002 Guideline

Good evidence from randomized, controlled trials was found that hormone replacement therapy (estrogen plus progestin) did not reduce the rate of coronary heart disease (CHD) events but in fact may increase the rates of CHD and thromboembolic events, especially in the first year of treatment.(119-121)



Comorbid Conditions

22. Hypertension: Target Blood Pressure

22.A. The optimal goal blood pressure for patients with CAD or CAD risk equivalents (AAA, peripheral arterial disease, or carotid arterial disease) is < 140/90 mm Hg. Consensus-based

22.B. The optimal goal blood pressure for patients with CAD and diabetes or renal disease is < 140/90 mm Hg. Consensus-based

Rationale:

2008 Guideline

No relevant RCTs or meta-analyses were identified in the peer-reviewed medical literature that assessed target blood pressure in patients with CAD. Based on consensus statements from the AHA and the European Hypertension Society, the GDT elected to continue the above recommendation. Note: Previously, this Guideline had labeled the Methodology for recommendation for patients with CAD and diabetes or renal disease as “Evidence-based: A.” However, upon examining the resources used to make this statement, this has been changed to “Consensus-based.”

Other Considerations This recommendation from the May 2007 American Heart Association guidelines is at the expert consensus level and is in keeping with similar recommendations for a lower blood pressure goal for higher-risk patients seen in the 2007 European Hypertension society.(123) Similar to the European report, this expert consensus involved representatives of both the hypertension and cardiology expert national societies. Supportive surrogate endpoint data come from the CAMELOT(12) (Comparison of Amlodipine Versus Enalapril to Limit Occurrences of Thrombosis) substudy, where 274 of the total of 1997 patients in the trial underwent intravascular coronary artery ultrasound to determine intracoronary atheroma volume at study entry and two years later.(124) CAMELOT enrolled men and women 30 to 79 years of age who required coronary angiography for clinical reasons and demonstrated at least one obstruction with angiographic stenosis diameter > 20%. Study eligibility required a diastolic blood pressure < 100 mm Hg, with or without treatment.



Regardless whether or not patients were treated with the ACE (angiotensin-converting enzyme) inhibitor or calcium channel blocker, patients with blood pressure at two years < 120/80 mm Hg had significantly reduced intracoronary atheroma volume compared with prehypertensive patients with blood pressure 120 to 139 / 80 to 89 mm Hg and compared with hypertensive patients with blood pressure 140/90 mm Hg, who had a mean increase in atheroma volume. There was progressive increase in atheroma value between systolic pressures of 100 to 140 mm Hg, demonstrating a gradual increase in risk relative to antihypertensive treatment that was independent of age, gender, diabetes mellitus, smoking, or body mass index (BMI). Well-established observational data have shown a continuum of risk for both fatal myocardial infarction and fatal stroke starting at a blood pressure of 115/75 mm Hg and extending to at least 180/110 mm Hg.(125) With this large meta-analysis of over one million patients and 17 million patient-years, for each age decile, there is a doubling of relative risk for each increase of 20 mm Hg systolic pressure and 10 mm Hg diastolic pressure. The INVEST study (Pepine et al., 2003; Mancia et al., 2007)(126, 127) involved a comparison of beta-blocker-based therapy versus verapamil-based antihypertensive therapy in patients with coronary artery disease established by coronary angiography or radioisotope scanning. In this study, which showed equivalent outcomes in the two treatment arms, there was a direct relationship between adverse cardiovascular events and systolic pressure, beginning with a systolic pressure of 130 mm Hg. However, the difference between systolic pressures of 130 and 140 mm Hg was nonsignificant. The primary outcome measure in INVEST was the first occurrence of all-cause death, nonfatal MI, and nonfatal stroke. Clinical debate based on retrospective analyses of subsets of the HOT, SHEP, INVEST, and SYST-EUR trials involves concern that a very low diastolic blood pressure may interfere with filling of diseased coronary arteries and lead to increased cardiac events, the so-called J-point. The J-point issue was addressed in the American Heart Association position paper(122) on guidelines and was estimated to be a diastolic pressure of 60 mm Hg. Caution should be exercised when the diastolic pressure falls below 60 mm Hg with application of antihypertensive therapy in patients with coronary artery disease. Inclusion of the three “coronary artery disease” conditions is based upon the high incidence of latent CAD seen in angiographic and autopsy studies of these patients.(128) These three conditions are atheromatous diseases commensurate with a generalized condition for which intracoronary atheromatous burden in the CAMELOT substudy is felt to be a surrogate measure in the expert consensus.

2006 Guideline

There is no evidence to support lower blood pressure targets in patients with CAD,(111) although the scientific literature confirms:(129, 130) Strong positive relationship between elevated systolic and diastolic blood pressure and CAD Treatment reduces cardiovascular disease risk



Therefore, the KP National Hypertension Treatment Guideline recommendations should be followed for patients with CAD and hypertension.


Atherosclerotic Vascular Disease: 2006 Update (Endorsed by the National Heart, Lung, and Blood Institute) which states: (112)

BLOOD PRESSURE CONTROL:

Goal: < 140/90 mm Hg or

For all patients: Initiate or maintain lifestyle modification—weight control; increased physical activity; alcohol in moderation; sodium reduction; and emphasis on increased consumption of fresh fruits, vegetables, and low-fat dairy products. I (B)

For patients with blood pressure ≥ 140/90 mm Hg (or ≥ 130/80 mm Hg for individuals with chronic kidney disease or diabetes):

As tolerated, add blood pressure medication, treating initially with beta-blockers and/or ACE inhibitors, with addition of other drugs such as thiazides as needed to achieve goal blood pressure. I (A)

< 130/80 mm Hg if patient has diabetes or chronic kidney disease

[For compelling indications for individual drug classes in specific vascular diseases, see Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7).]



23. Lipid Management - Choice of Drug*

23.A. A statin (simvastatin, lovastatin, atorvastatin, or pravastatin) is recommended as drug therapy for prevention of a future cardiovascular event in patients with established atherosclerotic disease. Evidence-based: A

23.B. Simvastatin is recommended as first-line therapy whenever statins are indicated. Consensus-based

23.C. There is insufficient evidence to determine which lipid-lowering therapy is superior, due to the lack of direct head-to-head trials. Evidence-based: I

Rationale:

2010 Update This recommendation was not reviewed in 2010.

2008 Guideline Two new meta-analyses and two post hoc studies have been cited. The recommendations are unchanged.

Search Strategy There are no head-to-head comparison studies of the efficacy of statins vs. fibrates, resins or niacin in reducing CAD events. Therefore, the choice of drug would be based on a comparison of individual drug treatments vs. placebos. See Appendix B for more information on the search strategy.

Statin Trials One systematic review [Clinical Evidence, Issue 10, May 2004 (on-line version)] and one RCT (Heart Protection Study, HPS, 2002) were identified that compared HMG Co-A reductase inhibitors (statins) versus placebo in patients up to age 80. Clinical Evidence, Issue 7, June 2002 reviewed several systematic reviews of the efficacy of

various drug therapies in reducing coronary heart disease events in patients with established atherosclerotic disease. (See Evidence Table 23.2 for details.) When statins were compared with placebo for secondary prevention over a mean of 5.4 years, statins significantly reduced coronary heart disease mortality (OR = 0.71, 95% CI: 0.63 to 0.80), cardiovascular mortality (OR = 0.73, 95% CI: 0.66 to 0.82), and all cause mortality (OR = 0.77, 95% CI: 0.70 to 0.85).




The following summary is excerpted from Clinical Evidence: “Statins: We found one systematic review (LaRosa et al., 1999) that compared long term ( 4 years) treatment with statins versus placebo. Combining the three secondary prevention trials, the review found that statins reduced coronary heart disease mortality, cardiovascular mortality, and all cause mortality compared with placebo over a mean of 5.4 years (coronary heart disease mortality: OR = 0.71, 95% CI: 0.63 to 0.80; cardiovascular mortality: OR = 0.73, 95% CI: 0.66 to 0.82; all cause mortality: OR = 0.77, 95% CI: 0.70 to 0.85). Differences between the baseline cholesterol concentration seemed to play no role in determining the results of the trials, in the ranges studied to date. Effects of statins in different groups of patients: Combining results from five primary and secondary prevention trials that included a total of 30,817 patients, the review found that, compared with placebo, statins reduced coronary events by a similar proportional amount in men (OR = 0.69, 95% CI: 0.65 to 0.74; ARR = 3.7%, 95% CI: 2.9% to 4.4%), in women (OR = 0.71, 95% CI: 0.64 to 0.76; ARR = 3.3%, 95% CI: 1.3% to 5.2%), in patients under 65 years (OR = 0.69, 95% CI: 0.64 to 0.76; ARR = 3.2%, 95% CI: 2.4% to 4.0%), and in patients over 65 years (OR = 0.68, 95% CI: 0.61 to 0.77; ARR = 4.4%, 95% CI: 3.0% to 5.8%). The reduction of coronary heart disease events in women involved more nonfatal and fewer fatal events than in men. One large RCT being reviewed found no significant difference in mortality with statins versus placebo for the subgroup of women, but the confidence interval was wide [28/407 (6.9%) with simvastatin vs. 25/420 (6.0%); RR = 1.16, 95% CI: 0.68 to 1.99)].

“Harms: Total noncardiovascular events, total and tissue specific cancers, and accident and violent deaths have been reported in statin trials. However, the systematic review of long term statin trials found no significant difference between statins and placebo in terms of noncardiovascular mortality, cancer incidence, asymptomatic elevation of creatine kinase (> 10 times upper reference limit), or elevation of transaminases (> three times upper reference limit) during a mean of 5.4 years of treatment (OR of event, statin vs. placebo 0.93, 95% CI: 0.81 to 1.07 for noncardiovascular mortality; 0.99, 95% CI: 0.90 to 1.08 for cancer; 1.25, 95% CI: 0.83 to 1.89 for creatine kinase increase; 1.13, 95% CI: 0.95 to 1.33 for transaminase increase). We found no evidence of additional harm associated with cholesterol lowering in elderly patients, or in patients following acute myocardial infarction.”

Following the publication of the Clinical Evidence systematic review, results from the Heart Protection Study (HPS) (2002) were published. The HPS is an RCT of 20,536 subjects who were treated with simvastatin 40 mg/day or placebo for five years. HPS included 18,344 subjects who had a prior myocardial infarction or a history of coronary or atherosclerotic vascular disease. It is the largest statin trial and it directly addressed the question whether statins should be used in patients at high risk of coronary heart disease events for patients with an average relatively low baseline LDL-C level of 131 mg/dL (please refer to Evidence Table 23.3 for details):



All-cause mortality (statins vs. placebo): 12.9% vs. 14.7%, p = 0.0003 (RR* = 0.88, 95% CI: 0.82 to 0.94).

No significant difference in all nonvascular deaths: 5.3% vs. 5.6%; p = 0.50 (RR = 0.96, 95% CI: 0.86 to 1.08).

First event rate (statins vs. placebo): nonfatal myocardial infarction or coronary death: 8.7% vs. 11.8%,

p < 0.0001 (RR = 0.74, 95% CI: 0.68 to 0.80). nonfatal or fatal stroke: 4.3% vs. 5.7%, p < 0.0001 (RR = 0.76,

95% CI: 0.67 to 0.86). coronary or noncoronary revascularization: 9.1% vs. 11.7%, p < 0.0001

(RR = 0.78, 95% CI: 0.72 to 0.84). any major vascular events: 19.8% vs. 25.2% p < 0.0001 (RR = 0.79,

95% CI: 0.75 to 0.83). Results from the trial estimated that five-years of simvastatin treatment would prevent about

70 to 100 people per 1,000 from experiencing at least one major vascular event, and longer treatment would produce further benefit. There were no significant adverse effects of treatment.

However, this RCT included 2,913 subjects in the primary prevention population. Effects of statins on secondary prevention might have been diluted by data from the primary prevention group.

The relative risk for the first coronary event in the secondary prevention subgroup = 0.76, 95% CI: 0.70 to 0.82. Compared with placebo, simvastatin resulted in a statistically significant reduction in future coronary events in the secondary prevention treatment group.

Moreover, HPS also suggested that statin therapy is effective in reducing major coronary events in people with relatively low baseline LDL-C. HPS included 6,793 subjects that had a baseline LDL-C < 116mg/dL. In the subgroup analysis of this population with LDL-C < 116 mg/dL, statin therapy was shown effective in reducing a major coronary event:

Coronary event: Rx: 7.9% (268/3,389) C: 10.5% (356/3,404) ARR = 2.6% RRR = 24.8% P < 0.0001

* Relative Risks (RR) and their confidence intervals were calculated from the reported data using the FastPro

program.



Fibrates Trials In trials comparing the various drugs vs. placebo, statins were found to have the greatest reduction in total mortality, CAD mortality, and CAD events. In the fibrates trials, participants often had low baseline LDL-C and high baseline TG. LDL-C levels were not changed much in these trials. The following summary is excerpted (verbatim) from Clinical Evidence:

“Fibrates We found one systematic review (Montagne et al., 1999), which included four RCTs, and two additional RCTs (Schlesinger et al., 2000; Ericsson et al., 1996). The systematic review compared fibrates versus placebo in people with known coronary heart disease. The review identified one RCT (2,531 men with coronary heart disease and a level of high density lipoprotein cholesterol < 1 mmol/L or < 38.7mg/dL) that found gemfibrozil versus placebo reduced the composite outcome of nonfatal myocardial infarction plus death from coronary heart disease after a median of 5.1 years [AR = 219/1,264 (17%) for gemfibrozil vs.275/1,267 (22%) for placebo; ARR = 4.4%, 95% CI: 1.4% to 7.0%; RR = 0.80, 95% CI: 0.68 to 0.94; NNT = 23, 95% CI: 14 to 73]. The review identified three trials comparing clofibrate versus placebo, which found no consistent difference between groups. The two additional RCTs both compared bezafibrate versus placebo. The larger RCT (Schlesinger et al., 2000) (3,090 people selected with previous myocardial infarction or stable angina, high density lipoprotein cholesterol < 45 mg/dL, and low density lipoprotein cholesterol < 180 mg/dL) found that bezafibrate versus placebo did not significantly reduce all cause mortality or the composite end point of myocardial infarction plus sudden death (AR for myocardial infarction or sudden death 13.6% with bezafibrate vs.15.0% with placebo; cumulative ARR at 6.2 years 7.3%; p = 0.24). The smaller RCT (Ericsson et al., 1996) (92 young male survivors of myocardial infarction) found that bezafibrate versus placebo significantly reduced the combined outcome of death, reinfarction, plus revascularization (26% with bezafibrate vs.7% with placebo; p = 0.019).”

Comparisons of Statins, Fibrates, Resins and Niacin No head-to-head comparison studies of the efficacy of statins vs. fibrates, resins or niacin were identified. Therefore, the decision on the choice of drug would be based on a comparison of individual drug treatments vs. placebos. Clinical Evidence [Issue 7, June 2002 (on-line version)] identified one systematic review that compared these drugs to placebo. Clinical Evidence concluded that statins demonstrated the greatest reduction in CAD events. The following summary is excerpted (verbatim) from Clinical Evidence:

“…We found one systematic review (Bucher et al., 1999), which did not differentiate primary and secondary prevention irrespective of duration, as long as mortality data were reported. The review included 59 RCTs of any cholesterol lowering intervention and 173,160 people receiving drug treatments, dietary intervention, or ileal bypass. Overall, baseline risk was similar in people allocated to all interventions.”



The Bucher et al. review concluded the following: CAD Mortality: Compared with placebo, only statins and resins achieved statistically

significant risk reduction in CAD mortality. The effect of statins resulted in the greatest reduction in CAD mortality: Statins vs. control: RR = 0.69 (95% CI: 0.59 to 0.80) Fibrates vs. control: RR = 0.98 (95% CI: 0.78 to 1.24) Resins vs. control: RR = 0.71 (95% CI: 0.51 to 0.99) Niacin vs. control: RR = 0.95 (95% CI: 0.83 to 1.10)

Total Mortality: Compared with placebo, only statins and resins resulted in a

reduction in total mortality, but statins were the only drug treatment that reached statistical significance and they resulted in the greatest reduction in reducing total mortality: Statins vs. control: RR = 0.79 (95% CI: 0.71 to 0.89) Fibrates vs. control: RR = 1.06 (95% CI: 0.78 to 1.46) Resins vs. control: RR = 0.85 (95% CI: 0.66 to 1.08) Niacin vs. control: RR = 0.96 (95% CI: 0.86 to 1.08)

Comparison of Statins Meta-Analyses and Systematic Reviews Results from a quantitative systematic review (Ebrahim et al., 1999) stated that the

different types of statins (lovastatin, simvastatin, and pravastatin) have a similar effect on reducing composite primary end points (coronary events, stroke, and revascularization) for both primary and secondary prevention. (See Evidence Table 23.4 for details.)

In the case of lovastatin on CAD mortality, Ebrahim et al. stated:

“The apparent lack of a class effect on CAD mortality is probably determined by the primary care clinical settings of the major trials which recruited only low risk patients. In these trials (WOSCOPS, AFCAPS/TexCAPS, 4S, CARE, and LIPID), the main aim was to detect an effect on a combined vascular end point outcome, including revascularization procedures. Consequently, the trials of lovastatin were underpowered to detect effects on CAD mortality.”



Otherwise, the 95% CIs overlap, suggesting that the effects on CAD mortality and composite primary end point are consistent with no difference among the three statins (lovastatin, simvastatin, pravastatin) when they were compared with placebo. The pooled analysis for the effects on CAD mortality and composite end points for the comparisons between statins are listed below:

Lovastatin vs. placebo CAD mortality OR = 1.02 (95% CI: 0.60 to 1.73) Composite primary end point OR = 0.62 (95% CI: 0.49 to 0.77)

Simvastatin vs. placebo CAD mortality OR = 0.60 (95% CI: 0.48 to 0.75) Composite primary end point OR = 0.68 (95% CI: 0.49 to 0.93)

Pravastatin vs. placebo CAD mortality OR = 0.77 (95% CI: 0.68 to 0.87) Composite primary end point OR = 0.69 (95% CI: 0.53 to 0.90)

A meta-analysis by Zhou et al., (2006) compared the relative efficacy of pravastatin, simvastatin and atorvastatin by pooling data from eight placebo-controlled RCTs (4S, HPS, WOSCOPS, CARE, LIPID, ALLHAT-LLT, ASCOT-LLA, CARDS, GREACE). Using adjusted indirect comparison methods, they found no statistically significant differences between the three statins in terms of their effect on major coronary events, cerebrovascular events and CHD death (see data below). However it is important to note that trials which have directly compared statins, have shown that more potent statins are more effective at reducing CAD event rates. CAD event reduction appears to be proportional to LDL-C reduction. A systematic review by Ward et al. (2007) pooled results from statin RCTs (excluding lovastatin) conducted among secondary prevention populations. They concluded that “in secondary prevention, statin therapy is associated with a statistically significant reduction in the risk of cardiovascular mortality, CHD mortality, fatal MI, nonfatal stroke, PAD, unstable angina and coronary revascularization.”





Afilalo et al. (2007) conducted a systematic review evaluating the effects of intensive statin

therapy (defined as simvastatin 80 mg, atorvastatin 80 mg, or rosuvastatin 20 to 40 mg) on major cardiovascular events among people with recent ACS or stable CHD. In patients with recent ACS, intensive statin therapy reduced all-cause mortality from 4.6% to 3.5% (OR = 0.75, 95% CI: 0.61 to 0.93, NNT = 90). In patients with stable CHD, intensive statin therapy did not reduce all-cause mortality (OR = 0.99, 95% CI: 0.89 to 1.11). Major adverse cardiovascular events were comparably reduced in patients with recent ACS (OR = 0.86, 95% CI: 0.73 to 1.01) and stable CHD (OR = 0.82, 95% CI: 0.75 to 0.91). The odds ratios for major adverse cardiovascular events in patients with recent ACS demonstrated significant statistical heterogeneity (I2 = 63%). Admissions to hospital for heart failure were reduced in patients with recent ACS (OR = 0.63, 95% CI: 0.46 to 0.86) and stable CHD (OR = 0.77, 95% CI: 0.64 to 0.92). Overall, the numbers needed to treat to prevent one major adverse cardiovascular event and one admission to hospital for heart failure were 46 and 112, respectively. In addition to the significant statistical heterogeneity, it should be noted that five out of six RCTs evaluated intensive atorvastatin therapy, with one evaluating simvastatin and none evaluating rosuvastatin. Thus, the external validity and generalizability to other statins is limited. (See Figures 2 and 3 below.)



From Afilalo et al., 2007

From Afilalo et al., 2007



Randomized Controlled Trials Seven RCTs published subsequent to the Ebrahim meta-analysis examined the effects of

atorvastatin and fluvastatin on the secondary prevention CAD health outcomes. A brief description of these RCTs follows:

Atorvastatin vs. Placebo The secondary prevention trial, MIRACL (Schwartz et al., 2001), compared the effects of

atorvastatin to placebo in patients who were recently admitted for an acute cardiac event. After 16 weeks, atorvastatin significantly reduced the risk of occurrence of the composite primary end point (death, nonfatal acute MI, cardiac arrest or myocardial ischemia with objective evidence and emergency rehospitalization) RR = 0.84 (95% CI: 0.70 to 1.00, p = 0.048). When comparing atorvastatin vs. placebo across each individual end point, there were no significant differences in the risk of death (RR = 0.94, 95% CI: 0.67 to 1.31), nonfatal acute MI (RR = 0.90, 95% CI: 0.69 to 1.16) or cardiac arrest (RR = 0.82, 95% CI: 0.33 to 2.06). Atorvastatin did however significantly reduce the risk of myocardial ischemia (RR = 0.74, 95% CI: 0.57 to 0.95).

In the Greek Atorvastatin and Coronary-heart-disease Evaluation study (GREACE, Athyros VG et al., 2002), 1,600 patients with prior cardiac events were randomized to “usual” care (may include lifestyle changes, weight loss, exercise, and lipid therapy including atorvastatin) vs. atorvastatin (10 to 80 mg, titrated to reach LDL-C < 100 mg/dL) for three years. The end points of total mortality (RR = -0.57, 95% CI: 0.39 to 0.78, p = 0.0021), coronary mortality (RR = 0.53, 95% CI: 0.29 to 0.74, p = 0.0017), and stroke (RR = 0.53, 95% CI: 0.30 to 0.82, p = 0.034) were significantly lower in the atorvastatin group at the end of the study.

The PROVE-IT study (Cannon CP et al., 2004) examined high risk patients who were randomized to atorvastatin (80 mg) or pravastatin (40 mg) after hospitalization for acute coronary syndromes (ACS: STEMI, nonSTEMI, or unstable angina). Patients had low baseline LDL-C values (median 106 mg/dL) with low HDL-C values (median 39 and 38 mg/dL in the pravastatin and atorvastatin groups, respectively). Results showed a statistically significant 16% risk reduction (95% CI: 5% to 26%, p < 0.001) in the hazard ratio for the composite primary end point of death from any cause, MI, UA requiring rehospitalization, or revascularization. The absolute risk for a primary end point event was 26.3% in the pravastatin group compared with 22.4% in the atorvastatin group, corresponding to a favorable and significant absolute risk reduction of 3.9% (NNT = 26). There were no significant differences found for CAD mortality, all-cause mortality, MI or stroke.

Fluvastatin vs. Placebo In one secondary prevention trial--LIPS (Lee CH et al., 2002) -- 1,677 patients who underwent

percutaneous coronary intervention were randomized to fluvastatin 80 mg/day or placebo for a period of four years. Patients who received fluvastatin experienced a significant reduction in the risk of the major acute coronary events, including cardiac death, MI or reintervention procedure (RR = 0.78, 95% CI: 0.64 to 0.95, p = 0.006, NNT = 19). No significant differences between fluvastatin and placebo were found for all-cause mortality and cardiovascular morality. Significant crossover (11% of placebo patients were also taking statins) and a 20% noncompliance rate in the treatment group may have adversely affected this outcome analysis.



Simvastatin 80 mg vs. Placebo plus 20 mg Simvastatin ● In phase Z of the A to Z Trial (de Lemos JA et al., 2004), 4,500 acute coronary syndrome

(ACS) patients were randomized to either high dose simvastatin (40 mg/day for one month and then 80 mg/day thereafter) or to placebo for four months and 20 mg/day thereafter. After four months, no statistically significant differences in primary composite end points (MI, cardiac mortality, stroke or readmission of for ACS) were found between the high dose vs. low dose regimens of simvastatin (ARR = 2.3%, HR = 0.89, 95% CI: 0.76 to 1.04). Between months four and 24 however, the primary end point was reduced from 9.3% in the placebo group to 6.8% in the high dose simvastatin group (ARR = 2.5%, HR = 0.75, 95% CI: 0.60 to 0.95).

Simvastatin 20 mg vs. Atorvastatin 80 mg ● An open-label unblinded RCT, the IDEAL study (2005), compared the effects of

atorvastatin 80 mg (n = 4,439) vs. simvastatin 20 mg (n = 4,449) on major coronary events (coronary death, MI or cardiac arrest with resuscitation). After five years of follow-up, there were no statistically significant differences in the rate of major coronary events between the treatment groups (10.4% simva vs. 9.3% Atorva, p = 0.07). Among the component primary end points, only rates of nonfatal MI were shown to be significantly reduced for those receiving atorvastatin (6.0% vs. 7.2%, p = 0.02). The rate of one secondary end point, any CHD event, was also significantly reduced among patients receiving atorvastatin (23% vs. 20%, p < 0.001).

Atorvastatin 10 mg vs. Atorvastatin 80 mg An RCT by La Rosa et al. (2005), Treating to New Targets (TNT), evaluated the effects of

intensive lipid-lowering therapy among 10,001 patients with stable CAD. After a median follow-up of ~five years, patients receiving 80 mg of atorvastatin had a significantly reduced risk of major CVD events* compared with those receiving atorvastatin 10 mg (8.7% vs. 10.9%, p < 0.001, ARR = 2.2%,NNT = 45). LDL-C levels at baseline were 98 mg/dL and were reduced in both the atorva 80 mg and 10 mg groups to 77 mg/dL and 101 mg/dL, respectively.

* Major CVD events=death from CHD, nonfatal MI, resuscitation after cardiac arrest, or fatal or nonfatal stroke.



Since the 2006 update, two post hoc analyses of data from the TNT trial have been published. Both publications support the recommendations listed above. A brief synopsis of both studies is presented below: Khush et al. (2008) conducted a subgroup analysis of data from the TNT trial to evaluate the

effects of atorvastatin 80 mg vs. 10 mg on the secondary end point of CHF hospitalizations. They found that during the five-year follow-up period, 122 of the 4,995 patients (2.4%) in the 80 mg group were hospitalized with a primary diagnosis of CHF, as compared with 164 of the 5006 patients (3.3%) in the 10-mg group (HR = 0.74; 95% CI: 0.59 to 0.94; p < 0.0116). In patients with a history of CHF, the incidence of CHF hospitalization was 10.6% in the 80 mg group and 17.3% in the 10 mg group (HR = 0.59; 95% CI: 0.40 to 0.88; p = 0.008). In patients without a history of CHF, the rates of hospitalization for CHF were much lower: 1.8% in the 80 mg group and 2.0% in the 10 mg group (HR = 0.87; 95% CI: 0.64 to 1.16; p = 0.34. Thus, the absolute risk reduction in hospitalization for CHF for the 80 mg group was much greater in patients with than in those without a CHF history. Although these results suggest that people with CHF should be treated with aggressive statin therapy, it is important to note that the history of CHF was determined by the study investigators through patient interviews at the time of study enrollment. Neither systolic nor diastolic function was assessed systematically at baseline in the patients, and no follow-up studies were done to monitor potential changes in ventricular function. Because patients with advanced CHF were excluded, the results should not be extrapolated to these groups.

In a post hoc subgroup analysis of data from the TNT trial, Wenger et al. (2007) compared the effectiveness of aggressive statin therapy (atorvastatin 80 mg vs. 10 mg) on major CVD events for women and men separately. Regardless of gender, intensive treatment with atorvastatin 80 mg significantly decreased the rate of major cardiovascular events as compared with atorvastatin 10 mg. In women; the relative and absolute reductions in the rate of the primary end point for atorvastatin were 27% and 2.7% (NNT = 29 over five years), respectively. In men, the corresponding rate reductions were 21% and 2.2% (NNT = 30 over five years). The effects of atorvastatin 80 mg vs. 10 mg on the primary outcome did not differ significantly by gender. (See Figure 1 below.)



From Wenger et al., 2007 - Figure 1: Clinical Events by Gender/Treatment in TNT Trial



Conclusion: The available evidence suggests that statins are more effective than fibrates, resins, and niacin

in reducing major coronary events, CAD mortality, and total mortality when compared with placebo. The GDT agreed that the data were sufficient to recommend a statin as first-line drug therapy.

Given that all the statins appear to be efficacious for lowering LDL-C, the choice of a drug should be based on cost and evidence of benefit on direct health outcomes. Simvastatin has been shown to be clinically effective for improving direct health outcomes and since it is available as generic in the formulary, it is significantly less expensive than other statins.

As a result, simvastatin should be used as first-line therapy whenever statins are indicated. NOTE: Evidence tables for major individual RCTs (4S, CARE, LIPID, and VA-HIT) have been included in the evidence table section (Evidence Tables 23.5 to 23.8) as supplemental information. An evidence summary table (Evidence Table 23.9) summarizing results from different secondary prevention trials has also been included for reference purposes. ADDITIONAL NOTE: Among the five statins being evaluated, only simvastatin and lovastatin are currently on the SCPMG and TPMG formulary.



24. Lipid Management - Treatment Strategy*

24A Initiate statins at a dose sufficient to reduce LDL-C to < 100 mg/dL and by at least 30% to 40%. Treatment is recommended even if baseline LDL-C is < 100 mg/dL. Evidence-based: B

24B In people with established CAD, an LDL-C goal of < 70 mg/dL is optional.† Consensus-based

Rationale:

2010 Update This recommendation was not reviewed in 2010.

2008 Guideline New evidence has been added from one post hoc analysis. No changes have been made to this recommendation.

Search Strategy See Appendix B for more information on the search strategy.

Comparison of LDL-C Treatment Goals One study among patients with acute coronary syndrome supports an LDL-C goal of < 70 mg/dL, while another study suggests that an LDL-C goal of < 80 mg/dL may be appropriate for patients with stable CAD. However, based on the balance of costs/harms vs. benefits, the LDL-C goal is optional. There is one RCT (Post-CABG) that compared LDL-C treatment goals in patients with established atherosclerotic disease using different doses of lovastatin. The Post-CABG trial, which included 1,351 subjects, provided evidence that using “aggressive therapy” (40 or 80 mg/dL lovastatin and 80 g cholestyramine/day, if needed) to treat patients down to LDL-C 60 to 85 mg/dL would result in a 24% reduction in a composite end point when compared with “moderate therapy” (2.5 or 5 mg/dL lovastatin and 8 g cholestyramine/day, if needed) that treated patients down to LDL-C 130 to 140mg/dL. The composite end point in this study included cardiovascular death, all-cause death, myocardial infarction, stroke, CABG, and PTCA.


† One study among patients with acute coronary syndrome supports an LDL-C goal of < 70 mg/dL, while another

study suggests that an LDL-C goal of < 80 mg/dL may be appropriate for patients with stable CAD. However, based on the balance of costs/harms vs. benefits, the LDL-C goal is optional.



The reduction was statistically significantly during the 7.5 years of follow-up. (Relative Reduction = 24%; p = 0.001). (See Evidence Table 24.1 for details.)

Post-CABG (1997) Attained LDL-C in control group = 136mg/dL. Attained LDL-C in treatment group = 93mg/dL. Effect on coronary events: Risk Reduction = 18%; p = 0.12 Follow-up: 4.3 years Population: people with established atherosclerosis, who had undergone a bypass

surgery, and who were being treated for secondary prevention of a future CAD event Post-CABG (2000) Attained LDL-C in control group = 136mg/dL. Attained LDL-C in treatment group = 93mg/dL. Effect on coronary events: Risk Reduction = 24%; p = 0.001 Follow-up: 7.5 years Population: people with established atherosclerosis, who had undergone a bypass

surgery, and who were being treated for secondary prevention of a future CAD event

Statin Trials Several statin RCTs have demonstrated improved outcomes in patients whose LDL-C was lowered well below 100mg/dL. Two trials have lowered LDL-C to a mean of less than 70, and these trials were in ACS patients and demonstrated improved outcomes. Other trials have shown improved outcomes in a variety of patients when the LDL-C was lowered below 80 mg/dL (MIRACL, AVERT, TNT, SPARCL [See section on Noncoronary atherosclerosis for a summary of SPARCL findings]). Although the trials summarized below compared pre and post-treatment LDL-C levels, it is important to note these trials were not explicitly designed to compare one LDL-C treatment goal versus another.

Treating to New Targets (TNT 2005)

Baseline mean LDL-C = 152 mg/dL Attained LDL-C in Atorva 10mg group = 98.6 mg/dL Attained LDL-C in Atorva 80mg group = 77 mg/dL Effect on coronary events (any death, MI angina, PTCI, CABG, stroke):

Absolute Risk Reduction = 2.2%, favors Atorva 80 mg; p < 0.001 Follow-up: 5 years Population: people with established atherosclerosis and who were being treated for

secondary prevention of a future CAD event

IDEAL (2005)

Baseline mean LDL-C = 121 mg/dL Attained LDL-C in Simva 20 mg group = 99.8 mg/dL Attained LDL-C in Atorva 80 mg group = 80 mg/dL Effect on major coronary events (any CHD death, MI, cardiac resuscitation):

No significant difference between simva 20 mg and atorva 80 mg Effect on nonfatal MI: 20% Atorva 80 mg vs. 23% Simva (p = 0.02). Follow-up: five years Population: people with history of acute MI



PROVE-IT (2004)

Pretreatment mean LDL-C = 106mg/dL Attained LDL-C in control group = 95 mg/dL Attained LDL-C in treatment group = 62mg/dL Effect on coronary events (any death, MI angina, PTCI, CABG, stroke):

Relative Risk Reduction = 15%; p = 0.005 Follow-up: 18 months Population: people with established atherosclerosis and who were being treated for

secondary prevention of a future CAD event Wiviott et al. (2005) conducted a post hoc analysis of data from the PROVE-IT trial to

examine safety and clinical outcomes among patients achieving very low levels (e.g., < 60 mg/dL) of cholesterol. They limited the analysis to those in the atorvastatin 80 mg arm and excluded all those who did not achieve LDL-C < 100 mg/dL. The subjects were divided into subgroups according to achieved lipid levels at four months (> 80 to 100, > 60 to 80, > 40 to 60, and ≤ 40 mg/dL). The results suggest that there was a lower rate of clinical events and no increase in adverse events in patients who achieved very low cholesterol levels (e.g., < 60 mg/dL). This analysis may be subject to significant bias because it uses subgroups based on an achieved parameter (LDL-C). The authors acknowledge that this “raises the concern that there may be important differences in patients who achieve one LDL level compared with those who achieve another.” As a consequence, the analysis may be subject to significant confounding, even though they attempted to control covariates by multivariate analysis. The effects of either unmeasured or unidentified covariates are not always taken into account.

From Wiviott et al. (2005)



Phase Z of A To Z Trial (2004)

Pretreatment mean LDL-C = 111 mg/dL Attained LDL-C in placebo + simvastatin 20 mg/day group @ 4 months = 124 mg/dL Attained LDL-C in placebo + simvastatin 20 mg/day group @ 24 months = 81 mg/dL Attained LDL-C in simvastatin 80 mg/day group @ 4 months = 62 mg/dL Attained LDL-C in simvastatin 80 mg/day group @ 24 months = 66 mg/dL Effect on coronary events: (MI, cardiac mortality, stroke or readmission of for ACS)

After four months, no statistically significant differences in primary composite end points were found between the high dose vs. low dose regimens of simvastatin (ARR = 2.3%, HR = 0.89 95% CI: 0.76-1.04).

Between months four and 24 the primary end point was reduced from 9.3% in the simvastatin 20 mg/day group to 6.8% in the higher dose simvastatin 80 mg/day group (ARR = 2.5%, HR = 0.75 95% CI: 0.60-0.95) any death, MI angina, PTCI, CABG, stroke): Relative Risk Reduction = 15%; p = 0.005

Follow-up: 24 months Population: people with established acute coronary syndrome and who were being

treated for secondary prevention of a future CAD event.

MIRACL (2001)

Pretreatment mean LDL-C = 124mg/dL Attained LDL-C in control group = 135mg/dL Attained LDL-C in treatment group = 72mg/dL Effect on coronary events: Relative Risk Reduction = 14.9% and

Relative Risk = 0.84, 95% CI: 0.70 to 1.00, p = 0.048 Follow-up: 16 weeks Population: people seen during the early period after an acute coronary syndrome

AVERT (1999)

Pretreatment mean LDL-C ≥ 115mg/dL Attained LDL-C in control group = 119mg/dL Attained LDL-C in treatment group = 77mg/dL Effect on coronary events: Risk Reduction = 36%; p = 0.048 Follow-up: 18 months Population: people with established atherosclerosis and who were being treated for




Four additional secondary prevention statin trials (4S, CARE, LIPID, HPS) provided supplemental evidence that achieving LDL-C levels near or below 100 mg/dL is more beneficial than having patients have higher LDL-C levels. (See Evidence Table 24.1 for details.) Results from these trials provided useful information on the consequent reductions in coronary event rates in relation to the achieved LDL-C levels when statins were compared with placebo. Two RCTs (CARE and Heart Protection Study) that involved a total of 21,869 subjects

decreased the mean LDL-C to a level below 100mg/dL. The results demonstrated a consistent relationship between achieved LDL-C level and the

risk reduction of coronary events in the treatment groups. In general, the lower the attained LDL-C in the treatment group, the stronger the impact on coronary events compared with the control group. The populations, pre- and post-treatment LDL-C levels, percent reduction in coronary artery events, and follow-up times are as follows:

CARE (1996)

Pretreatment mean LDL-C = 139mg/dL Attained LDL-C in control group >~ 131 mg/dL (presented graphically) Attained LDL-C in treatment group = 95mg/dL Effect on coronary events: Risk Reduction = 24%, p = 0.003 Follow-up: five years Population: people with established atherosclerosis and who were being treated for


Heart Protection Study (2002)

Pretreatment mean LDL-C = 131mg/dL Attained LDL-C in control group = 127 mg/dL Attained LDL-C in treatment group = 92 37mg/dL Effect on coronary events: Relative Risk Reduction = 27.8% and Relative Risk

(RR) = 0.76, 95% CI: 0.70 to 0.82 Follow-up: 5.0 years Population: people with established atherosclerosis.

NOTE: HPS included some primary prevention patients (2,913 with diabetes), who might have a slightly lower risk of developing a coronary event and could have attenuated the overall results. HPS included 3,421 patients with baseline LDL-C < 100mg/dL. Percent LDL-C reduction and rate reduction of coronary events in this subgroup were essentially the same compared with the overall results. The subgroup analysis for patients who had pretreatment LDL-C < 100mg/dL is summarized below:

Rx: 16.4% C: 21.0% ARR = 4.6% RRR = 21.9% P = 0.0006



Among this subgroup that had pretreatment LDL-C < 100mg/dL, reducing the average LDL-C from 97 mg/dL (placebo group) to 65 mg/dL (simvastatin group) was safe and produced essentially the same risk reduction as that seen among those presenting with LDL-C 100mg/dL.

Results from HPS suggested that patients with baseline LDL-C < 100mg/dL would receive the same benefit as those with baseline LDL 100mg/dL. Based on the evidence from HPS, statin therapy is recommended as first-line therapy for secondary prevention even if baseline LDL-C is < 100mg/dL.

The other two statin trials (4S and LIPID) that involved a total of 13,458 subjects failed to decrease the mean LDL-C to a level < 100mg/dL. However, the pretreatment LDL-C levels in 4S and LIPID were higher compared with those in the above four trials. Besides, the percent LDL-C reductions and the rate reductions in coronary events in 4S and LIPID were comparable to those in CARE, HPS, MIRACL, and AVERT. The results from 4S and LIPID are consistent with those from the CARE, HPS,

MIRACL, and AVERT. There is a consistent relationship between achieved LDL-C level and the risk reduction of coronary events in the treatment groups. The populations, pre- and post-treatment LDL-C levels, percent reduction in coronary artery events, and follow-up times are as follows:

4S (1994)

Pretreatment mean LDL-C = 188 mg/dL Attained LDL-C in control group = 186 mg/dL Attained LDL-C in treatment group = 122 mg/dL Effect on coronary events: Risk Reduction = 34%, p < 0.001 Follow-up: 5.4 years Population: people with established atherosclerosis and who were being treated for

secondary prevention of a future CAD event.

LIPID (1998)

Pretreatment mean LDL-C = 150 mg/dL Attained LDL-C in control group ~141 mg/dL Attained LDL-C in treatment group = 113 mg/dL Effect on coronary events: Risk Reduction = 24%, p < 0.0001 Follow-up: 6.1 years Population: people with established atherosclerosis and who were being treated for

secondary prevention of a future CAD event.



Effects on Clinical Outcomes per 39 mg/dL Reductions in LDL-C: One meta-analysis (N = 90,056, and 14 RCTs*) by the Collaboration of Cholesterol Treatment Trialists (2005) examined the effects of statins on clinical outcomes per 39 mg/dL reduction in LDL-C. Although the analysis included both primary and secondary prevention studies, this analysis is presented here because about 47% of the total patients included in the analysis had prior CHD, while 53% of study participants had no prior CHD. The results showed the following:

Mean Pretreatment LDL-C = 147 mg/dL Weighted average difference in LDL-C after one year = -42 mg/dL Mean Follow-up: 4.7 years All-Cause Mortality: 8.5% (3,832 deaths /45,054 statins) vs. 9.7% (4,354/45,002

controls), (RR = 0.88, 95% CI: 0.84 to 0.91). This represents a 12% proportional reduction in all-cause mortality per 39 mg/dL in LDL-C.

CHD Mortality: 3.4% statins vs. 4.4% control (RR = 0.81, 95% CI: 0.76 to 0.85, p < 0.0001), 19% proportional reduction in CHD per 39 mg/dL reduction in LDL-C. Authors also report that this represents a 14 fewer deaths per 1,000 among participants with pre-existing CHD and four fewer deaths per 1,000 among participants without pre-existing CHD.

Regardless of starting LDL-C level, the authors found that each 39 mg/dL (1.0 mmol/L) statin-induced reduction in LDL-C was associated with a one-eighth relative reduction in all-cause mortality and a one-fifth relative reduction in major vascular events. This corresponds to a 5.5% reduction in major vascular events per 10 mg/dL reduction in LDL-C. While this was true for relative risk, it was not true for absolute risk. The absolute risk reduction (ARR) for MI or coronary death was 3.8% for LDL cholesterol > 173 mg/dL (> 4.47 mmol/L) (number needed to treat [NNT] = 28), 2.3% for LDL cholesterol 135 to 173 mg/dL (3.49 to 4.47 mmol/L) (NNT = 43), and 1.9% for LDL cholesterol < 135 mg/dL (< 3.49 mmol/L) (NNT = 53).

* Primary Prevention studies: WOSCOPS, AFCAPS/TEXCAPS, ASCOT, CARDS.

Secondary Prevention studies: 4S, CARE POST-CABG, LIPID, GISSI PREV, LIPS, HPS, PROSPER, ALLHAT-LLT, ASCOT – LLA, ALERT.



Conclusion: The available evidence suggests that an achieved LDL-C treatment goal of < 100 mg/dL is

effective in reducing rates of coronary events in patients with established atherosclerotic disease. The only study that directly compared two different LDL-C targets was Post-CABG, which supports a target LDL-C < 100 mg/dL. Most trials used fixed doses of statins and have shown that, at increasingly lower LDL-C levels, CAD event rates are lower. One study among patients with acute coronary syndrome (PROVE-IT) indirectly supports an LDL-C goal of < 70 mg/dL, while another study (TNT) suggests that an LDL-C goal of < 80 mg/dL may be appropriate for patients with stable CAD. Given the indirect nature of the evidence, the optimal LDL-C is not known with certainty. Furthermore, the cost/benefit ratio of intensifying statin therapy beyond generically available simvastatin increases exponentially. Thus, an LDL-C goal of < 100 mg/dL for patients with established CAD is recommended while an LDL-C goal of < 70 mg/dL for patients with established CAD is optional.

Because of its proven effectiveness in event reduction, safety and cost, simvastatin is the preferred first-line statin.

Furthermore, based on the % LDL-C reductions observed in available RCT data, the GDT concluded that statins should be initiated at a dose sufficient to reduce LDL-C to < 100 mg/dL and by at least 30% to 40%. Treatment is recommended even if baseline LDL-C is < 100 mg/dL.

Supplemental Information from Hayward et al. (2006) and Subsequent Discussion: In 2006, a narrative review article by Hayward et al. examined the evidence for targeting specific LDL-C thresholds and associated reductions in CVD risk. Although this publication was technically a “narrative review” and not a systematic evidence review, it is referenced in this section because it engendered significant discussion in the outside and KP medical community regarding the value and evidence basis of treating patients to specific LDL-C targets. Hayward et al. concluded that published statin trials did not explicitly examine the effects of titrating lipid therapy to specific LDL-C goals and therefore “…the main results of these trials could not be used to support or refute the benefits of titrating lipid therapy to try to achieve these LDL cholesterol targets [e.g., LDL-C < 100, < 130 or < 70, etc.]” The Hayward review also concluded that based on the available evidence, the efficacy of statin treatment may have as much to do with the statin dose and potency as it does with reaching recommended LDL-C targets. Given the lack of direct evidence for LDL-C targets, Hayward et al. calls into question whether the use of combination pharmacologic therapies, which are frequently required to reach lower LDL-C levels, are ultimately worth the added potential risk of harm and expense. Although the GDT did not explicitly use the Hayward article as the basis for its treatment strategy recommendations, the GDT noted that the conclusions reached in the Hayward review are consistent with the recommendations presented above.



Clinical Evidence, Issue 7, June 2002 (on-line version) found: “no significant difference between statins and placebo in terms of noncardiovascular mortality, cancer incidence, asymptomatic elevation of creatine kinase (> 10 times upper reference limit), or elevation of transaminases (> three times upper reference limit) during a mean of 5.4 years of treatment (OR of event, statin vs. placebo 0.93, 95% CI: 0.81 to 1.07 for noncardiovascular mortality; 0.99, 95% CI: 0.90 to 1.08 for cancer; 1.25, 95% CI: 0.83 to 1.89 for creatine kinase increase; 1.13, 95% CI: 0.95 to 1.33 for transaminase increase). There is no evidence of additional harm associated with cholesterol lowering in elderly patients, or in patients following acute myocardial infarction.”



25. Acute Management – Statin Initiation

25. In patients with acute coronary syndrome, it is strongly recommended that treatment with a high-dose, high-potency statin, such as simvastatin 40 - 80mg, be initiated as soon as possible regardless of baseline LDL-C.

Note: Risk factors for rhabdomyolysis (e.g., advanced age, frailty, multiple comorbidities, impaired renal function, potentially interacting drugs) favor the lower end of this dose range.*

Rationale:

2010 Update

Search Strategy A comprehensive search was conducted in January 2010 to identify randomized controlled trials (RCTs) relevant to this problem formulation. See Search Strategy (located in Appendix B) for more information on specific search terms RCTs were included if they compared statin therapy initiated during hospitalization for an acute coronary syndrome (ACS) event to statin therapy initiated at or after hospital discharge or no statin therapy (placebo or usual care). An ACS event was defined as unstable angina, ST-segment elevation myocardial infarction (STEMI), or non-STEMI. A total of 13 studies were identified and included. One RCT, de Lemos et al. (2004),(131) evaluated the initiation of statin therapy before hospital discharge in patients with ACS to initiation of statin therapy after hospital discharge while 11 RCTs evaluated early initiation of statin therapy to no statin therapy. In addition, one RCT, Cannon et al. (2004),(132) evaluated early initiation of two different statin therapies at different dosages in ACS patients.

Evidence Summary A total of 11 studies were identified that compared initiation of statin therapy after hospital admission for an ACS event to no statin therapy (placebo or usual care). One study, de Lemos et al. (2004),(131) evaluated the use of simvastatin (40 to 80 mg/day) immediately post-ACS event compared to the delayed use of simvastatin (20 mg/day) after one month of placebo post-ACS event. Although not directly relevant to the clinical question, the PROVE-IT study, Cannon et al. (2004),(133) was identified and included for its evaluation of the “early” initiation of pravastatin 40 mg/day compared to the “early” initiation of atorvastatin 80 mg/day during admission for an ACS event. The GRADE system was used for assessing the quality of evidence.

* For details, please refer to the link for Table 3. Lipid-Lowering Medications from the Dysplidemia Guideline:

http://cl.kp.org/pkc/national/cmi/programs/dyslipidemia/guideline/files/DyslipidemiaMgmtinAdults2008.pdf#page=8



Summary Of Evidence On Efficacy Of Statin Initiation During Admission For ACS Event

Statin initiation during admission vs. No statin

The critical outcomes for efficacy identified by the GDT were all-cause mortality, cardiovascular mortality, myocardial infarction, stroke, and coronary revascularization. Among all these outcomes, statin initiation during hospital admission for ACS showed benefit (although not statistically significant) as compared to no statin therapy over four weeks to four years follow-up. For the outcome of all-cause mortality, “early” statin initiation showed statistically significant benefit as compared to no statin therapy over four weeks to four years follow-up. For all of these outcomes except cardiovascular mortality, the quality of evidence was deemed to be moderate due to the potential risk for publication bias across these predominantly industry-sponsored and/or funded studies. For cardiovascular mortality, in addition to the risk of publication bias, there was also significant imprecision in the pooled result resulting in a downgrading of the evidence for this outcome to low.

Typically, the overall quality of evidence for all four critical outcomes would be based on the outcome with the lowest quality - which in this case would be that for cardiovascular mortality - resulting in an overall assignment of low quality evidence. However, in the final analysis, the overall quality of evidence was deemed to be moderate given that the direction of all the critical outcomes favored immediate statin initiation and that the outcomes of all-cause mortality and myocardial infarction, by themselves, would suffice to support the recommendation.

Statin initiation during admission vs. Statin initiation post-hospital discharge For the comparison of statin initiation during hospital admission for ACS versus statin initiation after hospital discharge, the A to Z trial, de Lemos et al. (2004),(131) was the only RCT identified. The overall quality of the evidence on the efficacy outcomes in the A to Z trial was low due to the imprecision in effect size estimates based on small numbers of events and the potential for publication bias as this trial was funded by Merck and all investigators have received honoraria, research grants, and/or research support from Merck. The results of the A to Z trial are consistent with the body of evidence comparing “early” statin initiation to no statin treatment post-ACS. Among the efficacy outcomes of all-cause mortality, cardiovascular mortality, myocardial infarction, stroke, and coronary revascularization, initiation of simvastatin during hospital admission for ACS showed benefit as compared to initiation of simvastatin one month post-ACS. Although the hazard ratios were not statistically significant for any of these outcomes, the benefit of “early” simvastatin use for all-cause mortality and cardiovascular mortality neared statistical significance over a follow-up time of two years.

High-dose, high-potency statin vs. Low-dose, low-potency statin Although the PROVE-IT trial, Cannon et al. (2004),(133) does not directly relate to the clinical question, it showed that atorvastatin (a high-dose, high-potency statin) initiated immediately after a diagnosis of ACS reduced CVD event rates compared to pravastatin (a low-dose, low-potency statin). This finding is consistent with other evidence related to statin dosing. A pooled analysis of statin trials strongly suggests that the clinical benefit of all statins is directly related to their LDL-lowering effect which is directly related to their dose and potency.



All the statins currently available in the US market demonstrate clinical efficacy benefit that is directly proportional to LDL reduction. Furthermore, cardiovascular disease risk reduction is correlated with LDL reduction and statin dose potency. All the statins currently available in the US market demonstrate clinical efficacy benefit that is directly proportional to LDL reduction.(134) Furthermore, cardiovascular disease risk reduction is correlated with LDL reduction and statin dose potency.

Summary of Evidence on Safety of Statin Initiation during admission for ACS event

The important safety outcomes assessed across the 13 RCTs were elevated liver enzymes, serious myopathy, and non-serious muscle problems. Elevated liver enzymes included alanine aminotransferase (ALT) or aspartate transaminase (AST) greater than three times the upper limit of normal (ULN). Serious myopathy included rhabdomyolysis (defined as creatine kinase (CK) >10,000 units/L), serious myopathy (defined as CK >10 times ULN with or without symptoms), and myopathy (defined as CK 3-10 times ULN with symptoms). Non-serious muscle problems consisted of myalgia (defined as CK <3 times ULN with symptoms).

Overall, the quality of evidence for these safety outcomes was low due to the imprecision in effect size estimates based on small numbers of events and the potential for publication bias across these predominantly industry-sponsored and/or funded studies. There was an increase in risk for elevated liver enzymes with initiation of statin therapy during admission for an ACS event as compared to no statin therapy or “delayed” initation of statin. Furthermore, the PROVE-IT study, Cannon et al. (2004),(133) indicates that the risk for elevated liver enzymes increases with statin dose intensity as 69/2099 patients (3.3%) on atorvastatin at 40 mg/day had an elevated ALT compared to 23/2064 patients (1.1%) on pravastatin at 20 mg/day. Serious myopathy events, however, were rare across all 13 studies as there was no significant increase in risk for rhabdomyolysis or myopathy with “early” initiation of statins compared to no statin therapy or “delayed” statin therapy. The PROVE-IT study(133) reported no rhabdomyolysis events in either the pravastatin or atorvastatin arm over follow-up of two years. Non-serious muscle problems were extremely rare as only one myalgia event was reported.

Evidence Synthesis There is limited direct evidence from one RCT evaluating the use of statin initiation during

hospital admission for ACS compared to statin initiation after hospital discharge. There is strong evidence of the benefit of statin therapy in preventing CVD events and

mortality in patients with CHD.(134) The overall quality of evidence was moderate due to the imprecision in effect size estimates

and potential for publication bias across these predominantly industry-sponsored and/or funded studies. Given that all critical outcomes favored immediate statin initiation after an ACS event, the overall quality of evidence was considered to be moderate, rather than low, based upon the quality of evidence for the critical outcomes of all-cause mortality and myocardial infarction.

Given the moderate quality of available evidence, further research is very likely to have an important impact on our confidence in the estimate of effect and may change the estimate.

There is evidence from one RCT that a high-dose, high-potency statin initiated immediately after diagnosis of ACS reduced CVD event rates compared to a low-potency, low-dose statin.



Although only limited evidence directly addresses whether immediate statin treatment after hospital admission (less than 14 days) is more beneficial than statin treatment after hospital discharge (up to three months) in patients following ACS, data from the “early” statin initiation (before hospital discharge) versus no statin trials as well as the A to Z trial, de Lemos et al. (2004)],(131) suggest a beneficial effect of immediate initiation of statin in patients after an acute MI, regardless of baseline LDL-C.

In addition, it is strongly recommended that a high-dose, high-potency statin, such as simvastatin 40 to 80 mg, be used. The PROVE-IT trial(133)demonstrates greater efficacy in reducing cardiovascular events of a high-dose, high-potency statin as compared to a low-dose, low-potency statin. Furthermore, meta-analyses(134, 135) have shown that all statins lower LDL, which is directly related to cardiovascular event risk reduction and dose potency. Risk factors for rhabdomyolysis (e.g., advanced age, frailty, multiple comorbidities, impaired renal function, potentially interacting drugs) favor the lower end of this dose range.*

Although the level of certainty is moderate, the net benefits of decreased risks for mortality and cardiovascular events greatly outweigh the minimal risks for harm due to elevated liver enzymes or serious myopathy in ACS patients.

* For details, please refer to the link for Table 3. Lipid-Lowering Medications from the Dysplidemia Guideline:

http://cl.kp.org/pkc/national/cmi/programs/dyslipidemia/guideline/files/DyslipidemiaMgmtinAdults2008.pdf#page=8










Note: Not all studies measured total number of MI events. Some studies measure non-fatal MIs or recurrent MIs only.



Note: Not all studies measured total number of stroke events. One study measured fatal strokes only.











estimate of effect and is likely to change the estimate. Very Low = Any estimate of effect is very uncertain. GRADE also suggests using the following scheme for assigning the “grade” or strength of evidence:




GRADE Evidence Profile Statin therapy before hospital discharge vs. No statin therapy




Statin treatment before hospital

discharge

No statin treatment

(placebo or usual care)


Mortality, All-Cause; statin before discharge vs. no statin (follow-up 1 to 47 months) 81 randomised





reporting bias3 135/4540 (3%) 171/4517 (3.8%)

RR 0.79 (0.63 to

0.99)


14 fewer)

MODERATE

CRITICAL

Mortality, Cardiovascular; statin before discharge vs. no statin (follow-up 13 weeks to 2 years) 34 randomised




serious6 reporting bias3 10/386 (2.6%) 13/381 (3.4%)

RR 0.73 (0.32 to

1.69)


25 more)

LOW

CRITICAL

Myocardial Infarction; statin before discharge vs. no statin (follow-up 1 to 47 months) 107 randomised





reporting bias3 213/4623 (4.6%) 228/4599 (5%)

RR 0.94 (0.78 to

1.12)


7 more)

MODERATE

CRITICAL

Coronary Revascularization; statin before discharge vs. no statin (follow-up 13 weeks to 47 months) 89 randomised





reporting bias3 498/2877 (17.3%)

531/2864 (18.5%)

RR 0.93 (0.84 to

1.04)


9 more)

MODERATE

CRITICAL

Stroke; statin before discharge vs. no statin (follow-up 4 to 47 months) 411 randomised





RR 0.62 (0.33 to

1.16)


2 more)

LOW

CRITICAL

Elevated Liver Enzymes; statin before discharge vs. no statin (follow-up 4 to 47 months) 314 randomised




serious16 reporting bias3 48/2422 (2%) 12/2418 (0.5%)

Not estimable

5 greater per 1000

LOW

IMPORTANT17

Myopathy, Serious; statin before discharge vs. no statin (follow-up 1 to 47 months) 418 randomised




serious16 reporting bias3

0/4132 (0%) 3/4116 (0.1%) Not

estimable

1 fewer per 1000 (from 1

fewer to 1 fewer)

LOW

IMPORTANT20

Muscle Problems, Non-serious; statin before discharge vs. no statin (follow-up 16 weeks to 12 months) 221 randomised




serious16 reporting bias23 1/1578 (0.1%) 0/1589 (0%)

Not estimable

Not estimable LOW

IMPORTANT24



Statin therapy before hospital discharge vs. Statin therapy after hospital discharge


No of studies Design Limitations Inconsistency Indirectness Imprecision Other

considerations Statin treatment before hospital

discharge

Statin treatment after hospital

discharge Relative (95% CI) Absolute

Quality Importance

Mortality, All-Cause; statin before discharge vs. statin after discharge (follow-up median 1.98 years) 125 randomised

trials26 no serious limitations




HR 0.79 (0.61 to

1.02)


1 more)

LOW

CRITICAL

Mortality, Cardiovascular; statin before discharge vs. statin after discharge (follow-up median 1.98 years) 125 randomised





HR 0.75 (0.57 to

1.00)


0 more)

LOW

CRITICAL

Myocardial Infarction; statin before discharge vs. statin after discharge (follow-up median 1.98 years) 125 randomised





reporting bias28 151/2265 (6.7%) 155/2232 (6.9%)

HR 0.96 (0.77 to

1.21)


14 more)

MODERATE

CRITICAL

Coronary Revascularization; statin before discharge vs. statin after discharge (follow-up median 1.98 years) 125 randomised





HR 0.93 (0.73 to

1.20)


11 more)

LOW

CRITICAL30

Stroke; statin before discharge vs. statin after discharge (follow-up median 1.98 years) 125 randomised





HR 0.79 (0.48 to

1.30)


more)

LOW

CRITICAL

Elevated Liver Enzymes; statin before discharge vs. statin after discharge (follow-up median 1.98 years) 125 randomised





Not estimable

4 greater per 1000 LOW

IMPORTANT17

Myopathy, Serious; statin before discharge vs. statin after discharge (follow-up median 1.98 years) 125 randomised




serious reporting bias28 9/2265 (0.4%)33 1/2232 (0.04%)

Not estimable

0 greater per 1000 LOW

IMPORTANT20



1 Arntz 2000; Kayikcioglu 2002; Kesteloot 1997; Liem 2002; Okazaki 2004; Schwartz 2001; Serruys 2002; Thompson 2004. 2 Overall, most studies did not describe how the allocation sequence was generated or how allocation was concealed. Arntz 2000: This study had a high drop-out rate (approx. 20% per group). There was no description of drop-outs or how missingness was addressed. There was also no description of how the mortality outcome was assessed, thus it is possible that there was differential surveillance of patients. Furthermore, there was a high risk of selection bias as 14% (9 patients) in the usual care group withdrew because they were selected to the usual care group. Kayikcioglu 2002: This study broke randomization by applying inclusion criteria after randomization and 1 month of treatment. Serruys 2002: Non-compliance with study medication was >35% in each group. Cross-over was disproportionate so that 20% of treatment group took <80% of medications; however, would probably result in bias towards reduced effect of treatment and may partially account for non-statistically significant effect measure. Both Arntz 2000 and Kayikcioglu 2002 are small studies are thus have little weight and impact on the estimate of effect, so these studies are not likely to alter the confidence in the estimate of effect. 3 Most studies were sponsored and/or funded by industry. 4 Liem 2002; Den Hartog 2001; Arntz 2000. 5 Across the three studies, methods of allocation sequence and concealment were not adequately described. Arntz 2000: There was a high drop-out rate (approx. 20% per group) in this study. Drop-outs were not described and missingness was not addressed. There was a high risk of selection bias as 14% (n=9) of usual care group withdrew after learning they were assigned to the usual care group. Den Hartog 2001: Incomplete description of cardiovascular events (called serious adverse events in the study). Narrative reports that there were 68 events, but only 34 were described. Overall, given the small sample sizes and small number of events in these two studies, it is not likely that the results from these studies would alter the confidence in the estimate of effect. Furthermore, the evidence has already been downgraded for imprecision and publication bias. 6 The 95% confidence interval around the pooled relative risk estimate of effect includes both negligible effect and appreciable benefit as well as appreciable harm. The number of events is very small (23), indicating imprecision. 7 Colivicchi 2002; Den Hartog 2001; Kayikcioglu 2002; Kesteloot 1997; Liem 2002; Schwartz 2001; Serruys 2002. 8 Overall, most studies did not describe how the allocation sequence was generated or how allocation was concealed. Den Hartog 2001: Incomplete description of cardiovascular events (called serious adverse events in the study). Narrative reports that there were 68 events, but only 34 were described. Kayikcioglu 2002: This study broke randomization by applying inclusion criteria after randomization and 1 month of treatment. Kesteloot 1997: This study did not use intent-to-treat analysis, but instead used the study completors as the denominator in evaluating outcomes. Serruys 2002: Non-compliance with study medication was >35% in each group. Cross-over was disproportionate so that 20% of treatment group took <80% of medications; however, would probably result in bias towards reduced effect of treatment and may partially account for non-statistically significant effect measure. Den Hartog 2001, Kayikcioglu 2002 and Kesteloot 1997 were all small studies with small numbers of events, so these studies have less weight and thus are not likely to alter the confidence in the estimate of effect. 9 Arntz 2000; Den Hartog 2001; Kayikcioglu 2002; Kesteloot 1997; Liem 2002; Okazaki 2004; Schwartz 2001; Serruys 2002. 10 Overall, most studies did not describe how the allocation sequence was generated or how allocation was concealed. Arntz 2000: This study was not blinded, and it is possible that knowledge of treatment group could have influenced the decision for revascularization. This study had a high drop-out rate (approx. 20% per group). There was no description of drop-outs or how missingness was addressed. There was also no description of how the mortality outcome was assessed, thus it is possible that there was differential surveillance of patients. Furthermore, there was a high risk of selection bias as 14% (9 patients) in the usual care group withdrew because they were selected to the usual care group. Den Hartog 2001: Incomplete description of cardiovascular events (called serious adverse events in the study). Narrative reports that there were 68 events, but only 34 were described. Kayikcioglu 2002: This study broke randomization by applying inclusion criteria after randomization and 1 month of treatment. Kesteloot 1997: This study did not use intent-to-treat analysis, but instead used the study completors as the denominator in evaluating outcomes. Serruys 2002: Non-compliance with study medication was >35% in each group. Cross-over was disproportionate so that 20% of treatment group took <80% of medications; however, would probably result in bias towards reduced effect of treatment and may partially account for non-statistically significant effect measure. Okazaki 2004: This was an open-label study. Knowledge of treatment group may have affected the decision for target vessel revascularization. Although there are some risks of bias in these studies, all of these studies are small and accounted for few events and thus are not likely to alter the confidence in the estimate of effect. 11 Arntz 2000; Liem 2002; Schwartz 2001. 12 Arntz 2000: This study had a high drop-out rate (approx. 20% per group). There was no description of drop-outs or how missingness was addressed. There was also no description of how the mortality outcome was assessed, thus it is possible that there was differential surveillance of patients. Furthermore, there was a high risk of selection bias as 14% (9 patients) in the usual care group withdrew because they were selected to the usual care group. However, given that this study is small and has a very small number of events, this study is not likely to alter the confidence in the estimate of effect. 13 The 95% confidence interval around the pooled estimate of effect includes both negligible effect and appreciable benefit. The number of events is very small (41), indicating imprecision. 14 Kayikcioglu 2002; Schwartz 2001; Serruys 2002. 15 Kayikcioglu 2002: Methods of randomization, allocation concealment, and blinding were unclear as no details were provided.This study broke randomization by applying inclusion criteria after randomization and 1 month of treatment. Elevated liver enzymes were only reported for the treatment group so 'zero' is assumed for the control group. Serruys 2002: Non-compliance with study medication was >35% in each group. Cross-over was disproportionate so that 20% of treatment group took <80% of medications; however, would probably result in bias towards reduced effect of



treatment and may partially account for non-statistically significant effect measure. Given that the risks for bias in Serruys 2002 would probably reduce the demonstrated effect and that Kayikcioglu 2002 was such a small study, the results from these studies do not reflect serious limitations. 16 Given the small number of events, imprecision is highly likely. 17 Elevated Liver Enzymes includes alanine aminotransferase (ALT) >3x ULN or aspartate transaminase (AST) >3x ULN. 18 Kayikcioglu 2002; Schwartz 2001; Serruys 2002; Thompson 2004. 19 Kayikcioglu 2002: Methods of randomization, allocation concealment, and blinding were unclear as no details were provided.This study broke randomization by applying inclusion criteria after randomization and 1 month of treatment. Serruys 2002: Non-compliance with study medication was >35% in each group. Cross-over was disproportionate so that 20% of treatment group took <80% of medications; however, would probably result in bias towards reduced effect of treatment and may partially account for non-statistically significant effect measure. Overall, the risks of bias in these studies do not reflect serious limitations, especially given the small sample size of Kayikcioglu 2002 and that the bias of Serruys 2002 is likely to reduce the demonstrated effect. 20 Serious Myopathy includes rhabdomyolysis (CK >10,000 units/L), serious myopathy (CK >10x ULN with or without symptoms), and myopathy (CK 3-10x ULN with symptoms). 21 Colivicchi 2002; Schwartz 2001. 22 Colivicchi 2002: Patients' knowledge of treatment groups may have influenced patient perceptions of muscle problems. Muscle problems were reported in the treatment group only, so "zero" is assumed for control group. However, this study was very small and likely does not alter the confidence of the estimate of effect. 23 Schwartz 2001 was supported and funded by Pfizer. Colivicchi 2002 did not report funding or sponsorship. 24 Non-serious Muscle Problems included myalgia (CK <3x ULN with symptoms). 25 de Lemos 2004. 26 simvastatin 40 mg/day before discharge for first 30 days, then 80 mg/day thereafter vs. placebo for first 4 months, then simvastatin 20 mg/day thereafter. 27 The 95% confidence interval around the point estimate included negligible effect and appreciable benefit of using early, intensive statin therapy versus delayed moderate statin therapy. The result was not statistically significant. 28 This trial was funded by Merck and all investigators have received honoraria, research grants, and/or research support from Merck. 29 The 95% confidence interval around the point estimate included negligible effect and appreciable benefit of using early, intensive statin therapy versus delayed moderate statin therapy. The result was nearly statistically significant with a p-value = 0.5. 30 Coronary revascularization outcome was reported as due to documented ischemia. 31 The 95% confidence interval around the point estimate included negligible effect and appreciable benefit and harm with the use of early, intensive statin therapy versus delayed moderate statin therapy. The result was not statistically significant. 32 The number of events is very small, indicating likelihood for imprecision. 33 All cases of myopathy occurred in patients while taking the 80 mg/d dose. 3 of 9 patients with myopathy had CK levels >10,000 units/L and met the definition for rhabomyolysis.



Appendix A: Criteria for Grading the Evidence





Appendix B: Supporting Documentation

Problem Formulation 1

Clinical Question(s) Does treating major depressive disorder (MDD) in CAD patients improve cardiovascular outcomes?

Population Adult patients with a history of ischemic heart disease, MI, CABG, and/or PCI, or documented CAD (by angiography or noninvasive testing)

Health Intervention(s)

Antidepressant medication Psychotherapy Combinations of antidepressant medication and psychotherapy

Most Important Health Outcomes

Mortality due to cardiac causes All-cause mortality Hospitalization, including nonfatal MI, nonfatal stroke, transient ischemic attack (TIA), unstable angina, and revascularization procedures



Search Strategy 1

Selected evidence was restricted to systematic reviews, meta-analyses, and RCTs in populations of adults with CAD.

Database Search Terms

Article Type & Other Limits

Search Date

No. Included/Total

Retrieved *

PubMed coronary artery disease AND major depressive disorder: ("coronary artery disease"[MeSH Terms] OR coronary artery disease[Text Word]) AND ("depressive disorder, major"[MeSH Terms] OR major depressive disorder[Text Word])

Human, English, All Adult: 19+ years, Clinical Trials, RCTs, meta-analysis, only items with abstracts

1966 -

Dec 2007

1/4

PubMed coronary artery disease AND unipolar depression: ("coronary artery disease"[MeSH Terms] OR coronary artery disease[Text Word]) AND (("depressive disorder"[TIAB] NOT Medline[SB]) OR "depressive disorder"[MeSH Terms] OR unipolar depression[Text Word])


1966 -

Dec 2007

0/10

PubMed coronary artery disease AND clinical depression: ("coronary artery disease"[MeSH Terms] OR coronary artery disease[Text Word]) AND (("depressive disorder"[TIAB] NOT Medline[SB]) OR "depressive disorder"[MeSH Terms] OR clinical depression[Text Word])

Human, English, All Adult: 19+ years, RCTs, meta-analysis, only items with abstracts

1966 -

Dec 2007

1/10

* Note: “No. Included” refers to studies that are relevant to the problem formulation and, therefore, are included in

this analysis of the evidence. “Total Retrieved” refers to the number of studies retrieved in the search, regardless of relevance. Because individual studies can be captured in multiple databases, they may be counted more than once in the number included.





Search Date

No. Included/Total

Retrieved *

PubMed coronary artery disease AND antidepressant drugs: ("coronary artery disease"[MeSH Terms] OR coronary artery disease[Text Word]) AND (("antidepressive agents"[TIAB] NOT Medline[SB]) OR "antidepressive agents"[MeSH Terms] OR "antidepressive agents"[Pharmacological Action] OR antidepressant drugs[Text Word])


1966 -

Dec 2007

0/7

PubMed coronary artery disease AND psychotherapy AND depression: ("coronary artery disease"[MeSH Terms] OR coronary artery disease[Text Word]) AND ("psychotherapy"[MeSH Terms] OR psychotherapy[Text Word]) AND (("depressive disorder"[TIAB] NOT Medline[SB]) OR "depressive disorder"[MeSH Terms] OR "depression"[MeSH Terms] OR depression[Text Word])


1966 -

Dec 2007

0/7

PubMed coronary artery disease AND cognitive behavioral therapy AND depression: ("coronary artery disease"[MeSH Terms] OR coronary artery disease[Text Word]) AND (("cognitive therapy"[TIAB] NOT Medline[SB]) OR "cognitive therapy" [MeSH Terms] OR cognitive behavioral therapy[Text Word]) AND (("depressive disorder"[TIAB] NOT Medline[SB]) OR "depressive disorder"[MeSH Terms] OR "depression"[MeSH Terms] OR depression[Text Word]


1966 -

Dec 2007

0/0





Search Date

No. Included/Total

Retrieved *

PubMed coronary artery disease AND depression treatment NOT ST-segment depression: ("coronary artery disease"[MeSH Terms] OR coronary artery disease[Text Word]) AND ((("depressive disorder"[TIAB] NOT Medline[SB]) OR "depressive disorder"[MeSH Terms] OR "depression"[MeSH Terms] OR depression[Text Word]) AND ("therapy"[Subheading] OR ("therapeutics"[TIAB] NOT Medline[SB]) OR "therapeutics"[MeSH Terms] OR treatment[Text Word])) NOT (ST-segment[All Fields] AND (("depressive disorder"[TIAB] NOT Medline[SB]) OR "depressive disorder"[MeSH Terms] OR "depression"[MeSH Terms] OR depression[Text Word]))


1966 -

Dec 2007

1/99

PubMed myocardial infarction AND major depressive disorder: ("myocardial infarction"[MeSH Terms] OR Myocardial infarction[Text Word]) AND ("depressive disorder, major"[MeSH Terms] OR major depressive disorder[Text Word])


1966 -

Dec 2007

1/8

PubMed acute coronary syndromes AND major depressive disorder: acute[All Fields] AND (("cardiovascular system"[TIAB] NOT Medline[SB]) OR "cardiovascular system"[MeSH Terms] OR cardiovascular[Text Word]) AND (("syndrome"[TIAB] NOT Medline[SB]) OR "syndrome"[MeSH Terms] OR syndromes[Text Word])) AND ("depressive disorder,


1966 -

Dec 2007

0/2





Search Date

No. Included/Total

Retrieved *

major"[MeSH Terms] OR major depressive disorder[Text Word])

PubMed myocardial Infarction AND depression disorder treatment: ("myocardial infarction"[MeSH Terms] OR myocardial infarction[Text Word]) AND ((("depressive disorder"[TIAB] NOT Medline[SB]) OR "depressive disorder"[MeSH Terms] OR "depression"[MeSH Terms] OR depression[Text Word]) AND (("disease"[TIAB] NOT Medline[SB]) OR "disease"[MeSH Terms] OR disorder[Text Word]) AND ("therapy"[Subheading] OR ("therapeutics"[TIAB] NOT Medline[SB]) OR "therapeutics"[MeSH Terms] OR treatment[Text Word]))


1966 -

Dec 2007

1/46

PubMed acute coronary syndromes AND depression disorder treatment: (("acute coronary syndrome"[TIAB] NOT Medline[SB]) OR "acute coronary syndrome"[MeSH Terms] OR acute coronary syndromes[Text Word]) AND ((("depressive disorder"[TIAB] NOT Medline[SB]) OR "depressive disorder"[MeSH Terms] OR "depression"[MeSH Terms] OR depression[Text Word]) AND (("disease"[TIAB] NOT Medline[SB]) OR "disease"[MeSH Terms] OR disorder[Text Word]) AND ("therapy"[Subheading] OR ("therapeutics"[TIAB] NOT Medline[SB]) OR "therapeutics"[MeSH Terms] OR treatment[Text Word]))


1966 -

Dec 2007

1/19





Search Date

No. Included/Total

Retrieved *

PubMed ischemic heart disease AND depression disorder treatment: (ischemic heart disease[Text Word] OR ("myocardial ischemia"[TIAB] NOT Medline[SB]) OR "myocardial ischemia"[MeSH Terms] OR ischemic heart disease[Text Word]) AND ((("depressive disorder"[TIAB] NOT Medline[SB]) OR "depressive disorder"[MeSH Terms] OR "depression"[MeSH Terms] OR depression[Text Word]) AND (("disease"[TIAB] NOT Medline[SB]) OR "disease"[MeSH Terms] OR disorder[Text Word]) AND ("therapy"[Subheading] OR ("therapeutics"[TIAB] NOT Medline[SB]) OR "therapeutics"[MeSH Terms] OR treatment[Text Word]))


1966 -

Dec 2007

1/65



Evidence Table 1

Evidence Table 1.1: Randomized Controlled Trial on Treatment of Depression in Patients with CAD Death or Nonfatal

MI All-cause Mortality

Cardiovascular Mortality

BDI (Depressed Pts)

HAM-D-17 (Depressed Pts)

ESSI (LPSS Pts)

PSSS (LPSS Pts)

Name N Age (mean/S

D)

Female (%)

Event (%)

HR (95% CI)

Event (%)

HR (95% CI)

Event (%)

HR (95% CI)

Baseline 6 months (Δmean/SD

)

Baseline 6 months (Δmean/SD)

Baseline 6 months (Δmean/SD)

Baseline

6 months (Δmean/S

D)

Study Quality†

and Biases*

Berkman (2003) ENRICHD

UC: 1243 INT: 1238

6112.5 6112.6

44 43

24.1 24.2

1.01 (0.86,1.18)

13.8 13.6

0.98 (0.79,1.21)

9.3 7.8

0.83 (0.64,1.10)

18.07.6 17.78.1

-5.88.9 a -8.69.2 a

17.86.4 17.76.4

-8.47.7 a -10.17.8a

19.24.2 19.24.4

3.46.0 a 5.15.9 a

54.414.2 53.414.1

4.514.9 a 9.014.9 a

N

BDI (II) = Beck Depression Inventory (II), ESSI = ENRICHD Social Support Instrument, HAM-D-17 = 17-item Hamilton Rating Scale for Depression, INT = Intervention PSSS – Perceived Social Support Scale, UC = Usual Care * Biases: N: none; 1: sample selection bias; 2: detection bias (e.g., measurement error, power); 3: study procedure biases (e.g., blinding, adherence to reference standard) † Study quality measured by Jadad Scoring System (1 to 5 = low to high). a p < 0.001 versus baseline




Clinical Question(s) Should individuals be screened for CAD? If yes, who should be screened, with what test, and at what frequency?

Population Asymptomatic adults

Health Intervention(s)

Exercise stress test Coronary artery calcium scoring CT angiography


Mortality due to cardiac causes All-cause mortality Hospitalization, including nonfatal MI, nonfatal stroke,

transient ischemic attack (TIA), unstable angina, and revascularization procedures



Search Strategy 2

Selected evidence was restricted to the period since the updating of the USPSTF guidelines for screening for coronary artery disease.

Database: Search Terms:

Article Type and Other

Limits: Search Date

No. Included/ Total

Retrieved*

PubMed ((("coronary disease"[MeSH Terms] OR coronary disease[Text Word]) AND asymptomatic[All Fields]) OR (("myocardial infarction"[MeSH Terms] OR myocardial infarction[Text Word]) AND silent[All Fields])) AND ("electrocardiography"[MeSH Terms] OR electrocardiography[Text Word]) OR ("exercise test"[MeSH Terms] OR exercise test[Text Word]) OR ("x-ray computed tomography"[Text Word] OR "tomography, x-ray computed"[MeSH Terms] OR Tomography, X-Ray Computed[Text Word]) OR ("echocardiography"[MeSH Terms] OR echocardiography[Text Word]) AND ("diagnosis"[MeSH Terms] OR diagnosis[Text Word] OR ("prognosis"[MeSH Terms] OR prognosis[Text Word])]

Humans, Clinical Trial, Randomized Controlled Trial, Meta-Analysis, English, All Adult

6/01/2002 to

2/7/2008

3/77

* Note: “No. Included” refers to studies that are relevant to the problem formulation and, therefore, are included in this analysis of the evidence. “Total Retrieved” refers to the number of studies retrieved in the search, regardless of relevance. Because individual studies can be captured in multiple databases, they may be counted more than once in the number included.



Evidence Tables 2

Evidence Table 2.1: Evidence from Prospective Cohort Studies of Coronary Artery Calcium Scoring to Predict CAD

Name N Age %

Female

Death, MI, or Revascularization after 37 mo (12)

% High Cholesterol

% Smoker

CAC score Se Sp FP FN PPV NPV Biases*

Kondos, 2003

5635 51.0 26 53 39 48 >0 0.91 0.32 0.68 0.09 0.01 1.00 N

Comments: High risk was defined as any detectable CAC. 58 of the 5635 subjects (1.03%) met the endpoint definition during the study period. Gold standard was long-term follow-up for death, MI, or revascularization.

Name N Age % Female

CHD Death or Nonfatal MI after 75.9 mo (18.5) % Smoker % HTN

CAC score Se Sp FP FN PPV NPV Biases*

Greenland, 2004

1029 65.7 10 84 17.8 41.4 301 0.40 0.80 0.20 0.60 0.15 0.94 N

Comments: High risk was defined as CAC score 301. 34 of the 1380 subjects (2.46%) met the endpoint definition during the study period. Gold standard was long-term follow-up for CHD death or nonfatal MI.

Name N Age %

female CAD after 3.5 years (1.4)

% High Cholesterol %HTN

Upper Tertile CAC

Score Se Sp FP FN PPV NPV Biases* LaMonte, 2006

10,746 62.1 0 62 29.2% 19.5 250 0.55 0.87 0.13 0.45 0.03 1.00 N

Comments: High risk was defined as CAC score 250. 34 of the 1380 subjects (0.32%) met the endpoint definition during the study period. Gold standard was long-term follow-up for confirmed CAD

FP = False Positive, FN = False Negative, HTN = Hypertension, NPV = Negative Predictive Value, NR = Not Reported, PPV = Positive Predictive Value, SE = Sensitivity, Sp = Specificity * Biases: N: None; 1: sample selection bias; 2: detection bias (e.g., measurement error, power); 3: study procedure biases (e.g., blinding, adherence to reference standard)




Clinical Question: Is ACE inhibitor therapy recommended for patients with CAD with or without LVSD?

Population: Adults with the following characteristics: With or without LVSD A history of ischemic heart disease, MI, CABG and/or PCI, or

documented CAD (by angiography or noninvasive testing) No contraindications to ACE Inhibitor therapy

Health Intervention:

ACE Inhibitor therapy


Associated with the Intervention:





Search Strategy 3


Database: Search Terms: Article Type and

Other Limits: Search Date

No. Included/ Total

Retrieved

Cochrane Systemic Reviews

angiotensin converting enzyme inhibitor

Reviews 2006 -

2008

0/5


angiotensin converting enzyme inhibitor + coronary artery disease

Reviews 2006 -

2008

0/0


angiotensin converting enzyme inhibitor + coronary artery disease + left ventricular systolic dysfunction

Reviews 2006 -

2008

0/0

PubMed ("coronary artery disease"[MeSH Terms] OR coronary artery disease[Text Word]) AND (("peptidyl-dipeptidase a"[TIAB] NOT Medline[SB]) OR "peptidyl-dipeptidase a"[MeSH Terms] OR angiotensin converting enzyme[Text Word]) AND (left[All Fields] AND (("heart ventricles"[TIAB] NOT Medline[SB]) OR "heart ventricles"[MeSH Terms] OR ventricular[Text Word]) AND (("systole"[TIAB] NOT Medline[SB]) OR "systole"[MeSH Terms] OR systolic[Text Word]) AND ("physiopathology"[Subheading] OR dysfunction[Text Word]))

Human, English, All Adult: 19+ years, Clinical Trials, RCTs, meta-analysis, only items with

abstracts

1/01/06 -

1/02/08

2/3

PubMed ("coronary artery disease"[MeSH Terms] OR coronary artery disease[Text Word]) AND (("peptidyl-dipeptidase a"[TIAB] NOT Medline[SB]) OR "peptidyl-dipeptidase a"[MeSH Terms] OR angiotensin converting enzyme[Text Word])

Human, English, All Adult: 19+ years, RCTs,

meta-analysis, only items with

abstracts

01/01/06 -

01/02/08

2/30





No. Included/ Total

Retrieved

PubMed ("coronary artery disease"[MeSH Terms] OR coronary artery disease[Text Word]) AND (left[All Fields] AND (("heart ventricles"[TIAB] NOT Medline[SB]) OR "heart ventricles"[MeSH Terms] OR ventricular[Text Word]) AND (("systole"[TIAB] NOT Medline[SB]) OR "systole"[MeSH Terms] OR systolic[Text Word]) AND ("physiopathology"[Subheading] OR dysfunction[Text Word]))



abstracts

01/01/06 -

01/02/08

2/28

PubMed ("peptidyl-dipeptidase a"[TIAB] NOT Medline[SB]) OR "peptidyl-dipeptidase a"[MeSH Terms] OR angiotensin converting enzyme[Text Word]) AND (left[All Fields] AND (("heart ventricles"[TIAB] NOT Medline[SB]) OR "heart ventricles"[MeSH Terms] OR ventricular[Text Word]) AND (("systole"[TIAB] NOT Medline[SB]) OR "systole"[MeSH Terms] OR systolic[Text Word]) AND ("physiopathology"[Subheading] OR dysfunction[Text Word]))



abstracts

01/01/06 -

01/02/08

2/31

Note: The literature search for the 2006 update was conducted by Clin-eguide and is documented in the 2006 CAD Guideline.




Clinical Question: Is ARB therapy recommended for patients with CAD:

1. With LVSD?

2. Without LVSD?

Population: Adult Patients with the following characteristics: A history of ischemic heart disease, MI, CABG and/or PCI,

or documented CAD (by angiography or noninvasive testing) No contraindications to ARB therapy


Angiotensin II Receptor Blocker (ARB) therapy







Search Strategy 4




No. Included/ Total

Retrieved


Angiotensin receptor blocker Reviews 2006 -

2008

0/2


Angiotensin receptor blocker + coronary artery disease

Reviews 2006 -

2008

0/0


Angiotensin receptor blocker + coronary artery disease + left ventricular systolic dysfunction

Reviews 2006 -

2008

0/0

PubMed (("angiotensin receptors"[Text Word] OR "receptors, angiotensin"[MeSH Terms] OR angiotensin receptor[Text Word]) AND blocker[All Fields] AND ("therapy"[Subheading] OR ("therapeutics"[TIAB] NOT Medline[SB]) OR "therapeutics"[MeSH Terms] OR therapy[Text Word])) AND ("coronary disease"[MeSH Terms] OR coronary disease[Text Word])


01/01/06 -

01/02/08

0/7

PubMed (("angiotensin receptors"[Text Word] OR "receptors, angiotensin"[MeSH Terms] OR angiotensin receptor[Text Word]) AND blocker[All Fields]) AND ("coronary artery disease"[MeSH Terms] OR coronary artery disease[Text Word])


01/01/06 -

01/03/08

0/5

PubMed (ARB[All Fields] AND ("coronary artery disease"[MeSH Terms] OR coronary artery disease[Text Word]))


01/01/06 -

01/03/08

0/5





No. Included/ Total

Retrieved

PubMed (("angiotensin receptors"[Text Word] OR "receptors, angiotensin"[MeSH Terms] OR angiotensin receptor[Text Word]) AND blocker[All Fields]) AND (left[All Fields] AND (("heart ventricles"[TIAB] NOT Medline[SB]) OR "heart ventricles"[MeSH Terms] OR ventricular[Text Word]) AND (("systole"[TIAB] NOT Medline[SB]) OR "systole"[MeSH Terms] OR systolic[Text Word]) AND ("disease"[MeSH Terms] OR disease[Text Word]))


01/01/06 -

01/03/08

0/1

PubMed (("angiotensin receptors"[Text Word] OR "receptors, angiotensin"[MeSH Terms] OR angiotensin receptor[Text Word]) AND blocker[All Fields]) AND ("coronary artery disease"[MeSH Terms] OR coronary artery disease[Text Word]) AND (left[All Fields] AND (("heart ventricles"[TIAB] NOT Medline[SB]) OR "heart ventricles"[MeSH Terms] OR ventricular[Text Word]) AND (("systole"[TIAB] NOT Medline[SB]) OR "systole"[MeSH Terms] OR systolic[Text Word]) AND ("physiopathology"[Subheading] OR dysfunction[Text Word]))


01/01/06 -

01/03/08

0/0





No. Included/ Total

Retrieved

PubMed ("candesartan"[Substance Name] OR CANDESARTAN[Text Word]) OR ("eprosartan"[Substance Name] OR EPROSARTAN[Text Word]) OR ("irbesartan"[Substance Name] OR IRBESARTAN[Text Word]) OR ("losartan"[MeSH Terms] OR LOSARTAN[Text Word]) OR ("olmesartan"[Substance Name] OR OLMESARTAN[Text Word]) OR ("telmisartan"[Substance Name] OR TELMISARTAN[Text Word]) OR ("valsartan"[Substance Name] OR VALSARTAN[Text Word]) AND ("coronary artery disease"[MeSH Terms] OR coronary artery disease[Text Word]) OR ("coronary disease"[MeSH Terms] OR coronary disease[Text Word])

Human, English, All Adult: 19+ years, RCTs, only items with abstracts

01/01/06 -

01/03/08

0/8




Evidence Tables 4

Evidence Table 4.1: Meta-analyses on ACE Treatment of CAD Patients without LVSD

Name Study Population

Treatment Group size and Drug Results Conclusions Al-Mallah (2006) # studies found: 894 # studies included: 6 Random-effect model meta-analyses and quantification between-studies heterogeneity with I2

Randomized placebo-controlled trials of ACEI in pts w/CAD, w/PLVSF Outcome measures: cardiovascular mortality, nonfatal MI, all-cause mortality, revascularization rates Mean follow-up: 4.4 years ACEI: 16,772 pts Placebo: 16,728 pts Included trials: HOPE (2000), EUROPA (2003), PEACE (2004), QUIET (2001), PART-2 (2000), CAMELOT (2004)

ACEI therapy was associated with a decrease in cardiovascular mortality (RR 0.83, 95%CI 0.72-0.96, p=0.01), nonfatal MI (RR 0.84, 95%CI 0.75-0.94, p=0.003), all-cause mortality (RR 0.87, 95%CI 0.81-0.94, p=0.0003), and coronary revascularization rates (RR 0.93, 95%CI 0.87-1.00, p=0.04). Treatment of 100 patients for an average duration of 4.4 years prevents one death, or one nonfatal MI, or one cardiovascular death or one coronary revascularization procedure. The test for heterogeneity showed no difference in effect among studies as evidenced by I2 estimates for different outcomes.

There was a modest favorable effect of ACEIs on the outcomes of patients with CAD and PLVSF.



Table 4.2:


Treatment Group size and Drug Results Conclusions Danchin (2007) # studies found: 1142 # studies included: 7 Odds ratios were used as parameters of efficacy, and were combined using inverse variance-weighted averages of their logarithmic in fixed-effects models. Between-study heterogeneity was analyzed by a standard chi-2 test (Cochran).

Randomized placebo-controlled trials of ACEI in pts w/stable CAD, w/o LVSD Primary Outcome measures: cardiovascular mortality, all-cause mortality, MI Secondary Outcome measures: Stroke, cardiac arrest, myocardial revascularization, hospitalization, onset of diabetes mellitus Mean follow-up: 4.4 years ACEI: 17,001 pts Placebo: 16, 959 pts Included trials: HOPE (2000), PART-2 (2000), SCAT (2000), QUIET (2001), EUROPA (2003), PEACE (2004), CAMELOT (2004)

Tx w/ACEI decreased overall mortality (odds ratio 0.86, 95%CI 0.79-0.93, p<0.001), cardiovascular mortality (odds ratio 0.81, 95%CI 0.73-0.90, p<0.001), and MI (odds ratio 0.82, 95%CI 0.75-0.89, p<0.001) In addition ACEIs reduced stroke (0.77, 95%CI 0.66-0.88, p<0.001), myocardial revascularization (8%, p<0.01), and hospitalization (23%, p<0.001).

In this meta-analysis of CAD pts w/o HF or LVSD, ACEI resulted in a significant reduction in all-cause mortality, cardiovascular mortality, MI, stroke, hospitalization, and myocardial revascularization.

ACEI = Angiotensin-converting enzyme inhibitor CAMELOT = Effect of Antihypertensive Agents on Cardiovascular Events in Patients with Coronary Disease and Normal Blood Pressure Trial EUROPA = European Trial on Reduction of Cardiac Events with Perindopril in Stable Coronary Arteries Trial HF = Heart Failure HOPE = Heart Outcomes Prevention Evaluation trial HR = Hazard Ratio LVSD = Left Ventricular Systolic Dysfunction NR = Not Reported PART-2 = Prevention of Atherosclerosis with Ramipril trial PEACE = Angiotensin-Converting Enzyme Inhibition in Stable Coronary Artery Disease PLVSF = Preserved Left Ventricular Systolic Function QUIET = Quinapril Ischemic Event Trial RR = Risk Reduction



Table 4.3: RCT – Angiotensin-Converting Enzyme (ACE) Inhibitors and Angiotensin II Receptor Blockers (ARBs)

Study, Total n Treatment Groups

Size & Drug Study Population Results Comments The EURopean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease Investigators (EUROPA). Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomized, double-blind, placebo-controlled, multicentre trial (the EUROPA study). Lancet 2003;362:782-88. RCT Follow up: 4.2 years Initial N: 12,218 Final N: 12,215

Perindopril (8 mg/d) treated group N = 6,110 Placebo N = 6,108

Inclusion criteria: previous MI, percutaneous or surgical coronary revascularization, angiographic evidence of at least 70% narrowing of one or more major coronary arteries, Angina with positive ECG, echo, or nuclear stress test Exclusion criteria: heart failure planned revascularization hypotension uncontrolled hypertension recent (< 1 month) use of ACE Inhibitors or ARBs renal insufficiency (creatinine>150 mmol/L) serum potassium >5.5 mmol/L

Relative Risk Reduction (95% CI, p value) for CV mortality, MI, or cardiac arrest RRR = 20% (9 to 29, p = 0.0003) NNT= 50 patients treated for 4 years to prevent 1 major cardiac event (CV mortality, nonfatal MI, resuscitated cardiac arrest) the primary endpoint Absolute Risk(%) Perindopril 488 (8.0%) Placebo 603 (9.9%) Absolute Risk Reduction* 0.0188 *Calculated by KP staff

Conclusions In a broad range of patients with stable CAD and no evidence of heart failure or notable hypertension, perindopril reduced CV death, MI, and cardiac arrest. About 50 patients need to be treated for 4 years to prevent one major CV event. Limitations Investigators did not note a significant reduction in revascularization possibly due to the low rate of PCI and CABG in this low risk population.



Table 4.4:


Size & Drug Study Population Results Comments Dickstein K, Kjekshus J and the OPTIMAAL Steering Committee, for the OPTIMAAL Study Group. Effects of losartan and captopril on mortality and morbidity in high risk patients after acute myocardial infarction: the OPTIMAAL randomized trial. Lancet 2002;360:752-60. RCT Follow up: 2.7 years Initial N: 5,477 Final N: 4,394

Losartan treated group N=2744 Captopril treated group N=2733

Inclusion criteria: Acute MI defined as: a history of typical chest pain for > 20 minutes ST elevation on electrocardiograph or an increase in cardiac markers above the decision level AND Signs or symptoms of heart failure during the acute phase or a new Q-wave anterior infarction or reinfarction. Exclusion criteria: hypotension current receipt of an ACE inhibitor or ARB unstable angina stenotic valvular heart disease dysrhythmia planned coronary revascularization

Relative Risk of losartan compared to captopril (95% CI, p value) All-cause mortality RR=1.13 (0.99-1.28, p= 0.069 CV Death RR=1.17 (1.01-1.34, p=0.032) NNT*= 49 patients treated for 2.7 years to prevent 1 death.

Absolute Risk(%) Losartan Captopril 499 (18.2%) 447 (16.4%) 420 (15.3%) 363 (13.3%)

Absolute Risk Reduction* 0.0183 0.0203 *Calculated by KP staff

Conclusions There was a nonsignificant difference in total mortality and a significant difference in CV mortality in favor of captopril, suggesting that ACE inhibitors should remain the first choice treatment in patients after complicated AMI. Losartan was better tolerated and associated with fewer discontinuations. Limitations There was no placebo group in this trial. Although the role of losartan in patients intolerant of ACE inhibition is not clearly defined, because Losartan was better tolerated and associated with significantly fewer discontinuations than captopril in these study subjects, the study investigators conclude that it can be considered in patients intolerant of ACE inhibition.



Table 4.5:

Author Study Name Indication

Subject Charact-eristics

Subject Age

(years) Study Design

Evidence grade

Treatment (name :

dose : route : frequency) Duration

Subject Number

Study Controls Outcome

Study Endpoint

Daly CA, Fox KM, Remme WJ, et al, EUROPA Investigators. The effect of perindopril on cardiovascular morbidity and mortality in patients with diabetes in the EUROPA study: results from the PERSUADE substudy. European Heart Journal 2005;26(14):1369-78

PERSUADE Coronary artery disease

Objective evidence of coronary disease, but without clinical heart failure were enrolled in the study Patients also had diabetes mellitus Majority (70%) were CSS Class I

62 Randomized controlled trial Underpowered subgroup (prespecified) analysis

B1 Perindopril : 8mg : oral : once daily

Median 4.3 years

1502 Placebo Cardiovascular mortality, MI, and cardiac arrest Total mortality, nonfatal MI, unstable angina, and cardiac arrest Cardiovascular mortality, MI, and stroke Cardiovascular mortality, nonfatal AMI, and cardiac arrest with successful resuscitation Total mortality Cardiovascular mortality Non-q-wave infarction Stroke Heart failure

Non-q-wave infarction was lower in patients on perindopril (5.1%) than those on placebo (7.7%). Relative risk reduction 34% (95% CI, 0.1–56)



Table 4.6:

Author Study Name Indication

Subject Charact-eristics

Subject Age

(years) Study Design

Evidence grade

Treatment (name :

dose : route : frequency) Duration

Subject Number

Study Controls Outcome

Study Endpoint

PEACE Trial Investigators. Angiotensin-converting-enzyme inhibition in stable coronary artery disease. New England Journal of Medicine 2004;351(20):2058-68

PEACE Coronary artery disease

Coronary artery disease documented by any of: History of MI CABG or PCI >/=50% obstruction of >/=1 native vessel LVEF >40%

64 Double blind RCT Endpoint showing benefit was a retrospective analysis

D Trandolapril : 2-4mg : oral : daily

Median 4.8 years

8290 Placebo Death from cardiovascular causes, myocardial infarction, or coronary revascularization Plus 6 other composites

CHF as primary cause of hospitalization or death: HR 0.75 (95%CI, 59-95) Onset of new diabetes: HR 0.83 (95% CI, 0.72-0.96)




Clinical Question: Is oral anticoagulant therapy, aspirin, or a combination of aspirin and oral anticoagulant therapy recommended for patients with coronary artery disease (CAD) who are NOT at increased embolic risk?

Population: Adult patients with a history of ischemic heart disease, MI, CABG, and/or PCI or documented CAD (by angiography or noninvasive testing) who are not at increased embolic risk.


Antiplatelet therapy Anticoagulant therapy Antiplatelet plus anticoagulant therapy



Mortality due to cardiac causes All-cause mortality Hospitalization, including nonfatal stroke, transient ischemic

attack (TIA), unstable angina, and revascularization procedures



Search Strategy 5

The search strategy was to update the searches conducted previously. Selected evidence was restricted to systematic reviews, meta-analyses, and RCTs in populations of adults with CAD.


Article Type and Other Limits:

Search Date No. Included/ Total

Retrieved

Meta-analysis, Human, English

3/24/06 to

02/01/08

0/7 PubMed (“myocardial ischemia”[MeSH] AND “anticoagulants”[MeSH])

Randomized Controlled Trial, Human, English

3/24/06 to

02/01/08

0/37

Meta-analysis, English

10/8/2003 to

4/26/2006

0/5 PubMed (((“myocardial infarction”[MeSH] AND “anticoagulants”[MeSH])))

Randomized Controlled Trial,

English

10/8/2003 to

4/26/2006

0/19

PubMed (((“myocardial ischemia”[MESH] AND(“warfarin” [MESH] OR warfarin [Text word]) AND (“platelet aggregation inhibitors”[MESH] OR (“aspirin”[MESH] OR aspirin[Text word]))


English

3/26/2006 to

02/01/08

0/194


3/26/2006 to

02/01/08

0/19 PubMed (((left[All fields] AND ventricular[All fields]) AND (“thrombosis”[MeSH] OR thrombus[Text Word]) AND “anticoagulants”[MeSH])


English

3/26/2006 to

02/01/08

0/69


3/26/2006 to

02/01/08

0/35 PubMed ((((“myocardial ischemia”[MESH] AND (“stents”[MESH] AND (“anticoagulants”[MeSH] OR (“platelet aggregation inhibitors”[MESH])


English

3/26/2006 to

02/01/08

0/153

Cochrane Anticoagulants and coronary artery disease

Systematic Reviews 1st quarter 2006

Accessed 5/23/2006

0/4 (0 searches

after 9/2003)






Retrieved

Clinical Evidence

Cardiovascular disorders: Secondary prevention of ischaemic events

Oral anticoagulants in the absence of

antiplatelet treatment Oral

anticoagulants in addition to antiplatelet treatment

Search July 2004

Accessed 5/23/2006

1/1 systematic

review 1 RCT


9/12/03 to

4/24/06

0/0 PubMed (((“myocardial ischemia”[MeSH] AND “anticoagulants”[MeSH])))


9/12/2003 to

4/24/06

0/82


9/23/2003 to

4/26/2006

0/0 PubMed (((“myocardial ischemia”[MeSH] AND “atrial fibrillation”[MeSH])))


English

9/23/2003 to

4/26/2006

0/4


10/8/2003 to

4/26/2006



English

10/8/2003 to

4/26/2006

0/49

PubMed (((“myocardial ischemia” [MESH] AND(“warfarin” [MESH] OR warfarin[Text word]) AND (“platelet aggregation inhibitors”[MESH] OR (“aspirin”[MESH] OR aspirin[Text word]))


English

3/22/2004 to

4/26/2006

0/7


10/08/2003 to

4/26/2006



English

10/8/2003 to

4/26/2006

0/1






Retrieved


10/10/2003 to

4/26/2006

0/10 PubMed ((((“myocardial ischemia”[MESH] AND (“stents”[MESH] AND (“anticoagulants” [MeSH] OR(“platelet aggregation inhibitors”[MESH])


English

10/10/2003 to

4/26/2006

0/70




Clinical Question: Is aspirin recommended for CAD patients who are on oral anticoagulant therapy?

Population: Adult patients with a history of ischemic heart disease, MI, CABG, and/or PCI or documented CAD (by angiography or noninvasive testing) who are on oral anticoagulant therapy.

Health Intervention: Aspirin therapy plus oral anticoagulants Vs. Oral anticoagulant alone



All-cause mortality Myocardial infarctions Stroke Coronary Revascularization Major Bleeding Minor Bleeding



Search Strategy 6




No. Included/ Total

Retrieved

Meta-analysis, English, Human

2/1/08 to

1/6/10

0/3 PubMed (“myocardial ischemia” [MeSH] AND “anticoagulants”[MeSH])

Randomized Controlled Trial, English, Human

2/1/08 to

1/6/10

0/67

PubMed (((“myocardial ischemia” [MESH] AND(“warfarin” [MESH] OR warfarin [Text word]) AND (“platelet aggregation inhibitors”[MESH] OR (“aspirin”[MESH] OR aspirin[Text word]))


2/1/08 to

1/6/10

0/4


2/1/08 to

1/6/10

0/0 PubMed (((left[All fields] AND ventricular[All fields]) AND (“thrombosis”[MeSH] OR thrombus[Text Word]) AND “anticoagulants” [MeSH])


2/1/08 to

1/6/10

0/1


2/1/08 to

1/6/10

0/5 PubMed ((“myocardial ischemia” [MESH] AND “stents” [MESH]) AND (“anticoagulants”[MeSH] OR “platelet aggregation inhibitors”[MESH]))


2/1/08 to

1/6/10

0/65


Systematic Reviews Accessed 1/4/10

0/0 (0 found since

2/1/08)

Clinical Evidence



antiplatelet treatment Oral anticoagulants in addition to antiplatelet

treatment

Accessed 1/4/10

0/1 systematic review



Evidence Table 6

N Length Interventions Dose n Mean Age

% Female

Diabetes Mellitus

Myocardial Infarction, History

of ACE-Inhibitor, Concomitant

Beta Blocker, Concomitant

Stroke, History of

Hurlen 2424 4 yrs Warfarin 2.8ratio 1216 59.7yrs 21.5% 6.8% 13.1% n/a n/a n/a

2002 Aspirin/Warfarin 75mg/2.2ratio 1208 60yrs 22.2% 8.7% 13.2% n/a n/a n/a

Primary Objective: The main study outcome was a composite of death, reinfarction, or thromboembolic stroke, whichever came first, in an intention-to-treat analysis. Each of these outcomes was also analyzed separately. The number of therapeutic interventions, such as percutaneous coronary intervention and coronary-artery bypass grafting, was also recorded.

Primary Outcome(s): Myocardial Infarction, Recurrent (#) OR Mortality, All-Cause (#) OR Stroke, Thromboembolic (#)

Inclusion/Exclusion: Patients of either sex who were younger than 75 years of age were eligible for the study if they were hospitalized for acute myocardial infarction. Patients were excluded if they had any indication for or contraindication against either of the study drugs, if they had a malignant disease, or if poor compliance was anticipated.

Additional Treatment Info: 1216 patients received warfarin (Mareyvan, Nycomed) in a dose intended to achieve an international normalized ratio (INR) of 2.8 to 4.2. 1208 patients received 75 mg of aspirin (Albyl E, Nycomed) daily combined with warfarin with the goal of achieving an INR of 2.0 to 2.5.

Risk Of Bias: Sequence Generation: LOW – Randomization done in permutated blocks Allocation Concealment: UNCLEAR: Insufficient details provided Blinding: LOW – Although open-label, outcome assessors were blinded; unlikely to affect objective outcomes: mortality, MI,

Exception: Bleeding, coronary revascularization : HIGH – Knowledge of treatment may impact reporting of bleeding or decision for revascularization Incomplete Outcome Data: LOW – Very low LTFU (2%) and complete mortality data available Selective Outcome Reporting: LOW - Reported outcomes as specified in methodology Other Sources of Bias: LOW – No other issues identified




% Female

Diabetes Mellitus




Stroke, History of

Huynh 89 13 mo Warfarin 2-2.5ratio 45 67yrs 13.3% 15.6% 62.2% 35.6% 57.8% 0%

2001 Aspirin/Warfarin 80mg/2-2.5ratio 44 66yrs 29.5% 25% 72.7% 22.7% 70.5% 0%

Primary Objective: The primary study end point was a composite end point of any-cause death, myocardial infarction, or unstable angina requiring a new hospitalization. Other end points were performance of reperfusion procedure (either percutaneous or open chest).

Primary Outcome(s): Mortality, All-Cause OR Angina, Unstable, Requiring Hospitalization OR Myocardial Infarction, Any

Inclusion/Exclusion: All patients who presented with a diagnosis of unstable angina or non–ST-elevation myocardial infarction and prior CABG were considered for the study. Patients who had coronary angioplasty or repeat CABG during the index hospitalization were excluded; therefore, the study population was limited to patients who were poor candidates for a revascularization procedure. Other exclusion criteria were as follows: contraindication to the use of aspirin or warfarin, a treatable cause for angina pectoris, any major concomitant illness, congestive heart failure class 3 or 4 (New York Heart Association), uncontrolled systemic hypertension (blood pressure >180/95 mm Hg), recent major trauma, alcohol or drug abuse, females with child-bearing potential, coronary angioplasty within the last 6 months, conditions mandating treatment with aspirin (such as previous stroke) or with warfarin (such as metallic valve prosthesis), atrial fibrillation, or intracardiac thrombi.

Additional Treatment Info: Patients were randomized to warfarin plus placebo-aspirin. Warfarin was titrated to an international normalized ratio of 2.0 to 2.5 and given as crystalline warfarin sodium tablets . In-hospital follow-up visits were scheduled at 1, 3, 6, and 12 months of treatment. The study drugs were terminated at the 12-month follow-up visit, and aspirin (325 mg daily) was prescribed to all patients. Patients were reevaluated 1 month after the discontinuation of the study drugs. Concomitant medications could be prescribed at the discretion of the attending physicians, but drugs known interact with warfarin or to increase the bleeding risk (barbiturates, NSAIDs, and salicylates) were prohibited during the whole study period. Patients were randomized to aspirin plus warfarin. Aspirin was administered as a daily dose of 80 mg in nonenteric coated form. Warfarin was titrated to an international normalized ratio of 2.0 to 2.5 and given as crystalline warfarin sodium tablets . In-hospital follow-up visits were scheduled at 1, 3, 6, and 12 months of treatment. The study drugs were terminated at the 12-month follow-up visit, and aspirin (325 mg daily) was prescribed to all patients. Patients were reevaluated 1 month after the discontinuation of the study drugs. Concomitant medications could be prescribed at the discretion of the attending physicians, but drugs known interact with warfarin or to increase the bleeding risk (barbiturates, NSAIDs, and salicylates) were prohibited during the whole study period.

Risk Of Bias: Sequence Generation: UNCLEAR – Insufficient details provided Allocation Concealment: UNCLEAR – Insufficient details provided Blinding: LOW – Double-blind with mock placebo adjustments to maintain blinding Incomplete Outcome Data: LOW - Low drop out rate with similar reasons between treatment groups. Selective Outcome Reporting: LOW - Reported outcomes as specified in methodology Other Sources of Bias: LOW - No other issues identified.




% Female

Diabetes Mellitus




Stroke, History of

van Es 663 1 yrs Warfarin 3.2ratio 330 61.6yrs 26% 8% 12% 32.6% 80.9% 0%

2002 Aspirin/Warfarin 80mg/2.4ratio 333 60.8yrs 23% 8% 15% 33.4% 79.2% 0%

Primary Objective: The primary composite endpoint was first occurrence of myocardial infarction, stroke, or death. Secondary outcomes were death from all causes (vascular death, myocardial infarction, unstable angina, cardiac interventions, stroke) and episodes of bleeding.

Primary Outcome(s): Mortality, All-Cause OR Stroke, Any OR Myocardial Infarction, Any

Inclusion/Exclusion: Eligible patients were men or non-pregnant women who were admitted with acute myocardial infarction or unstable angina within the preceding 8 weeks. Exclusion criteria included established indications for treatment with oral anticoagulants (eg, atrial fibrillation, prosthetic heart valve, ventricular aneurysm) or platelet inhibitors (percutaneous transluminal coronary angioplasty, stent), contraindications for the study drug, planned revascularization procedure, serious comorbidity, increased risk of bleeding, abnormal blood platelets or erythrocytes, anemia, history of stroke, and inability to adhere to the protocol or to give written informed consent.

Additional Treatment Info: Patients were randomly allocated to oral anticoagulants with a target INR of 3.0–4.0. Concomitant drugs were left to the discretion of the attending physician. Patients were randomly allocated to low-dose aspirin (100 mg pulverized carbasalate calcium, metabolized to aspirin, daily; equal to 80 mg) plus oral anticoagulants (phenprocoumon or acenocoumarol) with a target INR of 2.0–2.5. Concomitant drugs were left to the discretion of the attending physician.

Risk Of Bias: Sequence Generation: UNCLEAR - Insufficient details provided. Allocation Concealment: LOW - Randomization was done by central telephone service. Blinding: LOW - Although open-label, outcome assessors were blinded; unlikely to affect objective outcomes:: mortality, MI, stroke

Exception: Bleeding, coronary revascularization : HIGH – Knowledge of treatment may impact reporting of bleeding or decision for revascularization Incomplete Outcome Data: HIGH - 10% more dropouts in gps - reasons differ than ASA gp Selective Outcome Reporting: LOW - Reported outcomes as specified in methodology Other Sources of Bias: LOW - No other issues identified




Clinical Question: Is oral anticoagulant therapy recommended for patients with CAD and either left ventricular thrombus or large transmural anterior infarctions?

Population: Adult patients with a history of ischemic heart disease, MI, CABG, and/or PCI or documented CAD (by angiography or noninvasive testing) with left ventricular thrombus or large transmural anterior infarctions.


Anticoagulant therapy



Mortality due to cardiac causes All-cause mortality Hospitalization, including nonfatal stroke, transient ischemic

attack (TIA), unstable angina, and revascularization procedures



Search Strategy 7




No. Included / Total

Retrieved


3/24/06 to

02/01/08



3/24/06 to

02/01/08

0/37


10/8/2003 to

4/26/2006



English

10/8/2003 to

4/26/2006

0/19

PubMed (((“myocardial ischemia”[MESH] AND(“warfarin” [MESH] OR warfarin [Text word]) AND (“platelet aggregation inhibitors”[MESH] OR (“aspirin”[MESH] OR aspirin[Text word]))


English

3/26/2006 to

02/01/08

0/194


3/26/2006 to

02/01/08



English

3/26/2006 to

02/01/08

0/69


3/26/2006 to

02/01/08

0/35 PubMed ((((“myocardial ischemia”[MESH] AND (“stents”[MESH] AND (“anticoagulants”[MeSH] OR (“platelet aggregation inhibitors”[MESH])


English

3/26/2006 to

02/01/08

0/153


Systematic Reviews 1st quarter 2006

Accessed 5/23/2006

0/4 (0 searches

after 9/2003)






Retrieved

Clinical Evidence



antiplatelet treatment Oral anticoagulants

in addition to antiplatelet treatment

Search July 2004

Accessed 5/23/2006

1/1 systematic review 1 RCT


9/12/03 to

4/24/06



9/12/2003 to

4/24/06

0/82


9/23/2003 to

4/26/2006

0/2 PubMed (((“myocardial ischemia”[MeSH] AND “atrial fibrillation”[MeSH])))


English

9/23/2003 to

4/26/2006

0/4


10/8/2003 to

4/26/2006



English

10/8/2003 to

4/26/2006

0/49

PubMed (((“myocardial ischemia”[MESH] AND(“warfarin”[MESH] OR warfarin[Text word]) AND (“platelet aggregation inhibitors”[MESH] OR (“aspirin”[MESH] OR aspirin[Text word]))


English

3/22/2004 to

4/26/2006

0/0


10/08/2003 to

4/26/2006

0 PubMed (((left[All fields] AND ventricular[All fields]) AND (“thrombosis”[MeSH] OR thrombus[Text Word]) AND “anticoagulants”[MeSH])


English

10/8/2003 to

4/26/2006

1

PubMed ((((“myocardial ischemia”[MESH] AND (“stents”[MESH] AND


10/10/2003 to

4/26/2006

10






Retrieved

(“anticoagulants” [MeSH] OR(“platelet aggregation inhibitors”[MESH])


English

10/10/2003 to

4/26/2006

70



Evidence Table 7

Table 7.1: RCTs

Study Name Treatment Groups Size &

Drug Study Population Results Comments Hurlen M, Abdelnoor M, Smith P, Erikssen J, Arnesen H. Warfarin, aspirin, or both after myocardial infarction. N Engl J Med 2002;347:969-74. RCT Follow-Up: Mean duration 4 years. Clinical exams at 6 wks. and at study term; patient questionnaires every 6 months. Initial n = 3,630 Final n = 3,614

Warfarin alone (to INR of 2.8 to 4.2) n = 1,216 Aspirin alone (160 mg) n = 1,206 Aspirin (75 mg) plus warfarin (to INR of 2.0 to 2.5) n = 1,208

Patients ≤ 75 years of age hospitalized for acute myocardial infarction. (Exclusions: Patients with contraindications against either of study drugs, malignancy, poor compliance anticipated.)

Absolute Risk of Death, Reinfarction, Thromboembolic Stroke Aspirin Group 241/1206 (20%) Warfarin Group 203/1216 (16.7%) Warfarin plus Aspirin Group 181/1208 (15%) Absolute Risk Reduction Warfarin vs. aspirin = 3.3% Warfarin plus aspirin vs. aspirin = 4.8% Warfarin plus aspirin vs. warfarin = 1.7% Rate Ratio for Death, Reinfarction, Thromboembolic Stroke Warfarin vs. aspirin = 0.81 (95% CI: 0.69-0.95; p=0.03) Warfarin plus aspirin vs. aspirin = 0.71 (95% CI: 0.60-0.83, p=0.001) NNT to prevent one major event (death, reinfarction, thromboembolic stroke) Warfarin plus aspirin group 67/yr Warfarin group 100/yr Risk NNT to cause 1 major bleeding episode Warfarin plus aspirin vs. aspirin alone 250/yr Warfarin vs. aspirin alone 200/yr Episodes of major, nonfatal bleeding observed: 0.62 % of patients/treatment year in both the warfarin group and warfarin plus aspirin group compared to 0.17% in the aspirin only group (p < 0.001).

Conclusion Warfarin alone or in combination with aspirin was superior to aspirin alone in reducing the incidence of composite events after an AMI. Combination of moderate-intensity warfarin and low-dose aspirin is most effective therapy. Adverse events Four times as many major bleeding episodes in the two groups receiving warfarin than in the aspirin only group.




Clinical Question: Which antiplatelet therapy is recommended for patients: With CAD? At what dose?

How long should antiplatelet therapy be continued in patients with CAD: Post event? Post-procedure?

Population: Patients with the following: A history of ischemic heart disease, MI, CABG and/or PCI, or

documented CAD (by angiography or noninvasive testing) No contraindications to aspirin therapy

Health Intervention: Aspirin therapy Thienopyridine therapy (clopidogrel, ticlopidine) Combination aspirin plus thienopyridine therapy







Search Strategy 8



No. Included/ Total

Retrieved

Cochrane Library

“antiplatelet therapy” and “coronary artery disease”


1966 -

01/08/08

0/15

Cochrane Library

“antiplatelet therapy” and “coronary disease”


1966 -

01/08/08

0/19

PubMed (antiplatelet[All Fields] AND ("therapy"[Subheading] OR ("therapeutics"[TIAB] NOT Medline[SB]) OR "therapeutics"[MeSH Terms] OR therapy[Text Word])) AND ("coronary artery disease"[MeSH Terms] OR Coronary Artery Disease[Text Word])

Human, English, All Adult: 19+ years,

RCTs, meta-analysis, only items

with abstracts

01/01/06 -

01/08/08

0/10

PubMed (antiplatelet[All Fields] AND ("therapy"[Subheading] OR ("therapeutics"[TIAB] NOT Medline[SB]) OR "therapeutics"[MeSH Terms] OR therapy[Text Word])) AND ("coronary disease"[MeSH Terms] OR Coronary Disease[Text Word])



with abstracts

01/01/06 -

01/08/08

0/19

PubMed ("aspirin"[MeSH Terms] OR aspirin[Text Word]) AND ("coronary artery disease"[MeSH Terms] OR Coronary Artery Disease[Text Word])



with abstracts

01/01/06 -

01/08/08

1/24

PubMed ("aspirin"[MeSH Terms] OR aspirin[Text Word]) AND ("coronary disease"[MeSH Terms] OR Coronary Disease[Text Word])



with abstracts

01/01/06 -

01/08/08

0/34





No. Included/ Total

Retrieved

PubMed ("thienopyridine"[Substance Name] OR thienopyridine[Text Word]) AND ("coronary artery disease"[MeSH Terms] OR Coronary Artery Disease[Text Word])



with abstracts

01/01/06 -

01/08/08

0/1

PubMed ("thienopyridine"[Substance Name] OR thienopyridine[Text Word]) AND ("coronary disease"[MeSH Terms] OR Coronary Disease[Text Word])



with abstracts

01/01/06 -

01/08/08

0/4

PubMed ("clopidogrel"[Substance Name] OR clopidogrel[Text Word]) AND ("coronary artery disease"[MeSH Terms] OR Coronary Artery Disease[Text Word])



with abstracts

01/01/06 -

01/08/08

1/17

PubMed ("clopidogrel"[Substance Name] OR clopidogrel[Text Word]) AND ("coronary disease"[MeSH Terms] OR Coronary Disease[Text Word])



with abstracts

01/01/06 -

01/08/08

0/31

PubMed (("clopidogrel"[TIAB] NOT Medline[SB]) OR "clopidogrel"[Substance Name] OR plavix[Text Word]) AND ("coronary artery disease"[MeSH Terms] OR Coronary Artery Disease[Text Word])



with abstracts

01/01/06 -

01/08/08

1/14

PubMed (("clopidogrel"[TIAB] NOT Medline[SB]) OR "clopidogrel"[Substance Name] OR plavix[Text Word]) AND ("coronary disease"[MeSH Terms] OR Coronary Disease[Text Word])



with abstracts

01/01/06 -

01/08/08

0/25





No. Included/ Total

Retrieved

PubMed antiplatelet[All Fields] AND ((("heart"[TIAB] NOT Medline[SB]) OR "heart"[MeSH Terms] OR coronary[Text Word]) AND (("syndrome"[TIAB] NOT Medline[SB]) OR "syndrome"[MeSH Terms] OR syndromes[Text Word]))



with abstracts

01/01/06 -

01/08/08

0/13

PubMed (antiplatelet[All Fields] AND ("therapy"[Subheading] OR ("therapeutics"[TIAB] NOT Medline[SB]) OR "therapeutics"[MeSH Terms] OR therapy[Text Word])) AND (("cardiovascular system"[TIAB] NOT Medline[SB]) OR "cardiovascular system"[MeSH Terms] OR cardiovascular[Text Word])



with abstracts

01/01/06 -

01/08/08

1/27

PubMed (antiplatelet[All Fields] AND ("therapy"[Subheading] OR ("therapeutics"[TIAB] NOT Medline[SB]) OR "therapeutics"[MeSH Terms] OR therapy[Text Word])) OR ("clopidogrel"[Substance Name] OR clopidogrel[Text Word]) OR ("thienopyridine"[Substance Name] OR thienopyridine[Text Word]) OR (("clopidogrel"[TIAB] NOT Medline[SB]) OR "clopidogrel"[Substance Name] OR plavix[Text Word]) OR ("aspirin"[MeSH Terms] OR aspirin[Text Word]) AND ("myocardial infarction"[MeSH Terms] OR myocardial infarction[Text Word])



with abstracts

01/01/06 -

01/10/08

1/94





No. Included/ Total

Retrieved

PubMed (antiplatelet[All Fields] AND ("therapy"[Subheading] OR ("therapeutics"[TIAB] NOT Medline[SB]) OR "therapeutics"[MeSH Terms] OR therapy[Text Word])) OR ("clopidogrel"[Substance Name] OR clopidogrel[Text Word]) OR ("thienopyridine"[Substance Name] OR thienopyridine[Text Word]) OR (("clopidogrel"[TIAB] NOT Medline[SB]) OR "clopidogrel"[Substance Name] OR plavix[Text Word]) OR ("aspirin"[MeSH Terms] OR aspirin[Text Word]) AND ("stroke"[MeSH Terms] OR stroke[Text Word])



with abstracts

01/01/06 -

01/10/08

1/61

PubMed (antiplatelet[All Fields] AND ("therapy"[Subheading] OR ("therapeutics"[TIAB] NOT Medline[SB]) OR "therapeutics"[MeSH Terms] OR therapy[Text Word])) OR ("clopidogrel"[Substance Name] OR clopidogrel[Text Word]) OR ("thienopyridine"[Substance Name] OR thienopyridine[Text Word]) OR (("clopidogrel"[TIAB] NOT Medline[SB]) OR "clopidogrel"[Substance Name] OR plavix[Text Word]) OR ("aspirin"[MeSH Terms] OR aspirin[Text Word]) AND (transient ischaemic attack[Text Word] OR "ischemic attack, transient"[MeSH Terms] OR transient ischemic attack[Text Word])



with abstracts

01/01/06 -

01/10/08

0/12





No. Included/ Total

Retrieved

PubMed (antiplatelet[All Fields] AND ("therapy"[Subheading] OR ("therapeutics"[TIAB] NOT Medline[SB]) OR "therapeutics"[MeSH Terms] OR therapy[Text Word])) OR ("clopidogrel"[Substance Name] OR clopidogrel[Text Word]) OR ("thienopyridine"[Substance Name] OR thienopyridine[Text Word]) OR (("clopidogrel"[TIAB] NOT Medline[SB]) OR "clopidogrel"[Substance Name] OR plavix[Text Word]) OR ("aspirin"[MeSH Terms] OR aspirin[Text Word]) AND (percutaneous[All Fields] AND (("heart"[TIAB] NOT Medline[SB]) OR "heart"[MeSH Terms] OR coronary[Text Word]) AND intervention[All Fields])



with abstracts

01/01/06 -

01/10/08

1/37

PubMed (antiplatelet[All Fields] AND ("therapy"[Subheading] OR ("therapeutics"[TIAB] NOT Medline[SB]) OR "therapeutics"[MeSH Terms] OR therapy[Text Word])) OR ("clopidogrel"[Substance Name] OR clopidogrel[Text Word]) OR ("thienopyridine"[Substance Name] OR thienopyridine[Text Word]) OR (("clopidogrel"[TIAB] NOT Medline[SB]) OR "clopidogrel"[Substance Name] OR plavix[Text Word]) OR ("aspirin"[MeSH Terms] OR aspirin[Text Word]) AND (("coronary artery bypass"[TIAB] NOT Medline[SB]) OR "coronary artery bypass"[MeSH Terms] OR coronary artery bypass graft[Text Word])



with abstracts

01/01/06 -

01/10/08

0/11





No. Included/ Total

Retrieved

PubMed (antiplatelet[All Fields] AND ("therapy"[Subheading] OR ("therapeutics"[TIAB] NOT Medline[SB]) OR "therapeutics"[MeSH Terms] OR therapy[Text Word])) OR ("clopidogrel"[Substance Name] OR clopidogrel[Text Word]) OR ("thienopyridine"[Substance Name] OR thienopyridine[Text Word]) OR (("clopidogrel"[TIAB] NOT Medline[SB]) OR "clopidogrel"[Substance Name] OR plavix[Text Word]) OR ("aspirin"[MeSH Terms] OR aspirin[Text Word]) AND revascularization[All Fields]



with abstracts

01/01/06 -

01/10/08

1/26

PubMed (antiplatelet[All Fields] AND ("therapy"[Subheading] OR ("therapeutics"[TIAB] NOT Medline[SB]) OR "therapeutics"[MeSH Terms] OR therapy[Text Word])) OR ("clopidogrel"[Substance Name] OR clopidogrel[Text Word]) OR ("thienopyridine"[Substance Name] OR thienopyridine[Text Word]) OR (("clopidogrel"[TIAB] NOT Medline[SB]) OR "clopidogrel"[Substance Name] OR plavix[Text Word]) OR ("aspirin"[MeSH Terms] OR aspirin[Text Word]) AND (("stents"[TIAB] NOT Medline[SB]) OR "stents"[MeSH Terms] OR stent[Text Word])



with abstracts

01/01/06 -

01/10/08

1/34





No. Included/ Total

Retrieved

PubMed (antiplatelet[All Fields] AND ("therapy"[Subheading] OR ("therapeutics"[TIAB] NOT Medline[SB]) OR "therapeutics"[MeSH Terms] OR therapy[Text Word])) OR ("clopidogrel"[Substance Name] OR clopidogrel[Text Word]) OR ("thienopyridine"[Substance Name] OR thienopyridine[Text Word]) OR (("clopidogrel"[TIAB] NOT Medline[SB]) OR "clopidogrel"[Substance Name] OR plavix[Text Word]) OR ("aspirin"[MeSH Terms] OR aspirin[Text Word]) AND post[All Fields]



with abstracts

01/01/06 -

01/10/08

0/23

PubMed (antiplatelet[All Fields] AND ("therapy"[Subheading] OR ("therapeutics"[TIAB] NOT Medline[SB]) OR "therapeutics"[MeSH Terms] OR therapy[Text Word])) OR ("clopidogrel"[Substance Name] OR clopidogrel[Text Word]) OR ("thienopyridine"[Substance Name] OR thienopyridine[Text Word]) OR (("clopidogrel"[TIAB] NOT Medline[SB]) OR "clopidogrel"[Substance Name] OR plavix[Text Word]) OR ("aspirin"[MeSH Terms] OR aspirin[Text Word]) AND ((("heart"[TIAB] NOT Medline[SB]) OR "heart"[MeSH Terms] OR coronary[Text Word]) AND event[All Fields])



with abstracts

1-Jan 2006 –

10-Jan 2008

1/16




Evidence Table 8

Table 8.1: RCT of Clopidogrel plus Aspirin versus Aspirin Alone Primary End Point a

N

Sample age (mean, range)

Female (%) (%)

RR (95%CI) p Study Quality† Biases*

Bhatt, 2006 Clopidogrel + Aspirin = 7802 Placebo + Aspirin = 7801

64.0, 39.0 to 95.0 64.0, 45.0 to 93.0

29.7 29.8

6.8 7.3

0.93 (0.83 to 1.05) 0.22 4 1

RR = Relative Risk † Study quality measured by Jadad Scoring System (1 to 5 = low to high) *Biases: N: none; 1: sample attrition >15%; 2: sample selection bias; 3: detection bias (e.g., measurement error, ITT analysis, power); 4: study procedure biases (e.g., blinding, randomization); 5: incomplete data presentation




Clinical Question: For patients with stable CAD who have not undergone coronary stent placement, when is clopidogrel indicated alone and in combination with aspirin?

Population: Patients with a history of ischemic heart disease, MI, CABG and/or PCI, or documented CAD (by angiography or noninvasive testing).


Thienopyridine therapy Combination aspirin plus thienopyridine therapy







Search Strategy 9



No. Included/ Total

Retrieved

Cochrane Library

“antiplatelet therapy” and “aspirin intolerance”


1966 -

01/15/08 0/0

Cochrane Library

“antiplatelet treatment” and “aspirin allergy”


1966 -

01/15/08 0/0

Cochrane Library

“antiplatelet therapy” and “stable CAD”


1966 -

01/15/08 0/0

PubMed (antiplatelet[All Fields] AND ("therapy"[Subheading] OR ("therapeutics"[TIAB] NOT Medline[SB]) OR "therapeutics"[MeSH Terms] OR therapy[Text Word])) OR (antiplatelet[All Fields] AND ("therapy"[Subheading]OR ("therapeutics"[TIAB] NOT Medline[SB]) OR "therapeutics"[MeSH Terms] OR treatment[Text Word])) AND (stable[All Fields] AND ("coronary disease"[MeSH Terms] OR coronary disease[Text Word])) AND (("aspirin"[MeSH Terms] OR aspirin[Text Word]) AND ("immediate hypersensitivity"[Text Word] OR "hypersensitivity, immediate"[MeSH Terms] OR ("hypersensitivity"[TIAB] NOT Medline[SB]) OR "hypersensitivity"[MeSH Terms] OR ("allergy and immunology"[TIAB] NOT Medline[SB]) OR "allergy and immunology"[MeSH Terms] OR allergy[Text Word])) OR (("aspirin"[MeSH Terms] OR aspirin[Text Word]) AND intolerance[All Fields]) OR (("aspirin"[MeSH Terms] OR aspirin[Text Word]) AND ("hypersensitivity"[MeSH Terms] OR hypersensitivity[Text Word]))

Human, English, All Adult: 19+ years, RCTs, only items

with abstracts

01/01/06 -

01/15/08

0/4





No. Included/ Total

Retrieved

PubMed (contraindication[All Fields] AND ("aspirin"[MeSH Terms] OR aspirin[Text Word]))


meta-analysis, only items with abstracts

01/01/06 -

01/15/08

0/2

PubMed (("secondary"[Subheading] OR secondary[Text Word]) AND ("prevention and control"[Subheading] OR prevention[Text Word])) AND ("clopidogrel"[Substance Name] OR clopidogrel[Text Word]) OR ("aspirin"[MeSH Terms] OR aspirin[Text Word]) AND ("coronary disease"[MeSH Terms] OR coronary disease[Text Word])



with abstracts

01/01/06 -

01/15/08

1/34

PubMed (("aspirin"[MeSH Terms] OR aspirin[Text Word]) AND resistance[All Fields]) AND ("coronary disease"[MeSH Terms] OR coronary disease[Text Word])



with abstracts

01/01/06 -

01/18/08

0/3

PubMed (stable[All Fields] AND ("coronary disease"[MeSH Terms] OR coronary disease[Text Word])) AND ("clopidogrel"[Substance Name] OR clopidogrel[Text Word])



with abstracts

01/01/06 -

01/18/08

0/8

PubMed (stable[All Fields] AND ("coronary disease"[MeSH Terms] OR coronary disease[Text Word])) AND ("aspirin"[MeSH Terms] OR aspirin[Text Word])



with abstracts

01/01/06 -

01/18/08

0/8




Evidence Table 9

Table 9.1: RCT of Clopidogrel plus Aspirin versus Aspirin Alone Primary End Point a

Name N

Sample age (mean, range)

Female (%) (%)

RR (95%CI) p Study Quality† Biases*

Bhatt, 2006 Clopidogrel + Aspirin = 7802 Placebo + Aspirin = 7801

64.0, 39.0 to 95.0 64.0, 45.0 to 93.0

29.7 29.8

6.8 7.3

0.93 (0.83 to 1.05) 0.22 4 1

RR = Relative Risk † Study quality measured by Jadad Scoring System (1 to 5 = low to high) *Biases: N: none; 1: sample attrition >15%; 2: sample selection bias; 3: detection bias (e.g., measurement error, ITT analysis, power); 4: study procedure biases (e.g., blinding, randomization); 5: incomplete data presentation.



Antiplatelet Therapy Post Stent Placement


Clinical Question: Bare Metal Stent Placement: 1. Which thienopyridine should be added to aspirin following bare

metal stent placement? 2. What is the optimal duration of dual antiplatelet therapy

following bare metal stent placement? Drug-Eluting Stent Placement:

3. Which thienopyridine should be added to aspirin following drug-eluting stent (DES) placement?

4. What is the optimal duration of dual antiplatelet therapy following DES placement?

Population: Post coronary stent placement (bare metal or drug-eluding) patients


Aspirin plus one type of thienopyridine (clopidogrel, ticlopidine, prasugrel) Vs. Aspirin plus another type of thienopyridine therapy

Important Health Outcomes


All-Cause Mortality Cardiovascular Mortality Myocardial Infarction Cardiac Event Stroke Coronary Revascularization Major Bleeding Stent Thrombosis



Search Strategy 10

Database Terms Article Type and Limits

Time Frame

# Found

# Included

Cochrane Library

“antiplatelet therapy” and “stent” Cochrane Systemic Reviews

01/15/08-

01/05/10

0 0

Cochrane Library

“antiplatelet treatment” and “stent” Cochrane Systemic Reviews

1966 -

01/15/08

0 0

(antiplatelet[All Fields] AND ("therapy"[Subheading] OR ("therapeutics"[TIAB] NOT Medline[SB]) OR "therapeutics" [MeSH Terms] OR therapy[Text Word])) OR (antiplatelet[All Fields] AND ("therapy"

Human, English, All Adult: 19+ years, RCTs, only items with abstracts

01/15/08-

01/05/10

162 5 PubMed

[Subheading] OR ("therapeutics"[TIAB] NOT Medline[SB]) OR "therapeutics" [MeSH Terms] OR treatment[Text Word])) OR ("aspirin"[MeSH Terms] OR aspirin[Text Word]) OR ("clopidogrel"[Substance Name] OR clopidogrel[Text Word]) OR ("ticlopidine"[Substance Name] OR ticlopidine[Text Word]) OR ("prasugrel"[Substance Name] OR prasugrel[Text Word]) AND (("stents"[TIAB] NOT Medline[SB]) OR "stents"[MeSH Terms] OR stent[Text Word]) OR stenting[All Fields] (antiplatelet[All Fields] AND ("therapy"[Subheading] OR ("therapeutics"[TIAB] NOT Medline[SB]) OR "therapeutics" [MeSH Terms] OR therapy[Text Word])) OR (antiplatelet[All Fields] AND ("therapy"

Human, English, All Adult: 19+ years, meta-analysis, only items with abstracts

01/15/08-

01/05/10

9 0 PubMed

[Subheading] OR ("therapeutics"[TIAB] NOT Medline[SB]) OR "therapeutics"[MeSH Terms] OR treatment[Text Word])) OR ("aspirin"[MeSH Terms] OR aspirin[Text Word]) OR ("clopidogrel"[Substance Name] OR clopidogrel[Text Word]) OR ("ticlopidine"[Substance Name] OR ticlopidine[Text Word]) OR ("prasugrel"[Substance Name] OR prasugrel[Text Word]) AND (("stents"[TIAB] NOT Medline[SB]) OR "stents"[MeSH Terms] OR stent[Text Word]) OR stenting[All Fields] antiplatelet[All Fields] OR ("thienopyridine"[Substance Name] OR thienopyridine[Text Word]) OR ("aspirin"[MeSH Terms] OR aspirin[Text Word]) AND (("stents"[TIAB] NOT Medline[SB]) OR "stents" [MeSH Terms] OR stent[Text


01/15/08-

01/05/10

108 0 PubMed

Word]) OR ("sirolimus"[MeSH Terms] OR sirolimus [Text Word]) OR ("paclitaxel"[MeSH Terms] OR paclitaxel[Text Word]) OR drug-eluting[All Fields] AND ("coronary disease"[MeSH Terms] OR coronary disease[Text Word])

Evidence Tables 10

Study N Length Interventions Dose n Mean Age

% Female

CABG, History of

Diabetes Mellitus


of Myocardial

Infarction, Acute Angina, Unstable, History of

Bertrand 685 28

days Aspirin/Ticlopidine 325mg/250mg 340 61yrs 25% 0% 12.1% 36.2% n/a 45.3%

2000 Aspirin/Clopidogrel325mg/75-

300mg 345 60yrs 23% 0% 11.3% 36.5% n/a 44.9%

Primary Objective: The primary endpoint was the incidence of any one of the following validated events occurring during the study drug treatment period between visits 1 and 4 or until discontinuation of study drug: (1) major peripheral bleeding complications (including false aneurysms, surgical repair of puncture site complications, blood transfusion [>=2 U of blood], intracranial bleeding, retroperitoneal bleeding, overt hemorrhage with a decrease of hemoglobin >= 3 g/dL compared with baseline; (2) neutropenia (neutrophil count <1.5 x 10^9/L); (3) thrombocytopenia (platelet count <100 x 10^9 /L; (4) early discontinuation of study drug because of a non-cardiac adverse event (including death of non-cardiac origin). The secondary (efficacy) end points were the incidence of the following events during the treatment period: (1) cardiac events (combined and separately): cardiovascular death (including all deaths not definitively ascribed to a specific noncardiac cause); MI (spontaneously or in association with angioplasty or CABG); or target vessel revascularization (performed because of recurrent ischemia, arrhythmia, or hemodynamic failure).

Primary Outcome(s): Complications, Bleeding, Major OR Complications, Peripheral, Major* Drug Discontinuation due to Allergic Reaction* Drug Discontinuation due to GI Disorder* Drug Discontinuation due to Non-Cardiac Event* Drug Discontinuation due to Other Reason* Drug Discontinuation due to Skin Disorder* Drug Discontinuation, Any* Neutropenia* Thrombocytopenia* Thrombocytopenia OR Complications, Bleeding, Major OR Complications, Peripheral, Major OR Neutropenia OR Drug Discontinuation due to Non-Cardiac Event

Inclusion/Exclusion: Randomized patients satisfied the following criteria: successful planned or unplanned coronary stenting (1 or 2 stents) in a single vessel (reference vessel diameter > 2.8 mm) with the use of any commercially available non–heparin-coated stents; < 10% adjacent residual stenosis; no angiographic evidence of thrombus formation or dissection within the treated vessel; blood flow of TIMI grade 3 in each stented segment and associated major side branches; preoperative creatine phosphokinase (CPK) levels less than twice the upper limit of normal (ULN); and eligibility to commence study drug within 6 hours after stent implantation. Principal exclusion criteria were stenting procedure involving >= stents or > 1 vessel, involving The left main coronary artery or a major bifurcation, or involving vein grafts; primary angioplasty for ongoing myocardial infarction with documented ST-segment elevation and/or elevated CPK-MB levels > 2x ULN and CPK MB levels greater than normal); persistent objective ischemia determined by 12-lead ECG between stenting and randomization; administration of oral anticoagulants, GP IIb/IIIa receptor antagonists and other antiplatelet agents, except for aspirin, within 1 month before randomization; administration of thrombolytics 2 weeks before randomization; need for anticoagulants, thrombolytic agents, or GP IIb/IIIa receptor antagonists after the procedure; percutaneous or surgical revascularization (PTCA, CABG) within 2 months before the procedure; history of allergy or intolerance or contraindication to aspirin, ticlopidine, or clopidogrel.

Additional Treatment Info: All study drugs (including aspirin) were administered on a blinded basis (double-dummy) and were to be initiated within 6 hours of completion of stenting. Patients were to receive 28 days of treatment with 250 mg BID ticlopidine and 325 mg/d aspirin (days 1 to 28). Heparin was discontinued at the end of the procedure and 4 hours before sheath removal. In cases in which stent placement was performed in the late afternoon, intravenous heparin could be continued for a few hours to avoid sheath removal during the night, provided that the total duration of administration did not exceed 36 hours. All study drugs (including aspirin) were administered on a blinded basis (double-dummy) and were to be initiated within 6 hours of completion of stenting. Patients were to receive 28 days of treatment with 300 mg clopidogrel (loading dose) and 325 mg/d aspirin on day 1, followed by 75 mg/d clopidogrel and 325 mg/d aspirin (days 2 to 28). Heparin was discontinued at the end of the procedure and 4 hours before sheath removal. In cases in which stent placement was performed in the late afternoon, intravenous heparin could be continued for a few hours to avoid sheath removal during the night, provided that the total duration of administration did not exceed 36 hours.

Risk Of Bias:Sequence Generation: UNCLEAR – No description of sequence generation process Allocation Concealment: UNCLEAR - No description of methods for allocation concealment Blinding: LOW – Double blind and outcome assessors blinded to treatment also Incomplete Outcome Data: UNCLEAR - Higher rate of discontinuation due to non CV AE in TIC vs. CLO - however unclear if enough difference to bias estimate of effect Selective Outcome Reporting: .LOW – Reported outcomes as specified in methodology Other Sources of Bias: LOW – No other issues identified


% Female

CABG, History of

Diabetes Mellitus


of Myocardial


Bertrand 675 28

days Aspirin/Ticlopidine 325mg/250mg 340 61yrs 25% 0% 12.1% 36.2% n/a 45.3%

2000 Aspirin/Clopidogrel 325mg/75mg 335 60yrs 22% 0% 10.4% 36.1% n/a 39.4%

Primary Objective: The primary endpoint was the incidence of any one of the following validated events occurring during the study drug treatment period between visits 1 and 4 or until discontinuation of study drug: (1) major peripheral bleeding complications (including false aneurysms, surgical repair of puncture site complications, blood transfusion [>=2 U of blood], intracranial bleeding, retroperitoneal bleeding, overt hemorrhage with a decrease of hemoglobin >= 3 g/dL compared with baseline; (2) neutropenia (neutrophil count <1.5 x 10^9/L); (3) thrombocytopenia (platelet count <100 x 10^9 /L; (4) early discontinuation of study drug because of a non-cardiac adverse event (including death of non-cardiac origin). The secondary (efficacy) end points were the incidence of the following events during the treatment period: (1) cardiac events (combined and separately): cardiovascular death (including all deaths not definitively ascribed to a specific noncardiac cause); MI (spontaneously or in association with angioplasty or CABG); or target vessel revascularization (performed because of recurrent ischemia, arrhythmia, or hemodynamic failure).

Primary Outcome(s): Complications, Bleeding, Major OR Complications, Peripheral, Major* Drug Discontinuation due to Allergic Reaction* Drug Discontinuation due to GI Disorder* Drug Discontinuation due to Non-Cardiac Event* Drug Discontinuation due to Other Reason* Drug Discontinuation due to Skin Disorder* Drug Discontinuation, Any* Neutropenia* Thrombocytopenia* Thrombocytopenia OR Complications, Bleeding, Major OR Complications, Peripheral, Major OR Neutropenia OR Drug Discontinuation due to Non-Cardiac Event

Inclusion/Exclusion: Randomized patients satisfied the following criteria: successful planned or unplanned coronary stenting (1 or 2 stents) in a single vessel (reference vessel diameter > 2.8 mm) with the use of any commercially available non–heparin-coated stents; < 10% adjacent residual stenosis; no angiographic evidence of thrombus formation or dissection within the treated vessel; blood flow of TIMI grade 3 in each stented segment and associated major side branches; preoperative creatine phosphokinase (CPK) levels less than twice the upper limit of normal (ULN); and eligibility to commence study drug within 6 hours after stent implantation. Principal exclusion criteria were stenting procedure involving >= stents or > 1 vessel, involving The left main coronary artery or a major bifurcation, or involving vein grafts; primary angioplasty for ongoing myocardial infarction with documented ST-segment elevation and/or elevated CPK-MB levels > 2x ULN and CPK MB levels greater than normal); persistent objective ischemia determined by 12-lead ECG between stenting and randomization; administration of oral anticoagulants, GP IIb/IIIa receptor antagonists and other antiplatelet agents, except for aspirin, within 1 month before randomization; administration of thrombolytics 2 weeks before randomization; need for anticoagulants, thrombolytic agents, or GP IIb/IIIa receptor antagonists after the procedure; percutaneous or surgical revascularization (PTCA, CABG) within 2 months before the procedure; history of allergy or intolerance or contraindication to aspirin, ticlopidine, or clopidogrel.

Additional Treatment Info: All study drugs (including aspirin) were administered on a blinded basis (double-dummy) and were to be initiated within 6 hours of completion of stenting. Patients were to receive 28 days of treatment with 250 mg BID ticlopidine and 325 mg/d aspirin (days 1 to 28). Heparin was discontinued at the end of the procedure and 4 hours before sheath removal. In cases in which stent placement was performed in the late afternoon, intravenous heparin could be continued for a few hours to avoid sheath removal during the night, provided that the total duration of administration did not exceed 36 hours. All study drugs (including aspirin) were administered on a blinded basis (double-dummy) and were to be initiated within 6 hours of completion of stenting. Patients were to receive 28 days of treatment with 75 mg/d clopidogrel and 325 mg/d aspirin (days 1 to 28). Heparin was discontinued at the end of the procedure and 4 hours before sheath removal. In cases in which stent placement was performed in the late afternoon, intravenous heparin could be continued for a few hours to avoid sheath removal during the night, provided that the total duration of administration did not exceed 36 hours.


% Female

CABG, History of

Diabetes Mellitus


of Myocardial

Infarction, Acute Angina, Unstable, History of Mueller 700 28 mo Aspirin/Clopidogrel 100mg/75mg 355 65yrs 26.2% 15% 23% 48% 11% n/a

2003 Aspirin/Ticlopidine100mg/250-

500mg 345 64yrs 26.4% 12% 21% 44% 11% n/a

Primary Objective: The primary end point was cardiovascular death during the entire follow-up period. It was defined as any death for which there was no clearly documented non-cardiac cause. The secondary end point was the composite of cardiac death and myocardial infarction (MI).

Primary Outcome(s): Mortality, Cardiovascular

Inclusion/Exclusion: Patients in whom primary or provisional stent implantation was successful (<50% residual stenosis without acute complications in the catheter laboratory resulting in death or emergency bypass grafting) were randomly assigned in equal proportions with the use of a prespecified randomization sequence to one of the antiplatelet regimens. Cardiogenic shock; mechanical ventilation; known allergy to aspirin, ticlopidine, or clopidogrel; long-term treatment with ticlopidine, clopidogrel, or warfarin; and stenting intended primarily as a bridge to coronary bypass grafting were exclusion criteria.

Additional Treatment Info: Stents were implanted with a high-pressure technique. Patients were assigned to receive clopidogrel (75 mg pd) orally for 4 weeks. The first dose of clopidogrel (75 mg) was given immediately after the procedure. All patients received aspirin (100 mg pd) for the duration of the study. Patients were scheduled for follow-up visits at our institution at six months and whenever clinically indicated thereafter. In addition, all patients were contacted by questionnaire to assess vital and functional status as well as major adverse cardiac events two years after enrollment of the last patient. If patients did not return a signed questionnaire or any uncertainties remained, a physician interviewed the patients and their family physician over the phone. All information derived from contingent hospital re-admission records or provided by the referring physicianor by the outpatient clinic was reviewed. Treatment was not blinded, but all endpoints were adjudicated by a clinical-events committee whose members were unaware of the patients treatment assignments. Stents were implanted with a high-pressure technique. Patients were assigned to receive ticlopidine (250 mg bid) orally for 4 weeks. The first dose of ticlopidine (500 mg) was given immediately after the procedure. All patients received aspirin (100 mg pd) for the duration of the study. Patients were scheduled for follow-up visits at our institution at six months and whenever clinically indicated thereafter. In addition, all patients were contacted by questionnaire to assess vital and functional status as well as major adverse cardiac events two years after enrollment of the last patient. If patients did not return a signed questionnaire or any uncertainties remained, a physician interviewed the patients and their family physician over the phone. All information derived from contingent hospital re-admission records or provided by the referring physician or by the outpatient clinic was reviewed. Treatment was not blinded, but all endpoints were adjudicated by a clinical-events committee whose members were unaware of the patients treatment assignments.


% Female

CABG, History of

Diabetes Mellitus


of Myocardial


Muller 700 30

days Aspirin/Clopidogrel 100mg/75mg 355 65yrs 26.2% 15% 23% 48% 11% n/a

2000 Aspirin/Ticlopidine100mg/250-

500mg 345 64yrs 26.4% 12% 21% 44% 11% n/a

Primary Objective: The primary cardiac endpoint included death from cardiac causes, urgent target vessel revascularization, angiographically evident TSO, or nonfatal myocardial infarction within 30 days. Death from any noncardiac cause, stroke, a severe peripheral vascular event (false aneurysms requiring surgery or prolonged ultrasound-guided compression and femoral artery dissection or occlusion requiring urgent percutaneous or surgical treatment), a hemorrhagic event requiring transfusion, or any adverse event resulting in the discontinuation of study medication were included in the primary noncardiac endpoint.

Primary Outcome(s): Cardiac Event, Any* Drug Discontinuation due to Diarrhea* Drug Discontinuation due to Hematological Abnormality* Drug Discontinuation due to Intolerance* Drug Discontinuation due to Liver Enzyme Elevation* Drug Discontinuation due to Nausea* Drug Discontinuation due to Skin Disorder* Drug Discontinuation, Any* Mortality, Other* Non-Cardiac Event* Occlusion, Stent, Thrombotic* Stroke, Any* Target Vessel Revascularization, Urgent* Thrombocytopenia OR Leukopenia

Inclusion/Exclusion: Patients in whom primary or provisional stent implantation was successful (<50% residual stenosis without acute complications in the catheter laboratory resulting in death or emergency bypass grafting) were randomly assigned in equal proportions with the use of a prespecified randomization sequence to one of the antiplatelet regimens. Cardiogenic shock; mechanical ventilation; known allergy to aspirin, ticlopidine, or clopidogrel; long-term treatment with ticlopidine, clopidogrel, or warfarin; and stenting intended primarily as a bridge to coronary bypass grafting were exclusion criteria.

Additional Treatment Info: Stents were implanted with a high-pressure technique. Patients were assigned to receive clopidogrel (75 mg pd) orally for 4 weeks. The first dose of clopidogrel (75 mg) was given immediately after the procedure. All patients received aspirin (100 mg pd) for the duration of the study. Treatment was not blinded, but all endpoints were adjudicated by a clinical-events committee whose members were unaware of the patients treatment assignments. Stents were implanted with a high-pressure technique. Patients were assigned to receive ticlopidine (250 mg bid) orally for 4 weeks. The first dose of ticlopidine (500 mg) was given immediately after the procedure. All patients received aspirin (100 mg pd) for the duration of the study. Treatment was not blinded, but all endpoints were adjudicated by a clinical-events committee whose members were unaware of the patients treatment assignments.

Risk Of Bias Sequence Generation: :UNCLEAR - Sequence generation process described only as ‘prespecified randomization sequence’ Allocation Concealment: UNCLEAR - No description of methods for allocation concealment Blinding: LOW - Although open-label, outcome assessors were blinded; unlikely to affect objective outcomes:: mortality, MI

Exception: Coronary revascularization, bleeding : HIGH – Knowledge of treatment may impact decision for revascularization, detection and/or tmt for major bleeding

Incomplete Outcome Data: UNCLEAR - Only the most severe CV event reported (MI, revascularization)– may be under-reporting of CV events when multiple events occur, however no data available to assess

Exception: mortality, bleeding: LOW – clinical follow-up was available for 99.9% of study group Selective Outcome Reporting: .LOW – Reported outcomes as specified in methodology Other Sources of Bias: LOW – No other issues identified


% Female

CABG, History of

Diabetes Mellitus


of Myocardial


Taniuchi 1016 30

days Aspirin/Ticlopidine 325mg/500mg 522 63.1yrs 39.8% 21% 28.4% 28.7% 42.1% n/a

2001 Aspirin/Clopidogrel 325mg/300mg 494 63.6yrs 38.5% 21.5% 30% 32.4% 40.7% n/a

Primary Objective: The primary endpoint was the failure to complete 2 weeks of the initiated thienopyridine, in conjunction with 325 mg of aspirin. Secondary endpoints were thrombocytopenia (platelet count < 100,000), major bleeding (requiring surgery or transfusion of >2 units of packed red blood cells), cardiac death, Q-wave myocardial infarction (defined by the development of new Q waves in 2 or more ECG leads), stent thrombosis (defined angiographically as a total occlusion of the stented segment), and target vessel revascularization (percutaneous or by bypass grafting).

Primary Outcome(s): Drug Discontinuation due to GI Disorder* Drug Discontinuation due to Hematological Abnormality* Drug Discontinuation due to Hemorrhage Event* Drug Discontinuation due to Other Reason* Drug Discontinuation due to Skin Disorder* Drug Discontinuation, Any

Inclusion/Exclusion: Patients with successful implantation (defined as <20% residual stenosis, with TIMI 2 or TIMI 3 flow) of an FDA-approved stent in a native coronary artery or in a coronary bypass graft were screened for enrollment. Exclusion criteria were (1) prior intolerance to aspirin, ticlopidine, or clopidogrel, (2) a comorbidity with expected survival of < 6 months, and (3) prior enrollment in a separate research protocol. Patients who were treated with a thienopyridine before catheterization were not enrolled.

Additional Treatment Info: Stent implantation was performed by 1 of 4 operators, using standard techniques. All enrolled patients had received 325 mg of aspirin before the procedure. After a stable stent implantation procedure, the patients were initiated, in a randomized, open-label manner, to therapy with twice-daily dosing of ticlopidine (500 mg). Oral loading doses of with ticlopidine were administered within 1 hours of stent implantation. Procedural use of intravenous IIb/IIIa inhibitors and post procedure anticoagulation were left to the discretion of the operator. Stent implantation was performed by 1 of 4 operators, using standard techniques. All enrolled patients had received 325 mg of aspirin before the procedure. After a stable stent implantation procedure, the patients were initiated, in a randomized, open-label manner, to therapy with single-daily dosing of clopidogrel (300 mg) for two weeks. Oral loading doses of with clopidogrel were administered within 1 hours of stent implantation. Procedural use of intravenous IIb/IIIa inhibitors and post procedure anticoagulation were left to the discretion of the operator.

Risk Of Bias: Sequence Generation: UNCLEAR – No description of sequence generation process Allocation Concealment: UNCLEAR - No description of methods for allocation concealment Blinding: HIGH – Open label – Knowledge of treatment may impact decision for revascularization, detection and/or tmt for major bleeding

Exception: mortality: LOW – Lack of blinding unlikely to impact short term mortality Incomplete Outcome Data: LOW - Follow-up complete on all participants, very low discontinuations Selective Outcome Reporting: .HIGH - Secondary cardiac outcomes not adequately described; bleeding included in primary tolerability outcome - was not adequately described Other Sources of Bias: LOW – No other issues identified


% Female

CABG, History of

Diabetes Mellitus


of Myocardial

Infarction, Acute Angina, Unstable, History of Wiviott 13608 15 mo Aspirin/Prasugrel _/10-60mg 6813 61yrs 25% 8% 23% 18% n/a n/a

2007 Aspirin/Clopidogrel _/75-300mg 6795 61yrs 27% 7% 23% 18% n/a n/a

Primary Objective: The primary efficacy end point was a composite of the rate of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke during the follow-up period. Key secondary end points at 30 and 90 days were the primary composite end point and a composite of death from cardiovascular causes, nonfatal myocardial infarction, or urgent target-vessel revascularization. Key secondary end points for the entire follow-up period were stent thrombosis and a composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or rehospitalization due to a cardiac ischemic event. Key safety end points were TIMI major bleeding not related to coronary-artery bypass grafting (CABG), non–CABG-related TIMI life-threatening bleeding, and TIMI major or minor bleeding.

Primary Outcome(s): Mortality, Cardiovascular OR Myocardial Infarction, Non-Fatal OR Stroke, Non-Fatal

Inclusion/Exclusion: The inclusion criteria for patients with unstable angina or non–ST-elevation myocardial infarction were ischemic symptoms lasting 10 minutes or more and occurring within 72 hours before randomization, a TIMI risk score of 3 or more, and either ST-segment deviation of 1 mm or more or elevated levels of a cardiac biomarker of necrosis. Patients with ST-elevation myocardial infarction could be enrolled within 12 hours after the onset of symptoms if primary PCI was planned or within 14 days after receiving medical treatment for ST-elevation myocardial infarction. Full exclusion criteria have been published previously. Key exclusion criteria included an increased risk of bleeding, anemia, thrombocytopenia, a history of pathologic intracranial findings, or the use of any thienopyridine within 5 days before enrollment. The protocol was approved by the institutional review boards associated with all participating centers, and written informed consent was provided by all patients.

Additional Treatment Info: A loading dose of 60 mg of prasugrel was administered, in a double-blind manner, anytime between randomization and 1 hour after leaving the cardiac catheterization laboratory. After PCI, patients received maintenance doses of prasugrel (10 mg) daily. Use of aspirin was required, and a daily dose of 75 to 162 mg was recommended. A loading dose of study medication of 300 mg of clopidogrel was administered, in a double-blind manner, anytime between randomization and 1 hour after leaving the cardiac catheterization laboratory. After PCI, patients received maintenance doses of clopidogrel (75 mg) daily. Use of aspirin was required, and a daily dose of 75 to 162 mg was recommended.

Risk Of Bias: Sequence Generation: UNCLEAR – No description of sequence generation process Allocation Concealment: UNCLEAR - No description of methods for allocation concealment Blinding: LOW – Double blind and outcome assessors were blinded to treatment also Incomplete Outcome Data: LOW – Only 0.1% LTFU Selective Outcome Reporting: .LOW – Reported outcomes as specified in methodology Other Sources of Bias: LOW – No other issues identified



Study N Length Interventions Dose n Mean Age %

Female

CABG, History

of Diabetes Mellitus

Myocardial Infarction, History of

Myocardial Infarction,

Acute Angina, Unstable, History of

Wallentin 18624 12 mo Aspirin/Ticagrelor 75-100 mg/90 mg

933362yrs

(median)28% 6% 25% 20% n/a 17%

2009 Aspirin/Clopidogrel 75-100

mg/75mg9291

62yrs (median)

28% 6% 25% 21% n/a 17%

Primary Objective: The primary efficacy variable was the time to the first occurrence of composite of death from vascular causes, myocardial infarction, or stroke. The principle secondary efficacy end point was the primary efficacy variable studied in the sub-group of patients for whom invasive management was planned at randomization. Additional secondary end points (analyzed for the entire study population) were the composite of death from any cause, myocardial infarction, or stroke; the composite of death from vascular causes, myocardial infarction, stroke, severe recurrent cardiac ischemia, recurrent cardiac ischemia, transient ischemia attack, or other arterial thrombotic events; myocardial infarction alone; death from cardiovascular causes alone; stroke alone; and death from any cause.

Primary Outcome(s): Time to the first occurrence of composite of death from vascular causes, myocardial infarction, or stroke.

Inclusion/Exclusion: Patients were eligible for enrollment if they were hospitalized for an acute coronary syndrome, with or without ST-segment elevation, with an onset of symptoms during the previous 24 hours. For patients who had an acute coronary syndrome without ST-segment elevation, at least two of the following three criteria had to be met: ST-segment changes on electrocardiography, indicating ischemia; a positive test of a biomarker, indicating myocardial necrosis; or one of several risk factors (age ≥60 years; previous myocardial infarction or coronary-artery bypass grafting [CABG]; coronary artery disease with stenosis of ≥50% in at least two vessels; previous ischemic stroke, transient ischemic attack, carotid stenosis of at least 50%, or cerebral revascularization; diabetes mellitus; peripheral arterial disease; or chronic renal dysfunction, defined as a creatinine clearance of <60 ml per minute per 1.73 m2 of body surface area). For patients who had an acute coronary syndrome with ST-segment elevation, the following two inclusion criteria had to be met: persistent ST-segment elevation of at least 0.1 mV in at least two contiguous leads or a new left bundle-branch block, and the intention to perform primary PCI. Major exclusion criteria were any contraindication against the use of clopidogrel, fibrinolytic therapy within 24 hours before randomization, a need for oral anticoagulation therapy, an increased risk of bradycardia, and concomitant therapy with a strong cytochrome P-450 3A inhibitor or inducer.

Additional Treatment Info: Ticagrelor was given in a loading dose of 180 mg followed by a dose of 90 mg twice daily. Patients in the clopidogrel group who had not received an open-label loading dose and had not been taking clopidogrel for at least 5 days before randomization received a 300-mg loading dose followed by a dose of 75 mg daily. Others in the clopidogrel group continued to receive a maintenance dose of 75 mg daily. Patients undergoing PCI after randomization received, in a blind fashion, an additional dose of their study drug at the time of PCI: 300 mg of clopidogrel, at the investigator’s discretion, or 90 mg of ticagrelor for patients who were undergoing PCI more than 24 hours after randomization. In patients undergoing CABG, it was recommended that the study drug be withheld — in the clopidogrel group, for 5 days, and in the ticagrelor group, for 24 to 72 hours. All patients received acetylsalicylic acid (aspirin) at a dose of 75 to 100 mg daily unless they could not tolerate the drug. For those who had not previously been receiving aspirin, 325 mg was the preferred loading dose; 325 mg was also permitted as the daily dose for 6 months after stent placement.

Risk Of Bias: Sequence Generation: LOW – Clear description of randomization using a block method (retrieved from published study protocol) Allocation Concealment: UNCLEAR - No description of methods for allocation concealment Blinding: LOW/HIGH – Double blind however it was unclear if outcome assessors were blinded to treatment also; An independent data and safety monitoring board had access to unblinded data Incomplete Outcome Data: LOW – Only 0.03 LTFU Selective Outcome Reporting: .LOW – Reported outcomes as specified in methodology Other Sources of Bias: LOW – No other issues identified




Clinical Question: Is beta-blocker therapy recommended for patients with CAD: With normal LV function? Without an MI? Without angina?

When should beta-blockers be started in patients with CAD: Post event? Post-procedure? How long should beta-blockers be continued in patients with

CAD: Post event? Post-procedure?

Population: Adult patients with the following characteristics: A history of ischemic heart disease, MI, CABG and/or PCI, or

documented CAD (by angiography of noninvasive testing) No contraindications to beta-blocker therapy

Health Intervention: Beta-blocker therapy





Frequency of angina episodes



Search Strategy 11



No. Included/ Total

Retrieved


10/01/07 -

01/05/10

0/6 PubMed Adrenergic beta-Antagonists [Mesh] OR Esmolol [Mesh] or metoprolol [Mesh] or carvedilol [Mesh] or atenolol [Mesh] or timolol [Mesh] or bisoprolol [Mesh] or sotolol [Mesh] or labetolol [Mesh] AND Myocardial Infarction [Mesh] AND Myocardial ischemia [Mesh]


10/01/07 -

01/05/10

0/28


10/01/07 -

01/05/10

0/0 PubMed Adrenergic beta-Antagonists [Mesh] AND Unstable Angina


10/01/07 -

01/05/10

0/0


10/01/07 -

01/05/10

0/0 PubMed Adrenergic beta-Antagonists [Mesh] AND asthma [Mesh], heart failure, congestive [Mesh] Randomized

Controlled Trial, English, Human

10/01/07 -

01/05/10

0/0


10/01/07 -

01/05/10

0/0 PubMed Adrenergic beta-Antagonists [Mesh] AND pulmonary disease, chronic obstructive [Mesh] Randomized


10/01/07 -

01/05/10

0/0


10/01/07 -

01/05/10

0/0 PubMed Adrenergic beta-Antagonists [Mesh] AND heart failure, congestive [Mesh]


10/01/07 -

01/05/10

0/0





No. Included/ Total

Retrieved


3/26/2006 to

02/01/08

0/13 PubMed Adrenergic beta-Antagonists [Mesh] OR Esmolol [Mesh] or metoprolol [Mesh] or carvedilol [Mesh] or atenolol [Mesh] or timolol [Mesh] or bisoprolol [Mesh] or sotolol [Mesh] or labetolol [Mesh] AND Myocardial Infarction [Mesh] AND Myocardial ischemia [Mesh]


3/26/2006 to

02/01/08

0/56


3/26/2006 to

02/01/08

0/0 PubMed Adrenergic beta-Antagonists [Mesh] AND Unstable Angina


3/26/2006 to

02/01/08

0/2


3/26/2006 to

02/02/08

0/0 PubMed Adrenergic beta-Antagonists [Mesh] AND asthma [Mesh], heart failure, congestive [Mesh] Randomized


3/26/2006 to

02/02/08

0/0


3/26/2006 to

02/02/08

0/1 PubMed Adrenergic beta-Antagonists [Mesh] AND pulmonary disease, chronic obstructive [Mesh] Randomized


3/26/2006 to

02/02/08

0/0


3/26/2006 to

02/02/08

0/3 PubMed Adrenergic beta-Antagonists [Mesh] AND heart failure, congestive [Mesh]


3/26/2006 to

02/02/08

0/35

Note: The literature search for the 2006 update was conducted by Clin-eguide and is documented in the 2006 CAD Guideline. Note: In addition to the searches above, the 2010 update included a search of Clinical Evidence in order to identify relevant publications and meta-analyses.




Clinical Question: Is beta-blocker therapy recommended for patients with CAD and mild to moderate reversible airway disease or chronic obstructive pulmonary disease (COPD)?


documented CAD (by angiography of noninvasive testing) Asthma or chronic obstructive pulmonary disease (COPD) No contraindications to beta-blocker therapy


Beta-blocker therapy






Clinical Question: Is beta-blocker therapy recommended for patients with CAD and Heart Failure?


documented CAD (by angiography of noninvasive testing) Heart Failure No contraindications to beta-blocker therapy


Beta-blocker therapy







Evidence Tables 13

Table 13.1: Beta-Blocker Therapy, Meta Analysis

Study Population Treatment Groups

Size & Drug Results Comments Ko DT, Hebert PR, Coffey CS, Sedrakyan A, Curtis JP, Krumholz HM. Beta-blocker therapy and symptoms of depression, fatigue, and sexual dysfunction. JAMA 2003;288(3):351-357. (Meta-Analysis) # studies found: 42 # studies included: 15 including over 35,000 patients

RCTs of beta-blockers used in the treatment of MI (6 trials), heart failure (3 trials), or hypertension (6 trials). Few elderly patients enrolled in trials included. Random-effects model employed.

Outcomes of interest Fatigue* Depressive symptoms Sexual dysfunction *w/ early generation β-blocker w/ late generation β -blocker

Relative Risks (95% CI:) 1.15 (1.05-1.26) 1.12 (0.89-1.41) 1.10 (0.96-1.25) 1.78 (1.08-2.93) 1.06 (1.00-1.12)

Conclusions No significantly increased risk of depressive symptoms or sexual dysfunction was found among patients assigned to beta-blocker therapy. Use of beta-blockers was associated with a small, but significantly increased risk of fatigue. The associated fatigue was significantly higher for early generation than for late generation beta-blocker use. Limitations Authors were unable to calculate true incidence due to absence of data.



Table 13.2:

Study, Total n Treatment Groups Size &

Drug Study Population Outcome Study Endpoint Beta-blockers: Clinical questions When should beta-blockers be started in patients with CAD: post event post-procedure How long should beta-blockers be continued in patients with CAD: post event post-procedure

Chen ZM, Pan HC, Chen YP, et al, COMMIT (ClOpidogrel and Metoprolol in Myocardial Infarction Trial) collaborative group. Early intravenous then oral metoprolol in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet 2005;366(9497):1622-32 Study Name: COMMIT Study Design: multicentre randomised Subject Number: 45852 Duration: Up to 4 weeks (mean 15 days)

Study controls : Placebo Treatment (name : dose : route : frequency) Metoprolol:5 mg IV q2-3min 1-3 doses then Metoprolol 200 mg/day PO q6h for 2 days then Metoprolol 200 mg/day PO od mean 15 days Evidence Grade: A1

Indications: Cardiogenic shock, Cardiovascular disorders, Heart arrest, Heart failure, Hypertension, Myocardial infarction, Respiration disorders, Ventricular fibrillation Subject characteristics: patients presented within 6h (34% of patients), 6 to <13h (33%), or 13-24h (33%) of symptom onset. ECG results showed ST-segment elevation (87% of patients), bundle branch block (6%) or ST-segment depression without ST-segment elevation (7%). Seventy-five percent of patients were in Killip class I, 20% were in class II, and 5% in class III. Medical histories included previous myocardial infarction (8% of patients) and previous hypertension (43%). Age: adult, elderly, mean 61 years

arrhythmias cardiovascular events death rate heart arrest event rate heart failure event rate myocardial infarction event rate stroke event rate

Early beta-blocker treatment decreased the risks of reinfarction (odds ratio [OR] 0.82; 95% CI: 0.72, 0.92; p <= 0.001) and ventricular fibrillation (OR 0.83; 95% CI: 0.75, 0.93; p <= 0.001), but increased the risk of cardiogenic shock (OR 1.30; 95% CI: 1.19, 1.41; p <= 0.001), compared with placebo, in patients with acute ST-segment elevation myocardial infarction.




Clinical Question: Is calcium channel blocker therapy effective for CAD patients with normal left ventricular function and contraindications to beta-blockers?

Population: Adult patients with the following characteristics: A history of ischemic heart disease, MI, CABG, and/or PCI or

documented CAD (by angiography or noninvasive testing) or with stable or unstable angina

No contraindications to calcium channel blocker therapy


Calcium channel blocker therapy No treatment with calcium channel blockers







Search Strategy 14




No. Included/ Total

Retrieved


3/26/06 to

02/01/08 0/1

PubMed ((((“myocardial ischemia”[MeSH] OR “myocardial revascularization”[MeSH] OR “myocardial infarction”[MeSH]) AND “calcium channel blockers” [MeSH])))


3/26/06 to

02/01/08 0/13

Cochrane Calcium Channel Blockers and coronary artery disease

Systematic reviews

1st quarter 2006

Accessed 5/23/06

0/6

Clinical Evidence

Cardiovascular disorders: Secondary prevention of ischemic events

Calcium Channel Blockers

Search July 2004

Accessed 5/23/06

0/1


11/5/03 to

4/26/06 0/1

PubMed ((((“myocardial ischemia”[MeSH] OR “myocardial revascularization”[MeSH] OR “myocardial infarction”[MeSH]) AND “calcium channel blockers” [MeSH])))


11/5/03 to

4/26/06 0/42




Clinical Question: Is calcium channel blocker therapy effective for CAD patients with left ventricular systolic dysfunction?


documented CAD (by angiography of noninvasive testing) Left ventricular systolic dysfunction No contraindications to calcium channel blocker therapy


Calcium channel blocker therapy






Clinical Question: What diet is recommended for adult patients with CAD?


documented CAD (by angiography or noninvasive testing) No known food allergies, intolerances, restrictions or

nutritional deficiencies


Therapeutic diet







Search Strategy 16



No. Included/ Total

Retrieved

PubMed "Myocardial Ischemia"[Mesh] AND "Diet"[Mesh] OR "Diet/therapy"[Mesh]

Humans, Meta-Analysis,


English, All Adult

12/1/2005 to

1/20/2008

1/19

PubMed "Folic Acid"[Mesh] OR "Vitamin B 6"[Mesh] OR "Vitamin B 12"[Mesh] AND "Myocardial Ischemia"[Mesh]



English, All Adult

12/1/2005 to

1/20/2008

1/14

PubMed ("Vitamin E"[Mesh] OR "Ascorbic Acid"[Mesh] OR "beta Carotene"[Mesh]) AND "Myocardial Ischemia"[Mesh]



English, All Adult

12/1/2005 to

1/20/2008

0/9

PubMed "Vitamins"[Mesh] OR "Folic Acid"[Mesh] OR "beta Carotene"[Mesh] OR "Antioxidants"[Mesh] AND “Coronary Disease"[Mesh]



English, All Adult

12/1/2005 to

1/20/2008

0/16





Clinical Question: Is a modification of dietary fat intake recommended for adult patients with CAD?


documented CAD (by angiography or noninvasive testing) No known food allergies, intolerances, restrictions or

nutritional deficiencies

Health Interventions:

Low total dietary fat intake Decreased saturated fatty acid intake Increased polyunsaturated fatty acid intake Increased n-3 polyunsaturated fatty acid intake






Clinical Question: Are dietary supplements recommended for adult patients with CAD?


documented CAD (by angiography or noninvasive testing) No known nutritional deficiencies


Supplemental B vitamins Supplemental antioxidants

(Vitamins C & E, beta carotene)







Evidence Tables 18

Table 18.1: Meta-Analyses: Diet Therapy

Study, Total n Study Population

Treatment Groups Size & Drug Results Comments Bucher HC, Hengstler, Schindler C, Meier G. n-3 Polyunsaturated fatty acids in coronary artery disease: A meta-analysis of randomized controlled trials. .Am J Med 2002;112:298-304. Meta-analysis Trials = 11 2 of dietary intervention; 9 of supplementation Mean follow-up = 20 months (range = 6 to 46 months) n = 15,806

All patients had either MI or angiographically established CAD for at least 6 months. Trials of restricted patients who had undergone coronary bypass surgery or heart transplantation were excluded. Intervention Group = 7,951 In the 9 trials of supplementation, dose of eicosapentaenoic acid varied from 0.3 to 0.6 g; dose for docosahexanoic acid varied from 0.6 to 3.7 g Control Group = 7,855 Data pooled using a fixed-effects model; random effects model employed if Breslow-Day test for heterogeneity yielded a p value < 0.10.

Outcome Nonfatal MI Fatal MI Sudden Death Overall Mortality No difference in summary estimates observed between dietary and supplemental interventions of n-3 PUFA’s for all endpoints.

Risk Ratio (95% CI) 0.8 (0.5 to 1.2, p = 0.16) Heterogeneity p = 0.01 0.7 (0.6 to 0.8, p < 0.001) Heterogeneity p > 0.20 0.7 (0.6 to 0.9, p < 0.01) Heterogeneity p > 0.20 0.8 (0.7 to 0.9, p < 0.001) Heterogeneity p > 0.20 NNT in low risk patients = 250 patients for 1.5 years to prevent 1 death. NNT in high risk patients = 24 patients for 1.5 years to prevent 1 death.

Conclusions Dietary and supplemental intake of n-3 polyunsaturated fatty acids reduces overall mortality, mortality due to MI, and sudden death in patients with coronary artery disease. Limitations Amount and type of n-3 polyunsaturated fatty acids varied considerably. Low scores for quality for those trials with open intervention design or unblinded clinical endpoint assessments.



Table 18.2: RCTs: Diet Therapy


Size & Drug Study Population Results Comments deLorgeril M, Salen P, Martin JL, Monjaud I, Delaye J, Mamelle N. Mediterranean diet, traditional risk factors, and the rate of cardiovascular complications after myocardial infarction: Final report of the Lyon Diet Heart Study. Circulation 1999;99:779-785. RCT Follow up: Mean = 46 months Initial n: 605 Final n: 423

Mediterranean α-linolenic acid-rich diet Treatment Group n = 302 “Prudent Diet” Control Group, n = 303 Treatment diet differed from control by substitution of butter and cream with olive and canola oils, substitution of meat with poultry and increased consumption of bread, fruit, vegetables, and fish.

Within 6 months following first MI (Exclusions: Heart failure, hypertension, inability to complete exercise test, ventricular arrhythmias, atrioventricular block)

Cardiovascular death Total major primary endpoints All-cause mortality Absolute Risk (%) for Total Primary Endpoints (cardiac deaths plus nonfatal MI

Risk Ratio (95% CI; p value) 0.35 (0.15 to 0.83; p=0.01) 0.28 (0.15 to 0.53; p=0.0001) 0.44 (0.21 to 0.94; p=0.03) Mediterranean Diet Group=14(4.6%) Prudent Diet Control Group=44(14.5%) ARR=9.9%*

NNT is 10 to prevent 1 cardiac death or nonfatal MI in 46 months*. *computed by Kaiser Permanente staff

Conclusions The rate of cardiac death and nonfatal infarction in the treatment group after 46 months is similar to that observed in the previously published results at 27 months. (See following evidence table). Since most subjects were still adhering to the treatment diet after 5 years, this supports the feasibility of long-term dietary change.



Table 18.2:


Size & Drug Study Population Results Comments deLorgeril M, Renaud S, Mamelle N, Salen P, Martin JL, Monjoud I, Guidollet J, Touboul P, Delaye J. Mediterranean alpha-linolenic acid-rich diet in secondary prevention of coronary heart disease. Lancet 1994;343:1454-1459. RCT Follow up: Mean = 27 months Initial n: 605 Final n: 584

Mediterranean α-linolenic acid-rich diet Treatment Group n = 302 “Prudent Diet” Control Group, n = 303 Treatment diet differed from control by substitution of butter and cream with olive and canola oils, substitution of meat with poultry and increased consumption of bread, fruit, vegetables, and fish.

Within 6 months following first MI (Exclusions: Heart failure, hypertension, inability to complete exercise test, ventricular arrhythmias, atrioventricular block)

Cardiovascular death Total major primary endpoints All-cause mortality Absolute Risk (%) For Total Primary Endpoints (CV deaths, nonfatal MI)

Risk Ratio(95% CI; p value) 0.24 (0.07 to 0.85; p=0.02) 0.27 (0.12 to 0.59; p=0.001) 0.30 (0.11 to 0.82; p=0.02) Mediterranean Diet Group=8(2.7%) Prudent Diet Control Group=33(10.9%) ARR=8.2%*

*NNT is 12 to prevent 1 cardiac death or nonfatal MI in 27 months. *computed by Kaiser Permanente staff

Conclusions Survivors of a first MI assigned to a Mediterranean-type diet had a reduced rate of recurrence of other cardiac events, and overall mortality. Limitations Dietary intake data only obtained from 192 Controls and 219 treated subjects at follow-up.



Table 18.3:


Size & Drug Study Population Results Comments Singh RB, Dubnov G, Niaz MA, Ghosh S, Singh R, Rastogi SS, Manor O, Pella D, Berry EM. Effect of an Indo-Mediterranean diet on progression of coronary artery disease in high risk patients (Indo-Mediterranean Diet Heart Study): a randomized single-blind trial. Lancet 2002;360:1455-61. RCT Follow up: 24 months Initial n: 1,000 Final n: 1,000

Indo-Mediterranean Diet Treatment Group n = 499 Step 1 NCEP Diet Control Group n = 501 Treatment diet differed from control by inclusion of at least: 250 to 300 g of fruit; 125 to 150 g of vegetables; 25 to 50 g of walnuts or almonds; 400 to 500 g of whole grains, legumes, rice, maize and wheat

1 or more risk factors for CAD: Hypertension Hypercholesterolemia Diabetes Angina Previous MI (Exclusions: Cancer, chronic diarrhea/dysentery, blood urea > 6.6 mmol/L, arthritis, refusal of diet or lab testing, death prior to randomization)

Nonfatal MI Fatal MI Sudden cardiac death Total cardiac endpoints Absolute Risk (%) For Total Cardiac Endpoints (Nonfatal MI, fatal MI, Sudden cardiac death)

Unadjusted Rate Ratio (95% CI) 0.49 (0.29 to 0.81) 0.69 (0.33 to 1.45) 0.37 (0.14 to 0.94) 0.50 (0.34 to 0.73) Indo-Mediterranean Diet Group =39(7.8%) Step 1 NCEP Control Group =76(15.2%) ARR=7.4%*

Adjusted Rate Ratio (95% CI) 0.47 (0.28 to 0.79) 0.67 (0.31 to 1.42) 0.33 (0.13 to 0.86) 0.48 (0.33 to 0.71) *NNT is 14 to prevent 1 nonfatal MI, fatal MI, or sudden cardiac death in 24 months. *computed by Kaiser Permanente staff

Conclusions Consumption of an Indo-Mediterranean diet resulted in statistically significant reductions in nonfatal MI, sudden cardiac death, and total cardiac endpoints. Limitations Non-Western population.



Table 18.4:


Size & Drug Study Population Results Comments Singh RB, Rastogi SS, Verma R. Laxmi B Singh R, Ghosh S, Niaz MA. Randomized controlled trial of cardioprotective diet in patients with recent acute myocardial infarction: Results of one year follow-up. BMJ 1992;304:1015-1019. RCT Follow up: 12 months Initial n: 406 Final n: 406

Diet Treatment Group n = 204 AHA “Prudent Diet” Control Group n = 202 Treatment diet differed from control by inclusion of (at least 400 g of) fruits and vegetables and pulses (legumes) nuts and fish.

Patients with acute MI or unstable angina pectoris (Exclusions: Cancer, diarrhea/dysentery, blood urea > 400mg/l, refusal of diet, noncardiac chest pain or death prior to randomization)

Nonfatal MI Fatal MI Sudden cardiac death Total cardiac mortality All cardiac events Absolute Risk (%) For Total Cardiac Endpoints (Nonfatal MI, fatal MI, Sudden cardiac death)

Relative Risk (95% CI) 0.62 (-0.42 to 0.83) 0.68 (0.32 to 1.03) 0.46 (0.12 to 0.29) 0.58 (0.34 to 0.83) 0.60 (0.31 to 0.75) Treatment Diet Group=50(24.5%) “Prudent Diet” Control Group=82(40.6%) ARR=16.1%* *NNT is 6 to prevent 1 cardiac death, nonfatal MI, or fatal MI in 12 months. *computed by Kaiser Permanente staff

Conclusions Consumption of a diet high in fruits, vegetables, legumes, nuts and fish resulted in a statistically significant reduction in cardiac events, including total cardiac mortality. Limitations Non-Western population.



Table 18.5: RCTs: Dietary Fat Modification -- n-3 Polyunsaturated Fatty Acids


Size & Drug Study Population Results Comments Singh RB, Niaz MA, Sharma JP, Kumar R, Rastogi V, Moshiri M. Randomized, double-blind placebo-controlled trial of fish oil and mustard oil in patients with suspected acute myocardial infarction: The Indian Experiment of Infarct Survival. Cardiovasc Drugs Ther 1997;11:485-491. RCT Follow up: 1 year Initial n: 360 Final n: 360

Fish oil (1.08 g/d eicosapentaenoic acid [EPA]) n = 122 Mustard oil (2.9 g/d α-linolenic acid [ALA]) n = 120 Placebo n = 118

Hospital admissions with AMI in preceding 24 hours (Exclusions: Those who died immediately after admission or who refused consent.)

Nonfatal reinfarction Sudden cardiac death Total cardiac mortality All cardiac events Absolute Risk (%) For Total Cardiac Endpoints (nonfatal MI, cardiac mortality, sudden cardiac death)

Relative Risk (95% CI) for Fish oil v Placebo 0.51 (0.23 to 1.28) 0.24 (0.03 to 2.0) 0.52 (0.22 to 1.21) 0.70 (0.29 to 0.90) Fish oil-treated Group=30(24.6%) Mustard oil-treated Group=34(28.3%) Placebo Group =41(34.8%) ARR for Fish oil v. Placebo=10.2% ARR for Mustard oil v. Placebo=6.5%*

Relative Risk (95% CI) for Mustard oil v Placebo 0.59 (0.24 to 1.40) 0.24 (0.03 to 2.0) 0.60 (0.23 to 1.40) 0.81 (0.30 to 1.12) *NNT for fish oil is 10 and NNT for mustard oil is 15 to prevent 1 cardiac death or nonfatal MI in 1 year. *computed by Kaiser Permanente staff.

Conclusions After 1 year post AMI, cardiac events were lower in fish oil and mustard oil supplemented groups than in the placebo groups. Authors suggest that early intervention (within 24 hours of symptom-onset) may contribute to positive findings. Limitations Low number of total events in the study period limits the strength of the findings.



Table 18.6:


Size & Drug Study Population Results Comments Marchioli R, Barzi F, Bomba E, Cieffo C, DiGregorio D, Mascio R, Franzosi MG, Geraci E, et al. on behalf of the GISSI-Prevenzione Investigators. Early protection against sudden death by n-3 polyunsaturated fatty acids after myocardial infarction: Time-course analysis of the results of the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico (GISSI)-Prevenzione. Circulation 2002;105(16):1897-1903. RCT Follow up: 3.5 years at 172 centers Initial n: 11,323 Final n: 11,323

n-3 PUFA Treatment Group (850 to 882 mg EPA & DHA/d in 1:2 ratio) n = 2,386 Vitamin E (300 mg/d) n = 2,830 n-3 PUFA plus Vit E n = 2,830 Untreated n = 2,828

Patients with recent (≤ 3 months, median 16 days) myocardial infarction. (Exclusions: Contraindications to the supplements; unfavorable short term outlook (e.g., heart failure, cancer, etc).

Relative Risk (95% CI) for: All fatal events Sudden death Absolute Risk (%) For Total Cardiac Endpoints (CV death, nonfatal MI, nonfatal stroke)

At 3 months 0.59 (0.36 to 0.97) 0.44 (0.19 to 1.02)* Assumes statistical significance by month 4 (RR=0.467; 95% CI: 0.219-0.995). At 3 months: n-3 PUFA-treated Group=122(2.3%) Untreated control Group=136(2.4%) ARR at 3 months=0.1%* * computed by Kaiser Permanente staff.

At 42 months 0.79 (0.66 to 0.93) 0.55 (0.39 to 0.77) At 42 months: n-3 PUFA-treated Group=556(10.7%) Untreated control Group=621(11.0%) ARR at 42 months=0.3%* NNT= 164 in 3.5 years

Conclusions The significant reduction in mortality with a low-dose of n-3 PUFA among post-MI patients in the GISSI trial appears within 3 months of treatment and is explained mainly by a decrease in sudden death. Findings support the hypothesis of an antiarrhythmic and/or antifibrillatory role of n-3 PUFA’s. Limitations: The attribution of cause of death to sudden death may be limited by the definition.



Table 18.7:


Size & Drug Study Population Results Comments Maresta A, Balduccelli M, Varani E, Marzilli M, Galli C, Heiman F, Lavezzari M, Stragliotto E, De Catarina R, on behalf of the on behalf of the ESPRIT Investigators. Prevention of postcoronary angioplasty restenosis by omega-3 fatty acids: Main results of the Esapent for prevention of restenosis Italian study (ESPRIT).Am Heart J. 2002;143(6):1045 RCT Follow up: 6 months Initial n: 339 Final n: 257 At 17 centers throughout Italy

Six 1g capsules of 3g EPA plus 2.1 g DHA/day (with 3 mg vitamin E) started 1 month before PCI and given for 1 month thereafter; continued at half dose for 6 months n = 125 Olive oil placebo (with 3 mg vitamin E) on same treatment schedule n = 132

Patients with clinical indication for PCI. (Exclusions: <18 years, or >75 years; < 15 days following AMI, unstable disease preventing pretreatment, culprit lesions, excessive bleeding risk, concomitant disease, allergy or hypersensitivity to fish products, other factors precluding follow-up.)

>50% final restenosis per patient in: Omega-3 Fatty Acid Group Placebo Group >50% loss of initial gain per patient in: Omega-3 Fatty Acid Group Placebo Group

Restenosis Rate 31.2% 40.9% 33.6% 37.1%

x2, p value 1.62, 0.05 0.58, 0.28

Conclusions Treatment 1 month before PCI with omega-3 fatty acids produces a small decrease in restenosis rate compared with placebo, Clinical applicability is questionable. Limitations Dose, formulation, term of treatment, and biological activity of the placebo, sensitivity and compliance of the populations have varied in previous studies, making comparisons difficult.



Table 18.8: Meta-Analysis: Dietary Supplements – Folic Acid


Treatment Group size and Drug Results Conclusions Bazzano (2006) # studies found: 165 # studies included: 12 Selected studies were analyzed using a random-effect model. Relative risk (RR) was used as a measure of association between FA supplementation and risk of CVD, CHD, stroke, or all-cause mortality. Heterogeneity tests, funnel plots, Egger linear regression and Begg rank correlation tests, and sensitivity analyses were performed.

Twelve RCTs of FA supplementation in pts w/CHD or ESRD were selected, with a total of 16,958 individuals. Outcome measures: CVD events, CHD events, stroke, all-cause mortality FA Dosage: 0.5mg/d-15mg/d Follow-up range: 6 mo-5 yr

All trials showed a reduction in homocysteine levels ranging from –1.5 to –26.0 μmol/L. Event rate and RR: CVD: 18.3% FA grp vs. 19.2% Ctr grp; RR 0.95 (95%CI: 0.88-1.03) CHD: 11.4% FA grp vs. 10.6% Ctr grp; RR 1.04 (95%CI: 0.92-1.17) Stroke: 4.7% FA grp vs. 5.8% Ctr grp; RR 0.86 (95%CI: 0.71-1.04) All-cause Mortality: 12.0% FA grp vs. 12.3% Ctr grp; RR 0.96 (95%CI: 0.88-1.04)

Among patients with a history of CVD or ESRD, no significant benefit or harm of FA supplementation on the risk of CVD, CHD, stroke, or all-cause mortality was found.

CHD = Coronary Heart Disease CVD = Cardiovascular Disease ESRD = End-stage Renal Disease FA = Folic Acid NR = Not Reported RR = Relative Risk



Table 18.9: Meta-Analyses: Dietary Supplements -- Antioxidants

Study, Total n Study Population

Treatment Groups Size & Drug Results Comments Vivekananthan DP, Penn MS, Sapp SK, Hsu A, Topol EJ. Use of antioxidant vitamins for the prevention of cardiovascular disease: meta-analysis of randomized trials. Lancet 2003;361:2017-23. Meta-analysis Although the meta-analysis includes 7 RCTs of vitamin E and 8 RCTs of Β-carotene only the results of the secondary prevention trials have been included in this summary. Vitamin E Trials=5, n = 72,536 Follow-up = 1.4 to 6.1 years B-carotene Trials=4, n = 69,788 Follow-up = 4 to 6.1 years

Vitamin E Dose=50 mg-800 IU/d [check mg to IU conversion]. Vitamin E Treatment Group = 36,289 Vitamin E Control Group = 36,247 Β-carotene Dose=15 to 50 mg, four times daily [Note: the CARET Trial (n = 9,420, treated) also added 25,000 IU retinol/d to the B-carotene treatment] Β-carotene Treatment Group = 35,162 Β-carotene Control Group = 34,626 Trial participants included were as follows: ATBC (n = 29,133): Male smokers. CARET (n = 18,314): Former/active smokers or asbestos-exposed. CHAOS (n = 2,002): CAD patients, confirmed by angiography. GISSI (n = 11,324): < 3 months post-MI HOPE (n = 9,541): CV disease or diabetes HPS (n = 20,536): Known or at risk of vascular disease SCP (n = 1,805): Previous nonmelanoma skin cancer Results of pooled analyses have not been shown due to selection of secondary prevention trials only from this meta-analysis.

Β-carotene Trial Name (n) ATBC (n = 29,133) CARET (n = 18,314) HPS (n = 20,536) SCP (n = 1805) Vitamin E Trial Name (n) ATBC (n = 29,133) CHAOS (n = 2002) GISSI (n = 11,324) HOPE (n = 9541) HPS (n = 20,536) Vitamin E Trial Name (n) CHAOS (n = 2,002) GISSI (n = 11,324) HPS (n = 20,536)

Absolute Event Rate All-cause Mortality B-Carotene Control p 12.7% 11.8% 0.02 4.9% 4.1% 0.02 14.1% 13.5% 0.25 8.7% 8.1% 0.66 Absolute Event Rate All-cause Mortality Vitamin E Control p 12.3% 12.1% 0.58 3.5% 2.7% 0.31 8.6% 9.3% 0.18 11.2% 11.2% 1.00 11.3% 11.1% 0.42 Absolute Event Rate Cardiovascular Death or Nonfatal MI Vitamin E Control p 4.0% 6.6% 0.01 8.0% 8.0% 1.0 13.1% 12.7% 0.47

Conclusions All-cause mortality was slightly elevated in the B-carotene treated group in all trials and reached statistical significance in 2 of the 4 secondary prevention trials cited in this summary. Patients assigned vitamin E had a nonsignificant excess in all-cause mortality in 3 of the 5 trials cited in this summary. In 1 trial, mortality was nonsignificantly reduced; in the other trial there was no difference in mortality between the vitamin E-treated and nontreated groups. Treatment with vitamin E had no effect on the combined endpoint of cardiovascular death and nonfatal MI. Limitations Because of lack of detailed outcome data, this meta-analysis did not assess the potential benefits of antioxidant treatment in sub-populations. The ATBC and CARET trials (contributing the largest numbers of patients) were exclusively of patients at high risk for lung cancer.



Table 18.10: RCTs: Dietary Supplements -- Antioxidants


Size & Drug Study Population Results Comments Waters DD, Alderman EL, Hsia J, Howard BV, Cobb FR, Rogers WJ, Ouyang P, Thompson, Tardif JC, Higginson L, Bittner V, Steffes M, Gordon DJ, Proschan M, Younes N, Verter JI. Effects of hormone replacement therapy and antioxidant vitamin supplements on coronary atherosclerosis in postmenopausal women: A randomized controlled trial. JAMA 2002;288(19):2432-2440. RCT WAVE Trial at 7 clinical centers in US and Canada. Mean follow up: 2.8 years (SD 0.9) Initial n: 423 Final n: 336

HRT Placebo plus Vitamin Placebo, n = 108 HRT plus Vitamin Placebo, n = 103 HRT Placebo plus Vita-mins C&E, n = 105 HRT plus Vitamins C&E, n = 107 Vitamin E Dose= 400 IU, 2 times/day Vitamin C Dose= 500 mg, two times/day

Postmenopausal women with 15-75% coronary stenosis at baseline coronary angiography. Exclusion criteria included HRT use within 3 months, concurrent use of > 60 mg/d of vitamin C or 30 IU/d of vitamin E, breast, uterine or cervical cancer, uncontrolled diabetes or hypertension, MI within 4 weeks, prior or planned CBAG, triglycerides > 500 mg/dL, creatinine > 2.0 mg/dL; gallstones, heart failure, bleeding diathesis, pulmonary embolus, idiopathic deep vein thrombosis, or untreated osteoporosis.

Women assigned to antioxidant vitamins compared with placebo Absolute Risk (%) For Total Cardiac Endpoints (CV death, nonfatal MI, nonfatal stroke)

All-cause mortality Hazard Ratio = 2.8 (95% CI, 1.1 to 7.2; p = 0.047) Antioxidant-treated Group = 14(6.9%) Control Group = 8(3.8%) ARR = -3.1%

Death or nonfatal MI Hazard Ratio = 2.1 (95% CI: 0.99 to 4.5; p = 0.09)

Conclusions Findings fail to demonstrate that antioxidant Vitamins C and E provide cardiovascular benefit to postmenopausal women with coronary disease. All-cause mortality was significantly higher in women assigned to antioxidant vitamins compared with vitamin placebo.



Table 18.11:


Size & Drug Study Population Results Comments Brown BG, Zhao X-Q, Chait A, Fisher LD, Cheung MC, Morse JS, Dowdy AA, Marino EK, Bolston EL, Alaupovic P, Frohlich J, Albers JJ. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med 2001;345(22):1583-1592. RCT HATS Trial in the US and Canada Initial n: 160 Final n: 160 Follow-up: 3 years

Simvastatin plus niacin, n = 38 Antioxidants, n = 42 Simvastatin-niacin plus antioxidants, n = 42 Placebo, n = 38 Antioxidant Daily Dose 800 IU vitamin E; 1,000 mg vitamin C; 25 mg Β-carotene; 100 mcg selenium “Active” Placebo Dose 50 mg niacin twice daily Niacin Dose 250 mg twice daily to 1000 mg twice daily at 4 weeks. Simvastatin Dose: 10 mg/d simvastatin for those with <110 mg/dL LDL and 20 mg/d for those w/ LDL cholesterol of > 110 mg/dL.

Patients with coronary disease (previous MI, coronary intervention, or confirmed angina) AND at least 3 stenoses of 30% or 1 stenosis of 50% AND low HDL cholesterol AND normal LDL cholesterol levels. Exclusions for lipid levels out of range, severe hypertension, recent gout, or liver, kidney, thyroid disease or uncontrolled diabetes.

In “active” placebo Antioxidant Group Simvastatin-niacin plus antioxidant Group Simvastatin-niacin Group

Mean Percent Change in Severity of Proximal Stenosis Compared to Placebo (p value) +3.9% +1.8% (p = 0.16) +0.7 (p = 0.004) -0.4 (p < 0.001)

Frequency of Clinical Cardiovascular Events 24% 21% 14% 3%

Conclusions Findings apply to the ~40% of patients with coronary disease who have low HDL, do not use combination therapy targeted at HDL and LDL and who use antioxidant vitamins. A reduction in coronary events and severity of proximal stenosis was observed in the simvastatin-niacin group. The addition of antioxidant vitamins to this treatment significantly diminished arterial and nonsignificantly diminished clinical benefits. Limitations Small study size.



Table 18.12: RCTs: Dietary Supplements – Vitamins B6, B12, Folic Acid


Size & Drug Study Population Results Comments Liem A, Reynierse-Buitenwerf GH, Zwinderman AH, Jukema JW, van Veldhuisen DJ. Secondary prevention with folic acid: Effects on clinical outcomes. J Am Coll Cardiol 2003;41:2105-13. RCT Initial n: 593 Final n: Not stated Follow-up: 24 months plus 10 months

Folic Acid Dose = 0.5 mg/d Folic Acid Treatment Group, n = 300 Control Group, n = 293 At baseline all patients had been on statin therapy for 3.2 years.

Patients with stable CAD (MI, significant coronary artery lesions, PCI, and/or CABG) AND statin therapy for at least 3 months (Exclusion criteria: < 18 years, history of low vitamin B12 levels, treatment for hyperhomocysteinemia, severe renal failure, hepatic disease, heart failure or any other illness precluding 3 year follow-up.)

Folic Acid Group vs. Control Group Absolute Risk (%) for all-cause mortality plus composite of vascular events*

Plasma Homocysteine Levels Decreased by 18% in treated group compared to no change in control group (p < 0.001) Folic Acid-treated group =37(12.3%) Control Group =33 (11.3%) ARR=-1.0% ** **computed by Kaiser Permanente staff.

All-cause Mortality plus Composite of Vascular Events* RR = 1.05, 95% CI: 0.63 to 1.75 *Vascular death (sudden death, fatal recurrent MI, fatal stroke, other cardiovascular death), noncardiovascular death, recurrent MI, invasive coronary procedures PCI, CABG), CVA, TIA or vascular surgery.

Conclusions Folic acid treatment of patients with stable CAD did not result in reduction of recurrence of cardiovascular events. Although plasma homocysteine levels at entry correlated with risk of recurrent events no decrement in risk was observed with reductions of plasma homocysteine with folic acid supplementation. Limitations Patients were randomly assigned to folic acid treatment but not blinded.



Table 18.13:


Size & Drug Study Population Results Comments Schnyder G, Roffi M, Flammer Y, Pin R, Hess OM. Effect of homocysteine-lowering therapy with folic acid, vitamin B12, and vitamin B6 on clinical outcome after percutaneous coronary intervention: The Swiss Heart Study: A randomized controlled trial. JAMA 2002;288(8):973-79. RCT Initial n = 553 Final n = 483 Follow-Up = 1 year

Vitamin B Treatment Dose: Folic acid = 1 mg/d Vitamin B6 = 10 mg/d Vitamin B12 = 400 mcg/d n = 272 Placebo n = 281 Treatment was continued for 6 months post-PCI only.

Patients who had undergone angioplasty of at least 1 significant coronary stenosis. (Exclusions: Patients with unstable angina, subacute MI, renal insufficiency, or taking vitamin supplements.)

Vitamin B treated compared to control group Absolute Risk (%) for target lesion revascularization Absolute Risk (%) for any major adverse coronary event

Major adverse coronary event RR = 0.68, 95% CI: 0.48 to 0.96, p = 0.03 B vitamin-treated Group =27(10%) Control Group =45(16%) ARR=-6%* B vitamin-treated Group =42(15.4%) Control Group =64(22.8%) ARR=-7.4%*

Restenosis RR = 0.70, 95% CI: 0.49 to 1.01, p = 0.06 NNT is 17 to prevent 1 target lesion revascularization in 1 year*. NNT is 14 to prevent any major adverse coronary event in 1 year*. *Computed by Kaiser Permanente staff. *

Homocysteine-lowering therapy with folic acid, and vitamins B12 B6 improves outcomes after PCI by reducing the need for repeat revascularization and decreasing the overall incidence of major adverse events 1 year after coronary angioplasty. This benefit is maintained at 1 year post-PCI despite discontinuation of treatment at 6 months. Limitations Design precludes assessment of separate effects of folic acid, and vitamin B6 and vitamin B12.



Table 18.14:


Size & Drug Study Population Results Comments Gruberg L. FACIT: Results from the folate after coronary intervention trial. Medscape conference coverage, American College of Cardiology 52nd Annual Scientific Session March 30-April 2, 2003. http://www.medscape.com/viewarticle/452026 RCT FACIT (Germany & Netherlands) Initial n: 636 Final n: 521 Follow up: 6 months for angiography and 250 days for clinical events

B Vitamin Treatment Dose: Folic Acid = 1.2 mg/d Vitamin B6 = 48 mg/d Vitamin B12 = 600 mcg/d B Vitamin treatment Group n = 316 Placebo Group n = 320 Treated patients received an IV bolus of the treatment and then were treated for 6 months orally.

Patients with elective stent implantation for CAD. (Exclusions: Patients with in-stent restenosis, bifurcation lesions, recent MI, chronic real insufficiency, regular multivitamin use.)

Treated Group Placebo Group

MACE Rate (death, MI, TLR) 16.8% 10.9% p = 0.03

Restenosis Rate 34.5% 26.5% p = 0.047

Conclusions The combination of folic acid, vitamin B6 and B12 is not effective in the prevention of restenosis and may have a detrimental effect in patients who undergo PCI with stents. Limitations The role of folic acid in the secondary prevention of CAD and in the prevention of restenosis in patients who undergo only balloon angioplasty is not addressed by these results.



Table 18.15:

Study, Total n Treatment Groups Size and Drug Study Population Results Comments

The Heart Outcomes Prevention Evaluation (HOPE) 2 Investigators. Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med 2006; 354. Location: 145 centers in 13 countries: Canada, United States, Brazil, Western Europe, and Slovakia Sponsor: Canadian Institutes of Health Research Grant and in-kind contributions by Jamieson Laboratories, Canada. Total N= 5,522

Type of Design: RCT Groups: C: placebo Rx: Combined pill of 2.5 mg folic acid; 50 mg B6; 1 mg B12 daily Blinding: Yes Follow-up: 5 years Initial N: 5,522 C: 2,764 Rx: 2,758 Final N: Vital status of 99.3% of patients ascertained at study end. 21 treated and 16 controls did not complete study.

Inclusion criteria: Men and women 55 yr or older with a history of vascular disease (coronary, cerebrovascular, or peripheral) or diabetes and additional risk factors for atherosclerosis from countries with and without mandatory folate fortification of food. Exclusion criteria: Patients taking vitamin supplements containing>0.2 mg folic acid daily.

Composite Outcomes of cardiovascular death, MI, stroke: RR=0.95 (95% CI: 0.84-1.07) Death from cardiovascular causes: RR=0.96 (95% CI: 0.81-1.13) MI: RR=0.98 (95% CI: 0.85-1.14) Stroke: 0.75 (95% CI: 0.59-0.97)

Supplements combining folic acid, B6, and B12did not reduce the risk of major cardiovascular events or secondary outcomes in patients with vascular disease. Biases Exposure to folic acid-fortified food in >70% of study patients, substantially reducing the # of patients with increased HCY, the subgroup most likely to benefit.



Table 18.16:

Study, Total n Treatment Groups Size

and Drug Study Population

Results on Primary Endpoint Composite of nonfatal or fatal MI, nonfatal or fatal stroke

(includes sudden death attributed to coronary heart disease) Comments Bonaa KH, Njolstad I, Ueland PM, Schirmer H, Tverdal, A, Steigen T, Wang H, Nordrehaug, Arnesen E, Rasmussen K, for the NORVIT Trial Investigators. Homocysteine lowering and cardiovascular events after acute myocardial infarction. N Engl J Med 2006;354 Location: Norway Sponsor: Norwegian Research Council, Council on Health and Rehabilitation, University of Tromso, The Norwegian Council on Cardiovascular Disease, the Northern Norway Regional Health Authority, The Norwegian Red Cross, the Foundation to Promote Research into Functional B12 Deficiency and an unrestricted private donation. Total N= 3,749

2x2 factorial design RCT Groups C: placebo Rx1: 0.8 mg folic acid; 0.4 mg B12; 40 mg B6 (combination therapy) daily Rx2: 0.8 mg folic acid plus 0.4 mg B12 daily Rx3: 40 mg B6 daily Initial N: C: 943 Rx:1 937 Rx:2 935 Rx:3 934 Mean length of follow-up: 36 mo. Compliance: 5 participants withdrew informed consent; 404 (11%) stopped medication. All patients in mortality analysis; 20 had incomplete data on nonfatal events.

Inclusion criteria: Men and women 30 to 85 yr. who had had an acute MI within 7 days prior to randomization. Exclusion criteria: Coexisting disease associated with a life expectancy of < 4 yr, prescribed treatment with B vitamins, or untreated vitamin B deficiency, inability to follow the protocol.

Folic Acid plus B12 vs No folic acid plus B12 RR=1.08 (95% CI: 0.93-1.25) This comparison is for the combination therapy group and the group given folic acid and vitamin B12 with the group given vitamin B6 and the placebo group

B6 vs No B6 RR=1.14 (95% CI: 0.98-1.32) This comparison is for the combination therapy group and the group given vitamin B6 with the group given folic acid and vitamin B12 and the placebo group.

Folic Acid plus B12 plus B6 vs Placebo RR=1.22 (95% CI: 1.00-1.50) This comparison is for the combination therapy group with the placebo group

Treatment with B vitamins did not lower the risk of recurrent cardiovascular disease after acute MI. A harmful effect from combined B vitamin treatment was suggested



Table 18.17: RCTs: Diet Therapy


Size & Drug Study Population Outcome Study Endpoint Stone PH, Lloyd-Jones DM, Kinlay S, Vascular Basis Study Group, et al. Effect of intensive lipid lowering, with or without antioxidant vitamins, compared with moderate lipid lowering on myocardial ischemia in patients with stable coronary artery disease: the Vascular Basis for the Treatment of Myocardial Ischemia Study. Circulation 2005;111(14):1747-55 Study Name: Study Design: double-blind randomised Subject Number: 300 Duration: 1 year

Study Controls: Placebo Treatment (name : dose : route : frequency): Ascorbic acid : 1000 mg/day : PO Atorvastatin : </= 80 mg/day : PO Atorvastatin : </= 80 mg/day : PO Lovastatin : median 5 mg/day : PO Tocopherol : 800 mg/day : PO Evidence Grade: A2

Indications: Coronary artery disease Study Characteristics: patients had stable coronary artery disease, characterized by exercise-induced ST-segment depression >=1.0mm and >=1 episode of reversible ST-segment depression of >=1.0mm during 48h ambulatory ECG monitoring. Sixty-six percent of patients had a history of angina pectoris with a mean New York Heart Association class of 1.3 and a mean duration of 7 months. Thirty-eight percent of patients had a family history of coronary artery disease and 65% had a history of smoking. Subject Age: </= 84 years

additional treatment required nitroglycerin consumption angina pectoris event rate cardiac parameters cardiovascular events cerebrovascular event rates coronary revascularisation event rate death rate ECG changes endothelial function exercise testing exercise time flow mediated dilation

In patients with coronary artery disease, intensive lipid lowering with atorvastatin, alone or in combination with ascorbic acid plus tocopherol, was not associated with any further benefits in ambulatory myocardial ischaemia, exercise time to onset of ischaemia or angina frequency than moderate lipid lowering with lovastatin.;




Clinical Question: Is smoking cessation recommended for patients with CAD?


documented CAD (by angiography or noninvasive testing) No contraindications to smoking cessation


Smoking cessation No smoking cessation





Search Strategy 19

Database Search Terms Article Type & Other Limits

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PubMed Smoking cessation AND myocardial ischemia [MESH]

Humans, Meta-Analysis, Randomized

Controlled Trial, English, All Adult:

19+ years

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1/17/2008

0/10





Clinical Question: Is exercise recommended for patients with coronary artery disease (CAD)?


documented CAD (by angiography or noninvasive testing) No contraindications to exercise


Exercise





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Evidence Table 20

Table 20.1:

Study, Total N Treatment Groups Size and Drug Study Population Results Comments

Is exercise recommended for patients with CAD? If yes, at what frequency and duration?

Clark AM, Hartling L, Vandermeer B, McAlister FA. Meta-analysis: secondary prevention programs for patients with coronary artery disease. Ann Intern Med 2005;143(9):659-672. Study design: Meta-analysis Unblinded studies Study duration: 3 weeks to 5 years Subject number: 27 trials, 6,940 patients in trials involving an exercise program

Study controls: Usual care Treatment (name : dose : route : frequency) Exercise program Exercise program plus education and counseling Education and counseling alone (The study design and the type and frequency of exercise varied across the studies. Of the 11 “exercise only” studies, only 1 did not have a supervised training arm.) Evidence Grade: B1

Indications: CAD Subject characteristics: Pre-existing CAD Subject age (years): Wide range of ages

All-cause mortality Recurrent MI

All-cause mortality summary risk ratio, 0.83 (95% CI: 0.72 to 0.96)




Clinical Question: Is hormone therapy recommended for postmenopausal women with CAD for the prevention of subsequent cardiovascular events?

Population: Postmenopausal women with the following characteristics: A history of ischemic heart disease, MI, CABG, and/or PCI or

documented CAD (by angiography or noninvasive testing) No contraindications to hormone therapy


Hormone therapy Estrogen plus progestin in women with an intact uterus Unopposed estrogen in women who have had a hysterectomy



Mortality due to cardiac events All-cause mortality Hospitalization, including nonfatal MI, nonfatal stroke, transient

ischemic attack (TIA), unstable angina, and revascularization procedures



Search Strategy 21



No. Included/ Total

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PubMed

(((“hormone replacement therapy”[MeSH] AND “myocardial ischemia” [MeSH])))



English, All Adult: 19+ years

3/26/06 to

12/31/07

0/9

Cochrane Hormone Replacement Therapy

Systematic reviews 1st quarter,

2006 0/2

Clinical Evidence

Cardiovascular Disorders: Secondary prevention of ischemic events

Hormone Replacement

Therapy

Search July, 2004 Accessed 5/23/06

0/0


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4/26/06

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((((“hormone replacement therapy”[MeSH] AND “myocardial ischemia”[MeSH]))) Randomized


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Evidence Tables 21

Table 21.1: Hormone Replacement Therapy, RCTs

Study, Total n

Treatment Groups Size & Drug Study Population

Results of WHI Subgroup Analyses

(nested case control study) Comments Manson JE, Hsia J, Johnson KC, Roussouw JE, Assaf AR, Lasser NL, Trevisan M, Black HR, Heckbert SR, Detrano R, Strickland OL, Wong ND, Crouse JR, Stein E, Cushman M. Estrogen plus progestin and the risk of coronary heart disease. N Engl J Med 2003;349:523-34. RCT Final Results of Women’s Health Initiative (WHI) Mean Follow up: 5.2 years (discontinued early from 8.5 years planned duration) Initial N: #16,608 Final N: #

Treatment Group (0.625 mg/d conjugated equine estrogens plus 2.5 mg/d medroxyprogesterone acetate) n = 8,506 Placebo Group n=8,102

Postmenopausal women, 50-79 years of age with an intact uterus.

No. of cases (annualized percentage) Estrogen plus Progestin Group Women w/ cardiovascular disease* at baseline NO=156(0.34) YES= 29(1.64) Women w/ CHD** at baseline NO=163(0.35) YES=22(2.18) OVERALL RESULTS from WHI: No. of cases of CHD (annualized percentage) Estrogen plus Progestin Group 188(0.39) *History of MI, CABG, stroke, or TIA. **History of MI, CABG, or PCI

No. of cases (annualized percentage) Placebo Group 118(0.28) 24(1.19) 124(0.29) 18(1.65) No. of cases of CHD (annualized percentage) Placebo Group 147(0.33)

Age-Adjusted Hazard Ratio (95% CI) p value*** 1.23(0.97-1.56) 1.45(0.84-2.49) p=0.64 1.23(0.97-1.55) 1.44(0.77-2.70) p=0.66 Adjusted Hazard Ratio 1.24 (1.00-1.54, nominal 95% CI: ) 0.97-1.60; 95% CI: adjusted for sequential monitoring) ***p value is for interaction between the subgroup variable and treatment

Conclusions Women with preexisting CHD or other cardiovascular disease did NOT have a significantly greater excess risk of subsequent coronary events with postmenopausal hormone therapy than did women without these risk factors. As previously reported in preliminary results from the WHI, estrogen plus progestin does NOT have a beneficial effect on the risk of CHD (nonfatal MI, including silent infarction and death due to CHD) among healthy postmenopausal women. Overall, the risks of treatment outweighed the benefits over 5.6 years. Limitations The study was designed to address the cardio-protective effects of HRT in healthy women.



Table 21.2: Study, Total n

Treatment Groups Size & Drug Study Population Results Comments

Waters DD, Alderman EL, Hsia J, Howard BV, Cobb FR, Rogers WJ, Ouyang P, Thompson, Tardif JC, Higginson L, Bittner V, Steffes M, Gordon DJ, Proschan M, Younes N, Verter JI. Effects of hormone replacement therapy and antioxidant vitamin supplements on coronary atherosclerosis in postmenopausal women: A randomized controlled trial. JAMA 2002;288(19):2432-2440. RCT WAVE Trial at 7 clinical centers in US and Canada. Mean follow up: 2.8 years (SD 0.9) Initial n: 423 Final n: 336

HRT Placebo plus Vitamin Placebo, n = 108 HRT plus Vitamin Placebo, n = 103 HRT Placebo plus Vita-mins C&E, n = 105 HRT plus Vitamins C&E, n = 107 Vitamin E Dose= 400 IU, 2 times/day Vitamin C Dose= 500 mg, two times/day NOTE: There was no interaction between the 2 treatment interventions.

Postmenopausal women with 15-75% coronary stenosis at baseline coronary angiography. Exclusion criteria included HRT use within 3 months, concurrent use of > 60 mg/d of vitamin C or 30 IU/d of vitamin E, breast, uterine or cervical cancer, uncontrolled diabetes or hypertension, MI within 4 weeks, prior or planned CBAG, triglycerides > 500 mg/dL, creatinine > 2.0 mg/dL; gallstones, heart failure, bleeding diathesis, pulmonary embolus, idiopathic deep vein thrombosis, or untreated osteoporosis.

OUTCOMES Death, Nonfatal MI, stroke Coronary progression* *Primary endpoint was change in coronary artery dimensions

HRT Absolute Risk= 26 Hazard Ratio=1.9, (95% CI: 0.97-3.6; p=0.07) Mean (SD) change 0.047 (0.15)mm/y

HRT Placebo Absolute Risk=15 Mean (SD) change 0.024(0.15) mm/y (p=0.17)

Conclusions In postmenopausal women with coronary disease HRT did not provide cardiovascular benefit. Instead a potential for harm was suggested with treatment Limitations 20% lost-to-follow-up and 67% took prescribed medication, limiting power to detect a treatment effect. Strength was imputing of unfavorable angiographic outcomes to patients who died or suffered interim infarctions.




Clinical Question: What is the appropriate target blood pressure in patients with CAD?

Population: Adult patients with a history of ischemic heart disease, MI, CABG, and/or PCI or documented CAD (by angiography or noninvasive testing) AND hypertension


Treatment to a target blood pressure of <140/90 mm Hg







Search Strategy 22



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Problem Formulation 23*

Population: Adults aged 18 or older with known atherosclerotic disease (angina, myocardial infarctions, CABG or PTCA, etc.).


Use statins (lovastatin, simvastatin, pravastatin, atorvastatin, fluvastatin, rosuvastatin) as first-line drug therapy. vs. Any of the following interventions as first-line therapy: Fibric Acid Derivatives (Fibrates)

Niacin (Nicotinic Acid)

Bile Acid Sequestrants - Colestipol or Cholestyramine (Resins)

No Drug Treatment


Angina Myocardial infarctions Stroke CAD mortality Total mortality CVD events




Search Strategy 23*



Limits: Search Date

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Cochrane drug AND primary prevention AND (hyperlipidemia OR dyslipidemia OR hypercholesterolemia)”

systematic reviews

6/3/02 0/1

Clinical Evidence

“statin AND (fibrate OR niacin OR colestipol OR cholestyramine)”

systematic reviews and RCTs

5/30/02 - 4/6/04

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Meta-analysis, All Adult: 19+ years, English, Human

1/1/66 - 6/4/02

1/25 PubMed Update of Clinical Evidence: ((("hyperlipidemia"[Mesh terms] OR "dyslipidemia"[tw]) OR "hypercholesterolemia"[tw]) AND ((((((((((((((((((("drug therapy"[All Fields] OR "medicine"[Mesh terms]) OR "anticholesteremic agents"[Mesh terms]) OR "lovastatin"[Mesh terms]) OR "simvastatin"[mesh terms]) OR "pravastatin"[mesh terms]) OR "atorvastatin"[text]) OR "fluvastatin"[text]) OR "gemfibrozil"[mesh terms]) OR "Fibric Acid Derivatives"[text]) OR "Fibrates"[text]) OR "cholestyramine"[mesh terms]) OR "Colestipol"[mesh terms]) OR "Bile Acid Sequestrants"[text]) OR "Resins"[mesh terms]) OR "niacin"[mesh terms]) OR "Nicotinic Acid"[text]) AND "meta-analysis"[pt]) AND "human"[mesh terms]) AND "adult"[mesh terms]))

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PubMed ((("hyperlipidemia"[Mesh terms] OR "dyslipidemia"[tw]) OR "hypercholesterolemia"[tw]) AND ((((((((((((((((((("drug therapy"[All Fields] OR "medicine"[Mesh terms]) OR "anticholesteremic agents"[Mesh terms]) OR "lovastatin"[Mesh terms]) OR "simvastatin"[mesh terms]) OR "pravastatin"[mesh terms]) OR "atorvastatin"[text]) OR "fluvastatin"[text]) OR "gemfibrozil"[mesh terms]) OR "Fibric Acid Derivatives"[text]) OR "Fibrates"[text]) OR "cholestyramine"[mesh terms]) OR "Colestipol"[mesh terms]) OR "Bile Acid Sequestrants"[text]) OR "Resins"[mesh terms]) OR "niacin"[mesh terms]) OR "Nicotinic Acid"[text]) AND "meta-analysis"[pt]) AND "human"[mesh terms]) AND "adult"[mesh terms]))

Meta-analysis, Randomized Controlled Trial, All Adult: 19+ years English, Human

6/2006 - 6/2008

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Note: Intermediate health outcome trials (e.g., REVERSAL and trials involving rosuvastatin) which have demonstrated reductions in LDL-C, have been excluded because they did not

measure direct health outcomes. Only studies where direct health outcomes were evaluated have been included.



Evidence Tables 23*

Evidence Table 23.1: Strategy for Lipid Lowering in the Elderly

Author & Title Last Updated Search

Database Study Characteristics & Results Conclusions Pignone M. What are the effects of cholesterol reduction? Clinical Evidence, Issue 7, October 2002 (on-line version) lipid-lowering trials included in the systematic review: AFCAPS/TexCAPS (Downs JR, et al. 1998) – lovastatin WOSCOPS (Shepherd J, et al. 1995) – pravastatin 4S (Scandinavian Simvastatin Survival Study Group, 1994) – simvastatin CARE (Sacks FM, et al., 1996) – pravastatin LIPID (The Long-term Intervention with Pravastatin in Ischemic Heart Disease Study Group, 1998) – pravastatin

LAST UPDATED: July 2001 SEARCH DATABASES AND SEARCH STRATEGY: Systematic Reviews - Cochrane Library CD, Medline and Embase RCTs - Cochrane Controlled Clinical Trials Register, Best Evidence CD, Medline and Embase looking back at least 3 years, or to their origin if there are no systematic reviews SEARCH TERMS: Not stated.

STUDY DESIGN Qualitative systematic review Effects of Statins specific to the Elderly Population Compared with placebo, the combined results from primary and secondary prevention trials indicated that: Statins reduced coronary events by a slightly higher proportional amount in patients over 65 years (OR 0.68, 95% CI: 0.61 to 0.77; ARR 4.4%, 95% CI: 3.0% to 5.8% than in patients under 65 years (OR 0.69, 95% CI: 0.64 to 0.76; ARR 3.2%, 95% CI: 2.4% to 4.0%). The absolute benefit over several years of lowering cholesterol is greatest in patients with the highest baseline risk of an ischemic cardiac event. Relative risk reduction may attenuate at older age, but the absolute risk reduction for ischemic cardiac events may be higher in elderly patients than in younger patients. (RR not reported)

Effects of statin therapy in reducing the risk of vascular events in patients 75 and older is greater than the effect in patients under age 75.




Evidence Table 23.2: Strategy for Lipid Lowering in the Elderly

Author & Title Study Characteristics Results Conclusion Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of Cholesterol Lowering with Simvastatin in 20,536 High Risk Individuals: A Randomized Placebo-controlled Trial. Lancet 2002; 360: 7-22

STUDY DESIGN: Prospective double-blind RCT OBJECTIVES: To access the possible benefits and risks of cholesterol-lowering therapy and antioxidant vitamin supplementation in patients at increased risk of heart disease. TOTAL POPULATION Aged < 65: 9839 (48%) Aged 65-69: 4891 (24%) Aged 70-74: 4543 (22%) Aged 74 and over: 1263 (6%) PATIENT INCLUSION CRITERIA Men and women aged about 40-80 years with an average baseline LDL-C level of 131 mg/dL were included provided that they were considered to be at substantial 5-year risk of death from coronary heart disease because of a past medical history of: (i) coronary; or (ii) occlusive disease of noncoronary arteries; or (iii) diabetes mellitus; or (iv) treated hypertension BASELINE PATIENT CHARACTERISTICS (18,344 out of 20,536 were secondary prevention patients) Mean LDL-C: 131 31mg/dL Mean HDL-C: 4113mg/dL Mean TC: 22839mg/dL Mean TG: 8154mg/dL METHODS Between July 1994 and May 1997, a total of 20,536 UK individuals (15,454 men and 5082 women) were randomized, with 9515 aged over 65 years at entry. Study participants with coronary disease, other occlusive arterial disease, or diabetes were randomly allocated to receive 40 mg simvastatin daily (average compliance: 85%) or matching placebo (average nonstudy statin use: 17%). Following randomization between July, 1994, and May, 1997, participants were to be seen in the study clinics for routine follow-up checks and blood safety monitoring at 4, 8, and 12 months and then every 6 months until the final follow-up visits between May and October, 2001. Analyses were of the first occurrence of particular events, and compared all simvastatin-allocated versus all placebo-allocated participants. These "intention-to-treat" comparisons assessed the effects of about two-thirds (85% minus 17%) taking a statin during the scheduled 5-year treatment period, which yielded an average difference in LDL cholesterol of 1.0 mmol/L (about two-thirds of the effect of actual use of 40 mg simvastatin daily).

NOTE: Since Clinical Evidence, Issue 7, October 2002, did not report data specific for the elderly population in the systematic review, the following results were directly extracted from the Heart Protection Study (HPS, 2002) that studied the effects of simvastatin vs. placebo in 20,536 patients aged 40-80 for 5.5 years: Relevant results from the Heart Protection Study: Major Vascular Events (coronary event, stroke, revascularization) Simvastatin Placebo (2033 total events) (2585 total events) Aged <65: 831 (16.9%) 1091 (22.1%) (ARR=5.2%; NNT=19) Aged 65-69: 512 (20.9%) 665 (27.2%) (ARR=6.3%; NNT=16) Aged 70-74 548 (23.8%) 620 (27.7%) (ARR=3.9%; NNT=26) Aged 75 142 (23.1%) 209 (32.3%) (ARR=9.2%; NNT=11)

HPS showed that statins significantly reduced the risk of vascular events among a wide range of patients aged over 75 years.



Problem Formulation 24*

Population: Adults aged 18 or older with known atherosclerotic disease (angina, myocardial infarctions, CABG or PTCA, etc.).


Reduce LDL-C to 100mg/dL. vs. Reduce LDL-C to 130mg/dL.


Angina Myocardial infarctions Stroke CAD mortality Total mortality CVD events




Search Strategy 24*



Limits: Search Date

No. Included/ Total

Retrieved

Cochrane drug AND primary prevention AND (hyperlipidemia OR dyslipidemia OR hypercholesterolemia)”

systematic reviews

6/3/02 0/0

Clinical Evidence

“statin AND (fibrate OR niacin OR colestipol OR cholestyramine)”

systematic reviews and

RCTs

5/30/02 - 4/6/04

1/4

Meta-analysis, All Adult: 19+ years, English,

Human

1/1/66 - 6/4/02

1/25 PubMed Update of Clinical Evidence: ((("hyperlipidemia"[Mesh terms] OR "dyslipidemia"[tw]) OR "hypercholesterolemia"[tw]) AND ((((((((((((((((((("drug therapy"[All Fields] OR "medicine"[Mesh terms]) OR "anticholesteremic agents"[Mesh terms]) OR "lovastatin"[Mesh terms]) OR "simvastatin"[mesh terms]) OR "pravastatin"[mesh terms]) OR "atorvastatin"[text]) OR "fluvastatin"[text]) OR "gemfibrozil"[mesh terms]) OR "Fibric Acid Derivatives"[text]) OR "Fibrates"[text]) OR "cholestyramine"[mesh terms]) OR "Colestipol"[mesh terms]) OR "Bile Acid Sequestrants"[text]) OR "Resins"[mesh terms]) OR "niacin"[mesh terms]) OR "Nicotinic Acid"[text]) AND "meta-analysis"[pt]) AND "human"[mesh terms]) AND "adult"[mesh terms]))

Randomized Controlled Trial, All

Adult: 19+ years English,

Human

1/1/001 - 7/16/02

0/163






Limits: Search Date

No. Included/ Total

Retrieved

Meta-analysis, All Adult: 19+ years, English, Human

7/16/02 - 2/20/04

0/8

Randomized Controlled Trial, All Adult: 19+ years English, Human

7/16/02 - 2/20/04

2/201


Human

2/20/04 - 5/2006


Adult: 19+ years English,

Human

5/2006 - 2/20/04

2/43


Human

5/2006 - 6/2008

0/425

PubMed ((("hyperlipidemia"[Mesh terms] OR "dyslipidemia"[tw]) OR "hypercholesterolemia"[tw]) AND ((((((((((((((((((("drug therapy"[All Fields] OR "medicine"[Mesh terms]) OR "anticholesteremic agents"[Mesh terms]) OR "lovastatin"[Mesh terms]) OR "simvastatin"[mesh terms]) OR "pravastatin"[mesh terms]) OR "atorvastatin"[text]) OR "fluvastatin"[text]) OR "gemfibrozil"[mesh terms]) OR "Fibric Acid Derivatives"[text]) OR "Fibrates"[text]) OR "cholestyramine"[mesh terms]) OR "Colestipol"[mesh terms]) OR "Bile Acid Sequestrants"[text]) OR "Resins"[mesh terms]) OR "niacin"[mesh terms]) OR "Nicotinic Acid"[text]) AND "meta-analysis"[pt]) AND "human"[mesh terms]) AND "adult"[mesh terms]))


Adult: 19+ years, English,

Human

5/2006 - 6/2008

1/425



Evidence Tables 24*

Evidence Table 24.1: Treatment Strategy for Lipid Lowering in People with Diabetes Mellitus (Primary Prevention) (adapted from CMI Diabetes Guideline)

Author & Title

Last Updated Search

Database Study Characteristics Results Conclusions Comments/

Biases Sigal R, Meggison H, and Malcolm J. WHAT ARE THE EFFECTS OF TREATING HYPERLIPIDAEMIAS IN PEOPLE WITH DIABETES? CLINICAL EVIDENCE, ISSUE 7, OCTOBER 2002 (ON-LINE VERSION) References of studies included in the systematic review: Downs JR, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/ Texas Coronary Atherosclerosis Prevention Study. JAMA 1998; 279(20):1615-22. Koskinen P, et al. Coronary heart disease incidence in NIDDM patients in the Helsinki Heart Study. Diabetes Care. 1992 Jul;15(7):820-5 (44) Elkeles RS, et al. Cardiovascular outcomes in type 2 diabetes. A double-blind placebo-controlled study of bezafibrate: the St. Mary's, Ealing, Northwick Park Diabetes Cardiovascular Disease Prevention (SENDCAP) Study. Diabetes Care. 1998 Apr;21(4):641-8 (45)

LAST UPDATED: August 2001 SEARCH DATABASES AND SEARCH STRATEGY: Systematic Reviews - Cochrane Library CD, Medline and Embase RCTs - Cochrane Controlled Clinical Trials Register, Best Evidence CD, Medline and Embase looking back at least 3 years, or to their origin if there are no systematic reviews SEARCH TERMS: Not stated.

STUDY DESIGN Qualitative systematic review Inclusion criteria: AFCAPS/TexCAPS included men aged 45–73 years and women aged 55–73 years, with total cholesterol 178.8-262.3 mg/l, LDL-C 129.2-188.8 mg/l, HDL-C ≤42.3 mg/l (men) or ≤46.92 mg/l (women), and triglycerides ≤369.5 mg/l. HELSINKI included 4081 Finnish men aged 40–55 years with a lipid concentration (minus HDL-C) ≥201mg/dL. SENDCAPS included 164 men and women with type 2 Diabetes, aged 35–65 years. Participants had total cholesterol to HDL-C ratio greater than 4.7 mmol/l (180.7 mg/l) , total cholesterol ranged from 201 mg/l, HDL-C less than 1.1 mmol/l (42.3 mg/l). Number of studies included: 3 RCTs that included at least 10 confirmed clinical cardiovascular events among people with diabetes (studies reporting only intermediate end points were not considered) Intervention: lovastatin vs. placebo plus diet bezafibrate vs. placebo gemfibrozil (600 mg BID) vs. placebo Sample size range: 135-164 Duration of Trials: 3-5.2 years

Primary Prevention In the first RCT (AFCAPS/TexCAPS), men aged 45–73 years and women aged 55–73 years were randomized to diet plus lovastatin 20–40 mg daily or diet plus placebo, and followed for a mean of 5.2 years. (cardiovascular events rate: 4.8% vs. 8.5%; RR=0.56) The second RCT (Helsinki) that included 4081 Finnish men aged 40–55 years compared gemfibrozil 600 mg twice daily versus placebo over 5 years. (cardiovascular events rate: 3.4% vs. 10.5%; RR=0.33) The third RCT (SENDCAP) that included 164 men and women with type 2 diabetes, aged 35–65 years, compared bezafibrate versus placebo for 3 years. (cardiovascular events rate: 7.8% vs. 25%; RR=0.31) (95% CI: and p values were not reported. It is uncertain whether the reported results reached statistical significance.) Mixed Primary and Secondary Prevention: There is one RCT (the Diabetes Atherosclerosis Interventions Study) that included 305 men and 113 women, with mean age 57 years and type 2 diabetes. The trial compared the effect of fenofibrate 200 mg daily versus placebo in type 2 diabetes for a minimum of 3 years. After 39 months on treatment and 6 additional months of follow up, fenofibrate versus placebo did not significantly reduce the number of patients who either had myocardial infarction or died. [15/207 (7.2%) with fenofibrate v 21/211 (9.9%) with placebo; ARR 2.7%, 95% CI: –2.8% to +8.3%; RR 0.73, 95% CI: 0.39 to 1.37].

From the available subgroup data for primary prevention, fibrates appeared to be more effective than statins in lowering cardiovascular event rate. However, 95% CI: and p values were not reported. It is uncertain whether the reported results reached statistical significance. Results for “mixed primary and secondary prevention” did not reach statistical significance.

SENDCAP only included type 2 diabetics and Helsinki only included men. Most studies with significant power to detect cardiovascular events have enrolled low numbers of diabetics and therefore were not included in this systematic review.




Evidence Table 24.2: Treatment Strategy for Lipid Lowering in People with Diabetes Mellitus (Secondary Prevention) (adapted from CMI Diabetes Guideline 2002)

Author & Title

Last Updated Search

Database Study Characteristics Results Conclusions Comments/

Biases Sigal R, Meggison H, and Malcolm J. WHAT ARE THE EFFECTS OF TREATING HYPERLIPIDAEMIAS IN PEOPLE WITH DIABETES? CLINICAL EVIDENCE, ISSUE 7, OCTOBER 2002 (ON-LINE VERSION) References of studies included in the systematic review: Pyorala K, et al. Cholesterol lowering with simvastatin improves prognosis of diabetic patients with coronary heart disease. A subgroup analysis of the Scandinavian Simvastatin Survival Study (4S) Diabetes Care. 1997;20(4):614-20 (46) Sacks FM, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. N Engl J Med. 1996;335(14):1001-9 (47) Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. N Engl J Med. 1998;339(19):1349-57 (48) Rubins HB, et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. N Engl J Med. 1999;341(6):410-18 (49)

LAST UPDATED: August 2001 SEARCH DATABASES AND SEARCH STRATEGY: Systematic Reviews - Cochrane Library CD, Medline and Embase RCTs - Cochrane Controlled Clinical Trials Register, Best Evidence CD, Medline and Embase looking back at least 3 years, or to their origin if there are no systematic reviews SEARCH TERMS: Not stated.

STUDY DESIGN Qualitative systematic review Number of studies included: 4 RCTs that included at least 10 confirmed clinical cardiovascular events among people with diabetes (studies reporting only intermediate end points were not considered) Inclusion criteria: 4S - 4444 men and women aged 35–70 years with previous acute myocardial infarction or angina pectoris, total cholesterol concentrations of 5.5–8.0 mmol/L, and triglycerides < 2.5 mmol/L. CARE - 4159 men and women aged 21–75 years, 3–20 months after acute myocardial infarction and with total cholesterol < 6.2 mmol/L, triglycerides < 3.92 mmol/L, and LDL-C 3.0–4.5 mmol/L. LIPID - 9014 men and women aged 31–75 years with acute myocardial infarction or unstable angina, plasma total cholesterol 4.0–7.0 mmol/L, and plasma triglycerides < 5.0 mmol/L. VA-HIT - 2531 men aged < 74 years with previous coronary vascular disease, acute myocardial infarction, angina, revascularization, or angiographically documented coronary stenosis; HDL-C < 1.0 mmol/L, LDL-C < 3.6 mmol/L, and triglycerides < 3.4 mmol/L. Intervention: simvastatin (20 mg QD then 40 mg QD depending on initial response) vs. placebo pravastatin (40 mg QD) vs. placebo pravastatin (40 mg QD) vs. placebo gemfibrozil (1200 mg) Sample size range: 2531-9014 patients (202-782 diabetics in subpopulations) Duration of Trials: 5-6.1 years

4S compared simvastatin versus placebo over a median of 5.4 years. The relative risk of main end points in people with diabetes treated with simvastatin were as follows: Total mortality 0.57 (95% CI: 0.30 to 1.08); Major cardiovascular events 0.45 (95% CI: 0.27 to 0.74); Any atherosclerotic event 0.63 (95% CI: 0.43 to 0.92). CARE compared pravastatin 40 mg daily versus placebo over a median of 5 years. Among the people with diabetes, the relative risk of major coronary events (death from coronary disease, nonfatal acute myocardial infarction, coronary artery bypass graft, or PTCA) = 0.75 (95% CI: 0.57 to 1.0). LIPID compared pravastatin 40 mg daily versus placebo for a mean of 6.1 years. Among the 782 participants with diabetes, the relative risk of coronary heart disease death or nonfatal acute myocardial infarction = 0.84 (95% CI: 0.59 to 1.10). VA-HIT compared gemfibrozil 1200 mg daily with placebo for a median of 5.1 years (treatment was intended to raise HDL-C levels rather than reduce LDL-C). Among the 627 participants with diabetes, the relative risk of coronary heart disease death or nonfatal acute myocardial infarction =0.76 (95% CI: 0.57 to 1.0).

From the available data for secondary prevention, statins and fibrates were shown to be essentially the same in their effectiveness in significantly reducing the rate of CAD events in the DM population.

Most studies with significant power to detect cardiovascular events have enrolled low numbers of diabetics and therefore were not included in this systematic review.




Clinical Question Should statins be initiated immediately post acute coronary syndrome?

Population: Adults aged 18 or older who have acute coronary syndrome (ACS). ACS is defined as unstable angina, ST-segment elevation myocardial infarction (STEMI), or non-STEMI.


Statin treatment initiated before hospital discharge Vs. a). Statin treatment initiated at/after hospital discharge b). No statin treatment



All-cause mortality Cardiovascular mortality Myocardial infarction Coronary Revascularization Stroke Elevated liver enzymes Serious myopathy Non-serious muscle problems



Search Strategy 25



No. Included/ Total

Retrieved

Cochrane statin AND “myocardial infarction” systematic reviews 1/6/10 0/4

Clinical Evidence

statins AND “myocardial infarction” via on-line search field

systematic reviews and RCTs

1/6/10 0/18

PubMed (((((("Drug Administration Schedule"[Mesh terms] OR Anticholesteremic Agents/therapeutic use[mesh]) OR antilipemic agents/administration and dosage[mesh]) OR antilipemic agents/therapeutic use[mesh]) OR Hydroxymethylglutaryl-CoA Reductase Inhibitors/administration and dosage[mesh]) AND (("myocardial infarction/drug therapy"[mesh] OR "myocardial infarction/therapy"[mesh]) OR "myocardial infarction/mortality"[mesh]))

Meta-analysis, Clinical Trial, Randomized Controlled Trial, All Adult: 19+ years, English, Human

6/1/08 –

1/6/10

2/49

PubMed ("acute coronary syndrome" OR "ACS" OR unstable angina OR "non-STEMI" OR "Non-ST Elevated Myocardial Infarction" OR "STEMI" OR "ST-Segment Elevation Myocardial Infarction") AND ((((((((("drug therapy"[All Fields] OR "medicine"[Mesh terms]) OR "statin"[All Fields] OR "HMG-CoA reductase inhibitors"[text] OR "HMG-CoA reductase inhibitor"[text] OR "anticholesteremic agents"[Mesh terms]) OR "lovastatin"[Mesh terms]) OR "simvastatin"[mesh terms]) OR "pravastatin"[mesh terms]) OR "rosuvastatin"[All Fields] OR "atorvastatin"[text]) OR "fluvastatin"[text])

Meta-analysis, Clinical Trial, Randomized Controlled Trial, All Adult: 19+ years, English, Human

6/1/08 – 1/6/10

0/50



Evidence Tables 25


% Female

Cholesterol, Total

Cholesterol, LDL

Cholesterol, HDL Triglycerides

Diabetes Mellitus

ACE-Inhibitor,

Concomitant

Beta Blocker,

ConcomitantAspirin,

Concomitant

Calcium Channel

Blockers, Concomitant

Arntz 135 2 yrs Pravastatin 20-

40mg 70 55yrs 19% 237mg/dL 176mg/dL 31mg/dL 146mg/dL 0% 18% 37.7% n/a 24.6%

2000 Usual Care _ 65 59yrs 21% 223mg/dL 172mg/dL 32mg/dL 137mg/dL 0% 25% 52% n/a 39%

Primary Objective: The combined clinical end points were total mortality, cardiovascular death, nonfatal myocardial infarction, need for coronary intervention, stroke, and new onset of peripheral vascular disease. Nonfatal myocardial infarction, coronary balloon angioplasty or bypass grafting, stroke, new onset of occlusive peripheral vascular disease, cardiovascular death, and all-cause mortality were prospectively defined as secondary end points.

Primary Outcome(s): Mortality, All-Cause OR Stroke, Any OR Myocardial Infarction, Non-Fatal OR Mortality, Cardiovascular OR Cardiac Intervention OR Peripheral Vascular Disease

Inclusion/Exclusion: Patients with total cholesterol of > 200 to < 400 mg/dl and low-density lipoprotein (LDL) cholesterol of > 130 to < 300 mg/dl (after exclusion of secondary forms of hyperlipidemia) with an acute myocardial infarction (defined by new Q waves and increase of enzymes of > 3-fold the normal value) and/or those who underwent emergency percutaneous transluminal coronary balloon angioplasty due to severe or unstable angina pectoris (defined by clinical symptoms and electrocardiographic [ECG] alterations during rest and/or exercise) were included in this study. Patients with an acute infarction were included only if their lipids could be determined within 8 hours after onset of symptoms; those in the balloon angioplasty group with a history of infarction were included only when the infarction was >= 3 months earlier. Patients > 75 years old, diabetics (fasting blood glucose > 125 mg/dl), patients with postcoronary artery bypass graft, known malignant disease, serious kidney or liver dysfunction (creatimine > 1.5 mg/dl, alanine aminotransferase and aspartate aminotransferase > 2 times normal value), or women of child-bearing age not using a reliable form of contraception were excluded.

Additional Treatment Info: Treatment began an average of 6 (+/- 5) days after qualifying event. Patients in this group with a baseline LDL cholesterol level of <160 mg/dl initially received pravastatin 20 mg/dl; those with an LDL cholesterol of >=160 mg/dl received 40 mg/day. To achieve LDL cholesterol levels of <=130 mg/dl, the pravastatin dosage was increased to 40 mg/day, and nicotinic acid (1.5 to 6 g/day) and/or cholestyramine (4 to 32 g/day) were added if necessary. Antilipidemic therapy was determined by the family physician.

Risk Of Bias: Sequence Generation: LOW – Used stratified randomization scheme, but no description of sequence generation process Allocation Concealment: UNCLEAR – Insufficient details provided to determine. Blinding: LOW - Although open-label, outcome assessors were blinded; unlikely to affect objective outcomes:: mortality, MI, stroke

Exception: Coronary revascularization : HIGH – Knowledge of treatment may impact decision for revascularization Incomplete Outcome Data: HIGH - As treated analysis done - did not include persons who withdrew after randomization in the denominator Selective Outcome Reporting: LOW - The study protocol was not available, but adequate detail given to specification of primary and secondary outcomes. Other Sources of Bias: LOW – No other issues identified.




% Female

Cholesterol, Total

Cholesterol, LDL


Diabetes Mellitus

ACE-Inhibitor,

Concomitant

Beta Blocker,

ConcomitantAspirin,

Concomitant

Calcium Channel


Cannon 4162 24 mo Atorvastatin 40mg 2099 58.1yrs 22.2% 181mg/dL 106mg/dL 38mg/dL 158mg/dL 17.8% n/a n/a 100% n/a

2004 Pravastatin 20mg 2063 58.3yrs 21.6% 180mg/dL 106mg/dL 39mg/dL 154mg/dL 17.5% n/a n/a 100% n/a

Primary Objective: The primary efficacy outcome measure was the time from randomization until the first occurrence of a component of the primary end point: death from any cause, myocardial infarction, documented unstable angina requiring rehospitalization, revascularization with either percutaneous coronary intervention or coronary-artery bypass grafting (if these procedures were performed at least 30 days after randomization), and stroke.Secondary end points were the risk of death from coronary heart disease, nonfatal myocardial infarction, or revascularization (if it was performed at least 30 days after randomization), the risk of death from coronary heart disease or nonfatal myocardial infarction, and the risk of the individual components of the primary end point.

Primary Outcome(s): Mortality, All-Cause* Mortality, Cardiovascular* Mortality, Other

Inclusion/Exclusion: Men and women who were at least 18 years old were eligible for inclusion if they had been hospitalized for an acute coronary syndrome — either acute myocardial infarction (with or without electrocardiographic evidence of ST-segment elevation) or high-risk unstable angina — in the preceding 10 days. Patients had to be in stable condition and were to be enrolled after a percutaneous revascularization procedure if one was planned. Finally, patients had to have a total cholesterol level of 240 mg per deciliter (6.21 mmol per liter) or less, measured at the local hospital within the first 24 hours after the onset of the acute coronary syndrome or up to six months earlier if no sample had been obtained during the first 24 hours. Patients who were receiving long-term lipid-lowering therapy at the time of their index acute coronary syndrome had to have a total cholesterol level of 200 mg per deciliter (5.18 mmol per liter) or less at the time of screening in the local hospital. Patients were ineligible for the study if they had a coexisting condition that shortened expected survival to less than two years, were receiving therapy with any statin at a dose of 80 mg per day at the time of their index event or lipid-lowering therapy with fibric acid derivatives or niacin that could not be discontinued before randomization, had received drugs that are strong inhibitors of cytochrome P-450 3A4 within the month before randomization or were likely to require such treatment during the study period (because atorvastatin is metabolized by this pathway), had undergone percutaneous coronary intervention within the previous six months (other than for the qualifying event) or coronary-artery bypass surgery within the previous two months or were scheduled to undergo bypass surgery in response to the index event, had factors that might prolong the QT interval, had obstructive hepatobiliary disease or other serious hepatic disease, had an unexplained elevation in the creatine kinase level that was more than three times the upper limit of normal and that was not related to myocardial infarction, or had a creatinine level of more than 2.0 mg per deciliter (176.8 µmol per liter).

Additional Treatment Info: The protocol specified that patients were to receive standard medical and interventional treatment for acute coronary syndromes, including aspirin at a dose of 75 to 325 mg daily, with or without clopidogrel or warfarin. Patients were not permitted to be treated with any lipid-modifying therapy other than the study drug. Eligible patients were randomly assigned ratio to receive 80 mg of atorvastatin daily in a double-blind, double-dummy fashion. In addition, patients were also randomly assigned to receive with the use of a two- by-two factorial design a 10-day course of gatifloxacin or placebo every month during the trial. The results of the antibiotic component of the trial are not reported here. Blood samples were obtained at randomization, at 30 days, at 4, 8, 12, and 16 months, and at the final visit for the measurement of lipids and other components that were part of the safety assessment. The protocol specified that patients were to receive standard medical and interventional treatment for acute coronary syndromes, including aspirin at a dose of 75 to 325 mg daily, with or without clopidogrel or warfarin. Patients were not permitted to be treated with any lipid-modifying therapy other than the study drug. Eligible patients were randomly assigned to receive 40 mg of pravastatin in a double-blind, double-dummy fashion. In addition, patients were also randomly assigned to receive with the use of a two- by-two factorial design a 10-day course of gatifloxacin or placebo every month during the trial. The results of the antibiotic component of the trial are not reported here. Blood samples were obtained at randomization, at 30 days, at 4, 8, 12, and 16 months, and at the final visit for the measurement of lipids and other components that were part of the safety assessment. The dose of pravastatin was to increase to 80 mg in a blinded fashion if the LDL cholesterol level exceeded 125 mg per deciliter on two consecutive visits and the patient had been taking study medication and had returned for the required study visits.

Risk Of Bias: Sequence Generation: LOW – Randomization done by permutated block design stratified by center, but no description of sequence generation process Allocation Concealment: UNCLEAR – Insufficient details provided to determine. Blinding: LOW – Described as double-blind Incomplete Outcome Data: LOW - Similar drop out rates and reasons for discontinuation Selective Outcome Reporting: LOW - The study protocol was not available, but adequate detail given to specification of primary and secondary outcomes. Other Sources of Bias: LOW – No other issues identified.




% Female

Cholesterol, Total

Cholesterol, LDL


Diabetes Mellitus

ACE-Inhibitor,

Concomitant

Beta Blocker,

ConcomitantAspirin,

Concomitant

Calcium Channel


Colivicchi 81 12 mo Atorvastatin 80mg 40 69yrs 42.5% 221mg/dL 131mg/dL 40mg/dL 169mg/dL 55% 82.5% 90% 95% 70%

2002 Usual Care _ 41 68yrs 41.5% 219mg/dL 129mg/dL 39mg/dL 165mg/dL 58.5% 82.9% 90.2% 92.7% 70.7%

Primary Objective: The primary combined end point of the study was cardiac death, non fatal acute myocardial infarction (AMI), or recurrent symptomatic myocardial ischemia with objective evidence (electrocardiographic, echocardiographic, or scintigraphic) requiring emergency hospitalization during the follow up period. Secondary end points were the occurrence of any of the primary end point components.

Primary Outcome(s): Mortality, Cardiac OR Myocardial Infarction, Non-Fatal OR Angina, Recurrent/Symptomatic

Inclusion/Exclusion: All patients consecutively admitted to our institution between January 1999 and July 2001 for unstable angina pectoris (UAP) or non–Q-wave acute myocardial infarction (AMI) were prospectively screened for inclusion in the study. In all cases the diagnosis of unstable angina pectoris (UAP) or non–Q-wave AMI was made in accordance with previously reported criteria. To be enrolled in the trial, patients were required to meet the following criteria: (1) angiographic evidence of severe and diffuse coronary artery disease, that was not amenable to direct revascularization by coronary artery bypass grafting or percutaneous transluminal coronary angioplasty, as determined by a cardiac surgeon and an interventional cardiologist during the index admission; (2) objective evidence of symptomatic reversible myocardial ischemia (>=0.1 mV ST-segment depression on the electrocardiogram) at a low exercise workload (<4 METs) while receiving medical treatment (>=2 antianginal medications at maximal tolerated doses), as assessed by treadmill ergometry (Bruce’s protocol) before discharge; and (3) left ventricular ejection fraction >35%. Exclusion criteria were the presence of congestive heart failure, the need for continuous use of intravenous antianginal medications, and the presence of any major concurrent illness. The study was planned as an open-label, prospective, randomized, controlled trial with parallel groups. Before enrollment, all patients were receiving maximal conventional combination therapy (nitrates, calcium antagonists, and beta blockers), including >=2 medications at maximal tolerated doses in all cases.

Additional Treatment Info: At discharge from the hospital, included patients were assigned according to a computer-generated randomization list to the conventional medical treatment plus atorvastatin 80 mg/day—maximal combination therapy was continued in all control subjects. Atorvastatin in the fixed dose of 80 mg/day was added to medical treatment at discharge and no other lipid-lowering treatment was allowed. Compliance with atorvastatin therapy was assessed by pill counting. Patients who withdrew because of intolerable side effects, adverse reactions, lack of adequate response to treatment, or any other reason were taken as complete cases for the intention-to-treat analysis. All patients randomized to the control group (conventional medical treatment) were discharged on the maximal tolerated combination therapy, which was begun during index admission. Whenever necessary during the study, the dosage of each medication could be modified to match clinical needs. Adherence to the National Cholesterol Education Program guidelines was followed. All of these patients had to be treated to attain low-density lipoprotein (LDL) cholesterol levels <100 mg/dl. For patients requiring statin treatment to reach the LDL cholesterol goal during the study, atorvastatin was started at the initial dosage of 20 mg/day. All patients already receiving other statins or any other lipid-lowering drug before inclusion were allowed to continue their treatment after randomization, but the dosage was titrated to reach LDL cholesterol levels <100 mg/dl

Risk Of Bias: Sequence Generation: LOW - Randomized by computer-generated randomized list. Allocation Concealment: UNCLEAR – Insufficient details provided Blinding: LOW - Although open-label, outcome assessors were blinded; unlikely to affect objective outcomes:: mortality, MI

Exception:muscle problems: HIGH – Knowledge of treatment may impact reporting or detection of muscle problems Incomplete Outcome Data: LOW - No LTFU, only 1/81 drop-out Selective Outcome Reporting: LOW - Primary and secondary outcomes specified and reported. Other Sources of Bias: LOW – Early study termination would not introduce bias - participant follow up was complete.




% Female

Cholesterol, Total

Cholesterol, LDL


Diabetes Mellitus

ACE-Inhibitor,

Concomitant

Beta Blocker,

ConcomitantAspirin,

Concomitant

Calcium Channel


de Lemos 4497 721 days

Simvastatin 40-

80mg 2265 61yrs 24% 185mg/dL 112mg/dL 39mg/dL 149mg/dL 23% 70% 90% 98% n/a

2004 Placebo (first 4 mo), then Simvastatin

20mg

2232 61yrs 25% 184mg/dL 111mg/dL 39mg/dL 149mg/dL 24% 72% 90% 98% n/a

Primary Objective: The primary objective of this study was to compare early initiation of an intensive statin regimen with delayed initiation of a less intensive regimen in patients with acute coronary syndrome (ACS). The primary efficacy end point of the trial was a composite of cardiovascular death, nonfatal myocardial infarction (MI), readmission for ACS (requiring new electrocardiographic changes or cardiac marker elevation), and stroke. Secondary end points included individual components of the primary end point, revascularization due to documented ischemia, all-cause mortality, new-onset congestive heart failure (requiring admission or initiation of heart failure medications), and cardiovascular rehospitalization.

Primary Outcome(s): Myocardial Infarction, Any OR Stroke, Any OR Mortality, Cardiovascular OR Readmission, ACS* Stroke, Any OR Mortality, Cardiovascular OR Myocardial Infarction, Any OR Readmission, ACS

Inclusion/Exclusion: Inclusion criteria: Patients between the ages of 21 and 80 years with either non–ST-elevation acute coronary syndrome (ACS) or ST-elevation myocardial infarction (MI) were eligible for enrollment if they had a total cholesterol level of 250 mg/dL (6.48 mmol/L) or lower. The protocol was amended to allow patients with non–ST-elevation ACS who were not enrolled in phase A and patients with ST-elevation MI to enter directly into phase Z. Patients in the latter category were required to receive fibrinolytic therapy or primary percutaneous coronary intervention (PCI) if they presented within 12 hours of symptom onset and no reperfusion therapy if symptom onset was longer than 12 hours prior to presentation. Patients were also required to meet criteria for stability and have at least 1 high-risk feature in addition to cardiac biomarker elevation. Exclusion criteria: patients receiving statin therapy at the time of randomization, if coronary artery bypass graft surgery (CABG) was planned, or if PCI was planned within the first 2 weeks after enrollment, alanine aminotransferase (ALT) level higher than 20% above the upper limit of normal (ULN); increased risk for myopathy due to renal impairment (serum creatinine level>2.0 mg/dL [176.8 µmol/L]) or concomitant therapy with agents known to enhance myopathy risk, such as fibrates, cyclosporine, macrolide antibiotics, azole antifungals, amiodarone, or verapamil; or for having a prior history of nonexercise-related elevations in creatine kinase level or nontraumatic rhabdomyolysis.

Additional Treatment Info: Patients received 40 mg/d of simvastatin for 30 days and then 80 mg/d of simvastatin thereafter. If after 6 weeks the LDL cholesterol remained higher than 130 mg/dL, the investigator could add a bile acid sequestrant or discontinue the study drug and initiate open-label statin therapy. Patients received placebo for 4 months and then 20 mg/d of simvastatin thereafter. If after 6 weeks the LDL cholesterol remained higher than 130 mg/dL, the investigator could add a bile acid sequestrant or discontinue the study drug and initiate open-label statin therapy.

Risk Of Bias: Sequence Generation: LOW - Treatments were assigned randomly to the allocation numbers using a blocked randomization scheme. A patient was randomized by being assigned to the next available allocation number at the site. Allocation Concealment: LOW - Each center was assigned 1 or more blocks of 4 allocation numbers and blinded study supplies corresponding to these allocation numbers.Blinding: LOW - Patients and investigators blinded to assignment. All primary end points were adjudicated by an independent clinical end point committee blinded to treatment assignment. Secondary end points included individual components of the primary end point. Incomplete Outcome Data: LOW - Intent to treat analysis; patients who did not achieve expected follow-up were censored at the time they withdrew consent or were lost to follow-up. Missing outcome data balanced in numbers across intervention groups, with similar reasons for missing data across groups. Low loss to follow-up (<1%). Selective Outcome Reporting: LOW – Primary and secondary outcomes specified and reported. Other Sources of Bias: LOW – No other issues identified.




% Female

Cholesterol, Total

Cholesterol, LDL


Diabetes Mellitus

ACE-Inhibitor,

Concomitant

Beta Blocker,

ConcomitantAspirin,

Concomitant

Calcium Channel


Den Hartog

99 3 mo Pravastatin 40mg 50 64.2yrs 30% 7.6mmol/L 4.5mmol/L n/a 2.3mmol/L n/a n/a n/a n/a n/a

2001 Placebo _ 49 62.7yrs 24% 7.6mmol/L 4.6mmol/L n/a 2.18mmol/L n/a n/a n/a n/a n/a

Primary Objective: The purpose of this study was to determine the safety and tolerability of early initiation of pravastatin therapy for unstable angina or acute myocardial infarction (MI). Secondary goals were to assess the effects of early pravastatin treatment on lipid profiles and coronary events.

Primary Outcome(s): Adverse Event* Adverse Event, Severe* Angina, Any* Angina, Recurrent* CABG* Cardiac Catheterization* Coronary Revascularization, Any* Mortality, Cardiovascular* Myocardial Infarction, Any* Myocardial Infarction, Recurrent, Non-Fatal* PTCA

Inclusion/Exclusion: Participants who were suitable for entry were men aged 18-80 years or postmenopausal women with serum total cholesterol levels of > 5.2mmol/l and LDL cholesterol levels > 3.5 mmol/l. All eligible patients evidenced signs of either unstable angina (UA) or acute myocardial infarction (MI). Acute MI was defined as ST segment elevation >= 1 mm in two leads or T-wave inversion. In addition, patients who met the definition of MI had Q or QS findings on the electrocardiogram, typical symptoms of acute MI and elevated serum enzyme levels. Exclusion criteria included: hypersensitivity to statins or formulation components, severe congestive heart failure or cardiomyopathy, significant liver disease, significant gastrointestinal disease or abdominal surgery that might affect drug absorption, substance or alcohol abuse, history or present use of any other lipid-lowering or investigational agent, uncontrolled diabetes, thyroid disease, severe renal impairment, dysproteinemia, primary muscle disease.

Additional Treatment Info: Patients with acute myocardial infarction (MI) or unstable angina (UA) who were hospitalized for less than 48 hours were randomly allocated to treatment with a 40 mg tablet of Pravastatin daily. After hospital discharge, patients remained on study medication and returned for safety and efficacy evaluations at months 1, 2, and 3 (study conclusion). The Pravastatin was administered orally once daily, beginning within 48 hours of hospital admission, no dose modifications allowed. Patients with acute myocardial infarction (MI) or unstable angina (UA) who were hospitalized for less than 48 hours were randomly allocated to treatment with a placebo tablet daily. After hospital discharge, patients remained on study medication and returned for safety and efficacy evaluations at months 1, 2, and 3 (study conclusion). The placebo was administered orally once daily, beginning within 48 hours of hospital admission.

Risk Of Bias: Sequence Generation: UNCLEAR - No information about the sequence generation process. Allocation Concealment: UNCLEAR - Methods not described. Blinding: LOW - Patients and investigators blinded to assignment. Incomplete Outcome Data: HIGH – Incomplete description of outcome events; also 10% greater discontinuation rate in the placebo arm – may be related to outcome Selective Outcome Reporting: UNCLEAR - Primary outcomes not pre-specified. Other Sources of Bias: LOW – No other issues identified




% Female

Cholesterol, Total

Cholesterol, LDL


Diabetes Mellitus

ACE-Inhibitor,

Concomitant

Beta Blocker,

ConcomitantAspirin,

Concomitant

Calcium Channel


Dupuis 60 6 wks Pravastatin 40mg 30 55yrs 7.1% 5.85mmol/L 3.88mmol/L 0.91mmol/L 2.46mmol/L 3.6% 7.1% 89.3% 100% 14.3%

1999 Placebo _ 30 56yrs 18.5% 5.62mmol/L 4.05mmol/L 0.99mmol/L 2.08mmol/L 0% 22.2% 85.2% 92.6% 18.5%

Primary Objective: The primary objective was to evaluate the effect of therapy on noninvasively measured endothelial function as assessed by brachial artery flow-mediated dilatation using high-resolution ultrasonography. Secondary objectives included evaluation of the variations of hemostatic factors, platelet activity, and plasma immunoreactive endothelin-1 (ET-1) concentrations. A tertiary objective was to confirm the reliability of the admission lipid profile and compare the effects of dietary and combined dietary plus pharmacological cholesterol reduction on plasma lipids after only 6 weeks of therapy.

Primary Outcome(s): Flow-Mediated Dilatation

Inclusion/Exclusion: Patients admitted to the coronary care unit of the Montreal Heart Institute with a diagnosis of acute myocardial infarction or unstable angina were eligible if they had admission total serum cholesterol >=5.2 mmol/L or LDL cholesterol >=3.4 mmol/L and serum triglycerides >=4.5 mmol/L. Exclusion criteria were the presence of heart failure with an ejection fraction of <40%, administration of lipid lowering agents in the preceding 8 weeks, renal failure with serum creatinine level >200 mmol/L, and patients requiring coronary artery bypass surgery. Premenopausal women were also excluded as well as postmenopausal women on hormone replacement therapy. All patients received and were taught American Heart Association step 2 diet. Vitamin supplements were not permitted. All medications were held constant throughout the entire study.

Additional Treatment Info: Subjects were randomized to pravastatin (40 mg daily at bedtime) for a duration of 6 weeks. Subjects were randomized to placebo for a duration of 6 weeks.

Risk Of Bias: Sequence Generation: UNCLEAR - No method of randomization specified. Allocation Concealment: UNCLEAR - No mention of method to conceal treatment allocation. Blinding: LOW – Described as double-blind, but no other details provided Incomplete Outcome Data: LOW - Per protocol analysis done; 5 (8%) pts withdrew and not included in analysis, however data available on all for AE- MI was reported as AE Selective Outcome Reporting: LOW - Primary and secondary outcomes specified and reported. Other Sources of Bias: UNCLEAR - Small sample size (n=60) with some imbalance across groups- UC group may be higher risk – but only 1 outcome reported in UC group




% Female

Cholesterol, Total

Cholesterol, LDL


Diabetes Mellitus

ACE-Inhibitor,

Concomitant

Beta Blocker,

ConcomitantAspirin,

Concomitant

Calcium Channel


Kayikcioglu 77 6 mo Pravastatin 40mg 40 50yrs 15% 223mg/dL 139mg/dL 39mg/dL 225mg/dL 15% n/a n/a n/a n/a

2002 Placebo _ 37 53yrs 19% 228mg/dL 128mg/dL 39mg/dL 219mg/dL 13.5% n/a n/a n/a n/a

Primary Objective: The aim of this study was to determine whether statin therapy initiated early in acute myocardial infarction (MI) together with thrombolytic therapy in patients with acute MI results in clinical benefit (reduction of cardiovascular events, and restenosis rate after coronary intervention) through early plaque stabilization.

Primary Outcome(s): Angina, Any* Coronary Revascularization, Any* Coronary Revascularization, Surgery OR Angioplasty* Mortality, Cardiac* Myocardial Infarction, Any OR Angina, Any OR Mortality, Cardiac* Myocardial Infarction, Recurrent

Inclusion/Exclusion: The study population consisted of 77 patients who underwent coronary balloon angioplasty of the infarct-related artery during the first month of acute myocardial infarction. Exclusion criteria were: contraindications for thrombolytic therapy, age > 75 years, history of myocardial infarction (MI), previous percutaneous transluminal coronary angioplasty (PTCA), coronary artery bypass graft (CABG) surgery, or congestive heart failure (CHF); severe hyperlipidemia (total cholesterol > 300 mg/dl or triglycerides > 300 mg/dl), secondary hyperlipidemia, uncontrolled hypertension or diabetes mellitus, liver disease, thyroid dysfunction, use of anticoagulant drugs other than aspirin, and use of steroids or hormone replacement therapy.

Additional Treatment Info: Patients initially belonged to the cohort of the Pravastatin Turkish Trial. They received thrombolytic therapy (streptokinase 1.5 million units or tissue plasminogen activator 100 mg accelerated regimen) during the first six hours of ST-segment elevated acute myocardial infarction. Patients received immediate pravastatin (40 mg/day) therapy adjunctive to thrombolytic therapy for approximately one month prior to PCTA (Percutaneous Coronary Transluminal Angioplasty) regardless of serum lipid levels and received statin treatment throughout the study. All patients received an AHA step II diet during the study. All patients received aspirin (100 mg/day). Patients with a left ventricular ejection fraction >40% received beta-blockers and patients with a systolic blood pressure > 100 mm Hg received angiotensin-converting enzyme inhibitors. Patients initially belonged to the cohort of the Pravastatin Turkish Trial. They received thrombolytic therapy (streptokinase 1.5 million units or tissue plasminogen activator 100 mg accelerated regimen) during the first six hours of ST-segment elevated acute myocardial infarction. Patients received thrombolytic therapy only for approximately one month prior to PCTA (Percutaneous Coronary Transluminal Angioplasty) and continued on this therapy for six months after their PCTA. All patients received an AHA step II diet during the study. All patients received aspirin (100 mg/day). Patients with a left ventricular ejection fraction >40% received beta-blockers and patients with a systolic blood pressure > 100 mm Hg received angiotensin-converting enzyme inhibitors.

Risk Of Bias: Sequence Generation: UNCLEAR - No method of randomization specified. Allocation Concealment: UNCLEAR - No mention of method to conceal treatment allocation. Blinding: UNCLEAR – Unclear whether blinded or open labeled. Only outcome assessors described as blinded Incomplete Outcome Data: UNCLEAR – Insufficient details re dropouts and LTFU provided Selective Outcome Reporting: LOW – Reported primary and secondary outcomes as specified Other Sources of Bias: HIGH - Broke randomization: applied inclusion criteria AFTER randomization and 1 month of treatment




% Female

Cholesterol, Total

Cholesterol, LDL


Diabetes Mellitus

ACE-Inhibitor,

Concomitant

Beta Blocker,

ConcomitantAspirin,

Concomitant

Calcium Channel


Kesteloot 69 3 mo Pravastatin 10-

20mg 36 n/a 0% 221.5mg/dL 154mg/dL 37.8mg/dL n/a n/a n/a n/a n/a n/a

1997 Placebo _ 33 n/a 0% 235.1mg/dL 161.3mg/dL 34.8mg/dL n/a n/a n/a n/a n/a n/a

Primary Objective: The purpose of this study is to examine the behavior of various serum lipids and apolipoproteins up to 3 months after a myocardial infarction and its modification by pravastatin, a lipid lowering drug.

Primary Outcome(s): Apolipoprotein A1* Apolipoprotein B* Cholesterol, HDL* Cholesterol, LDL* Cholesterol, Total

Inclusion/Exclusion: Only definite cases of acute myocardial infarction were accepted using accepted electrocardiographic and enzymatic criteria. No lipid lowering drugs other than pravastatin were allowed.

Additional Treatment Info: The experimental treatment consisted of 10 mg/day pravastatin starting on day 3, after the drawing of the blood and continued for one week. Then the dose was increased to 20 mg/day of pravastatin up to the end of the study. Treatment was allocated randomly on a double-blind basis. The patients received the usual care for acute myocardial infarction as defined by the policy of each participating center. No lipid lowering drugs other than pravastatin were allowed. Placebo treatment was allocated randomly on a double-blind basis. The patients received the usual care for acute myocardial infarction as defined by the policy of each participating center. No lipid lowering drugs other than pravastatin were allowed.

Risk Of Bias: Sequence Generation: UNCLEAR - No method of randomization specified. Allocation Concealment: UNCLEAR - No mention of method to conceal treatment allocation. Blinding: LOW – Described as double-blind, but no other details provided. Incomplete Outcome Data: LOW – Although no mention of the magnitude of missing data, used repeated measures analysis which can accommodate missingness Selective Outcome Reporting: LOW - Primary outcomes not specified but reports expected outcomes. Other Sources of Bias: UNCLEAR - Need to consider success of randomization with small n (50). Did not provide enough details re characteristics of treatment groups to assess




% Female

Cholesterol, Total

Cholesterol, LDL


Diabetes Mellitus

ACE-Inhibitor,

Concomitant

Beta Blocker,

ConcomitantAspirin,

Concomitant

Calcium Channel


Liem 540 12 mo Fluvastatin 40mg 265 61yrs 19% 5.3mmol/L 3.5mmol/L 1.2mmol/L 1.7mmol/L n/a 37.7% 91% 97% 17.4%

2002 Placebo _ 275 60yrs 15% 5.4mmol/L 3.6mmol/L 1.2mmol/L 1.6mmol/L n/a 36.4% 91% 97% 14.9%

Primary Objective: The primary end-point of this study was a composite end-point: ischaemia or the occurrence of a major clinical event: cardiovascular death (sudden death, fatal recurrent acute myocardial infarction (AMI), fatal stroke or other cardiovascular death), non-cardiovascular death, recurrent AMI or recurrent ischaemia necessitating hospitalization or revascularization (percutaneous coronary intervention - PCI, coronary artery bypass graft surgery - CABG). Secondary end-points: 6-week occurrence of the composite end-point, the 6-week and 12-month occurrence of ischaemia on the ambulatory electrocardiogram (ECG) (without taking clinical events into account), the 6-week and 12-month change in ischaemic burden, the time to a major clinical event and the 12-month change in lipid profile.

Primary Outcome(s): Mortality, All-Cause OR Angina, Any OR CABG OR PTCA OR Myocardial Infarction, Recurrent OR Angina, Recurrent

Inclusion/Exclusion: All consecutive patients with an acute myocardial infarction (AMI) were screened for inclusion in the trial if the total cholesterol value taken at admission or within 24 hours after onset of symptoms was <= 6.5 mmol/L. For the confirmation of the qualifying AMI, an elevation of the myocardial band of creatinine phosphokinase (CK-MB) and/or total CK twice the upper limit of normal was required. In addition, eligibility for the study also required one of the following: new or markedly increased chest pain lasting longer than 30 minutes, or a new pathological Q wave of 0.04 seconds duration, or 25% of the corresponding R wave amplitude, both in at least two contiguous leads. Exclusion criteria: age <18; use of lipid-lowering agents in prior 3 months; baseline triglycerides (TG) >174mg/dL; known familial dyslipidemia; severe renal failure; known liver disease; severe congestive heart failure (New York Heart Assocation (NYHA) class IV); scheduled percutaneous coronary intervention (PCI) or coronary artery bypass graph surgery (CABG); concomittant medication that effects ST-segment on electrocardiogram (EKG) (digoxin, quinidine, TCA's); atrial fibrillation; Wolf-Parkinson-White (WPW) syndrome; complete left bundle branch block (LBBB); known pre-existing ST-segment changes before AMI; left ventricular hypertrophy with a strain pattern on EKG or permanent pacemaker.

Additional Treatment Info: Fluvastatin 40 mg b.i.d. commenced at least 1 day prior to hospital discharge but not later than 14 days after AMI Treatment with placebo was commenced at least 1 day prior to hospital discharge but not later than 14 days after AMI and was continued for 1 year. It was left to the discretion of the attending cardiologist to start other standard medication, including aspirin, beta-blocking agents and/or ACE-inhibitors.

Risk Of Bias: Sequence Generation: UNCLEAR - No method of randomization specified. Allocation Concealment: UNCLEAR - No mention of method to conceal treatment allocation. Blinding: LOW - Described as double-blind, with outcome assessors blinded to treatment. Incomplete Outcome Data: LOW - Similar drop-out rates and exclusions. As treated analysis done for AECG outcomes, but this OC not included in our evaluation Selective Outcome Reporting: LOW - Primary outcome specified and reported. Other Sources of Bias: LOW – No other issues identified




% Female

Cholesterol, Total

Cholesterol, LDL


Diabetes Mellitus

ACE-Inhibitor,

Concomitant

Beta Blocker,

ConcomitantAspirin,

Concomitant

Calcium Channel


Okazaki 70 6 mo Atorvastatin 20mg 35 61.3yrs 14.3% 191.8mg/dL 124.6mg/dL 45.5mg/dL 108.7mg/dL 34.3% 40% 40% n/a n/a

2004 Usual Care _ 35 62.5yrs 14.3% 190.7mg/dL 123.9mg/dL 44.3mg/dL 112.3mg/dL 31.4% 40% 54.3% n/a n/a

Primary Objective: The primary outcome was percent change in plaque volume; the secondary outcome was the correlation between percent change in plaque volume and follow-up LDL-Cholesterol levels or percent LDL-Cholesterol reduction.

Primary Outcome(s): Plaque Volume (% Change)

Inclusion/Exclusion: Patients were eligible for inclusion if they had acute coronary syndrome (ACS) with significant stenosis on initial coronary angiography and received percutaneous coronary intervention (PCI). ACS was defined as high-risk unstable angina, non–ST elevated myocardial infarction (MI) or ST-elevated MI. MI was diagnosed by the rise (>=2 times) in serum creatine phosphokinase and positivity for troponin T. Exclusion criteria were failed PCI, diseased bypass graft, recommended coronary artery bypass graft surgery (CABG), cardiogenic shock, and administration of lipid-lowering drugs (statin, clofibrate, probucol or analog, nicotinic acid, or other prohibited drug) before enrollment.

Additional Treatment Info: All patients underwent emergency coronary angiography and PCI with or without stent placement and post-PCI management were performed in a standard manner. Intravenous heparin and oral 162 mg aspirin were administered during the procedures. After PCI, all patients received aspirin 100 mg once daily and ticlopidine 100 mg twice daily for >3 weeks and cilostazol 100 mg twice daily for 4 days. Patients were randomized to receive intensive lipid-lowering therapy (atorvastatin 20 mg PO once daily). Randomization was undertaken by minimization method controlling for a culprit vessel, baseline total cholesterol level, and presence of diabetes mellitus. All patients underwent emergency coronary angiography and PCI with or without stent placement and post-PCI management were performed in a standard manner. Intravenous heparin and oral 162 mg aspirin were administered during the procedures. After PCI, all patients received aspirin 100 mg once daily and ticlopidine 100 mg twice daily for >3 weeks and cilostazol 100 mg twice daily for 4 days. Patients were randomized to usual care [lipid-lowering diet, and if LDL cholesterol (LDL-C) level was still high (>150 mg/dL) at the outpatient visit, a cholesterol absorption inhibitor was initiated] after PCI and intravascular ultrasound (IVUS) measurement were performed. Randomization was undertaken by minimization method controlling for a culprit vessel, baseline total cholesterol level, and presence of diabetes mellitus.

Risk Of Bias: Sequence Generation: LOW - Randomized by minimization method. Allocation Concealment: UNCLEAR – Insufflicient details provided Blinding: LOW - Open-label design so patients and investigators not blinded to assignmen, however outcomes assessors were blinded. Unlikely to impact objective outcomes: mortality, MI

Exception: Coronary revascularization : HIGH – Knowledge of treatment may impact decision for revascularization Incomplete Outcome Data: LOW – Low dropouts and balanced between treatment groups Selective Outcome Reporting: LOW - Primary and secondary outcomes specified and reported. Other Sources of Bias: LOW – No other issues identified.




% Female

Cholesterol, Total

Cholesterol, LDL


Diabetes Mellitus

ACE-Inhibitor,

Concomitant

Beta Blocker,

ConcomitantAspirin,

Concomitant

Calcium Channel


Schwartz 3086 16 wks Atorvastatin 80mg 1538 65yrs 35.5% 206mg/dL 124mg/dL 46mg/dL 63.96mg/dL 22.2% 48.5% 77.5% 91% 47.8%

2001 Placebo _ 1548 65yrs 34.1% 206mg/dL 124mg/dL 42.8mg/dL 63.96mg/dL 24.1% 49.7% 77.5% 91.2% 48.1%

Primary Objective: The primary combined end point was death, nonfatal acute myocardial infarction (MI), cardiac arrest with resuscitation, or recurrent symptomatic myocardial ischemia with objective evidence requiring emergency hospitalization. Secondary end points were the occurrence of each primary end point components as well as nonfatal stroke, congestive heart failure, worsening angina, coronary revascularization, time to occurrence of event, and percentage changes in blood lipid levels.

Primary Outcome(s): Mortality, All-Cause OR Angina, Recurrent/Symptomatic OR Cardiac Resuscitation OR Myocardial Infarction, Non-Fatal

Inclusion/Exclusion: Eligible patients were adults aged 18 years or older with chest pain or discomfort of at least 15 minutes duration that occurred at rest or with minimal exertion within the 24-hour period preceding hospitalization and represented a change from their usual angina pattern. In addition, diagnosis of unstable angina required evidence of myocardial ischemia by at least 1 of the following: new or dynamic ST-wave or T-wave changes in at least 2 contiguous standard electrocardiographic leads, a new wall motion abnormality by echocardiography, a new and reversible myocardial perfusion defect by radionuclide scintigraphy, or elevation of cardiac troponin to a level not exceeding 2 times the upper limit of normal. Patients were excluded if the serum total cholesterol level at screening exceeded 270 mg/dL, planned coronary revascularization at time of screening, evidence of Q-wave myocardial infarction (MI) within preceding four weeks, bypass surgery within preceding 3 months, percutaneous coronary intervention (PCI) within preceding 6 months, the New York Heart Classification (NYHC) IIIb or IV, left bundle branch block (LBBB), paced ventricular rhythm, concurrent treatment with other lipid lowering agents (except niacin at 500 mg/day), Vitamin E (except doses lower than 400 IU/day), drugs associated with rhabdomyolysis in combination with statins, severe anemia, renal failure requiring dialysis, hepatic dysfunction (ALT >2x upper limit of normal-ULN), insulin-dependent diabetes mellitus (IDDM), pregnancy, or lactation.

Additional Treatment Info: Patients were assigned to Atorvastatin treatment between 24 and 96 hours after hospital admission. Patients were randomly assigned placebo between 24 and 96 hours after hospital admission.

Risk Of Bias: Sequence Generation: LOW - Described as randomly assigned, stratified by center, but no method of randomization specified. Allocation Concealment: UNCLEAR - No description of method to conceal treatmen allocationt. Blinding: LOW - Patients and investigators as well as outcome assessors blinded to assignment.. Incomplete Outcome Data: LOW - Intent to treat analysis; censoring occurred for patients who did not experience an end point prior to completing the study as planned or prior to early withdrawal from the study. Missing outcome data balanced in rate and reason with low loss to follow-up. Selective Outcome Reporting: LOW - Primary and secondary outcomes specified and reported. Other Sources of Bias: LOW – No other issues identified.




% Female

Cholesterol, Total

Cholesterol, LDL


Diabetes Mellitus

ACE-Inhibitor,

Concomitant

Beta Blocker,

ConcomitantAspirin,

Concomitant

Calcium Channel


Serruys 1677 3.9 yrs Fluvastatin 40mg 844 60yrs 16% 200mg/dL 131mg/dL 38mg/dL 160mg/dL 14% 38% 69.2% 97.4% 58.8%

2002 Placebo _ 833 60yrs 17% 199mg/dL 132mg/dL 37mg/dL 160mg/dL 10% 38.1% 70.9% 97.8% 56.3%

Primary Objective: The primary clinical composite end point was development of major adverse cardiac endpoints, defined as cardiac death, non fatal myocardial infartcion (MI), or a reintervention procedure. Prespecified secondary clinical end points were major adverse cardiac events (MACE) in the first 6 months of follow-up for lesions treated at the index procedure, cardiac mortality, non-cardiac mortality, all-cause mortality, combined cardiac mortality and MI, and combined all-cause mortality and MI. Secondary end points also included treatment effects on measured lipid levels throughout the trial, as well as safety and tolerability of fluvastatin.

Primary Outcome(s): Mortality, Cardiac OR Myocardial Infarction, Non-Fatal OR CABG OR PCI

Inclusion/Exclusion: Men and women aged 18-80 years were recruited. All patients had successfully undergone their first percutaneous coronary intervention (PCI) (index procedure) of 1 or more lesions in the native coronary arteries. Successful PCI was defined as a reduction of the stenosis diameter to less than 50% in the target lesion without evidence of myocardial necrosis, need for repeat PCI or coronary artery bypass graft surgery (CABG), or death before hospital discharge. Any type of PCI was allowed and included balloon angioplasty with or without stent replacement, rotational or directional atherectomy, laser ablation, transluminal extraction catheter, or cutting balloon. Patients were eligible for enrollment in the study if they had a total cholesterol level between 135 and 270 mg/dL (3.5-7.0 mmol/L) with fasting triglyceride levels of less than 400 mg/dL (4.5 mmol/L) before the index procedure. The upper cholesterol limit for eligibility was 212 mg/dL (5.5 mmol/L) for patients whose baseline lipids were measured from blood drawn 24 hours to 4 weeks following myocardial infarction (MI) and 232 mg/dL (6.0 mmol/L) for patients with type 1 or 2 diabetes mellitus. Exclusion criteria: sustained systolic blood pressure (SBP) >180 mmHg or diastolic blood pressure (DBP) >100 mmHg; left ventricular ejection fraction (LVEF) <30%; history or prior PCI, prior CABG, severe valvular disease, idiopathic cardiomyopathy, or congenital heart disease; severe renal failure; body mass index (BMI) >35; cancer; any other disease with a life expectancy < 4 years.

Additional Treatment Info: Patients received fluvastatin, 40 mg twice per day. The first dose was adminstered at the time of the patients' hospital discharge an average of 2 days following patients' first PCI. All patients received dietary and lifestyle counseling at hospital discharge. Patients received placebo. The first dose was adminstered at the time of the patients' hospital discharge an average of 2 days following patients' first PCI. All patients received dietary and lifestyle counseling at hospital discharge.

Risk Of Bias: Sequence Generation: LOW - Randomization by block method by medication pack number. Allocation Concealment: LOW - Patients were to be allocated to treatment in the order in which they were enrolled into the study at each center according to medication pack numbers Blinding: LOW - Blinding of participants and study investigators however, investigators were unblinded when patients’ total cholesterol exceeded 278mg/dL. Incomplete Outcome Data: LOW - Similar dropouts and reasons for dropout. Selective Outcome Reporting: LOW - Primary outcome specified and reported. Other Sources of Bias: HIGH - High non-compliance and treatment crossovers – with disproportionate % of placebo group given other drugs. Would probably bias toward null and may partially account for non-statistically significant effect




% Female

Cholesterol, Total

Cholesterol, LDL


Diabetes Mellitus

ACE-Inhibitor,

Concomitant

Beta Blocker,

ConcomitantAspirin,

Concomitant

Calcium Channel


Thompson 3408 30

days Pravastatin

20-40mg

1710 23.5% 217mg/dL n/a n/a n/a 14.3% 18.6% 16.5% n/a 16.4%

2004 Placebo _ 1698 24.3% 219.7mg/dL n/a n/a n/a 13.8% 18.1% 9% n/a 16.7%

Primary Objective: The primary endpoint was a composite endpoint of fatal and non-fatal myocardial infarction (MI), new unstable angina, recurrent unstable angina, and death excluding fatal MI. Other preplanned analyses were the incidence of individual causes of death, AMI other than the index event and readmission to hospital for angina in the first month, urgent or unscheduled revascularization procedures (percutaneous coronary intervention or coronary artery bypass grafting), and other nonfatal cardiovascular events (stroke, peripheral vascular disease, transient ischemic attack, and pulmonary embolism).

Primary Outcome(s): Mortality, All-Cause OR Myocardial Infarction, Any OR Angina, Unstable, Requiring Hospitalization

Inclusion/Exclusion: Patients were enrolled in the study within 24 hours of the onset of symptoms if they had electrocardiographic changes suggestive of an acute myocardial infarction (AMI) or unstable angina (UAP). All patients were between 18 and 85 years of age and gave written informed consent. Patients in whom the diagnosis of AMI or UAP was not confirmed were withdrawn from randomized therapy. Exclusion criteria: prior statin use, participation in any other clinical trial or taking an investigational drug within the past 30 days; planned coronary revascularization or cardiac transplantation; severe renal or hepatic disease; other severe disease; drug/alcohol related problems; gastrointestinal disease; history of gastrointestinal surgery that might affect drug reabsorption; hypersensitivity or prior adverse reaction to statin; or women of child-bearing potential.

Additional Treatment Info: Patients received 40 mg pravastatin (20 mg for those subjects enrolled in the early stages of the study) within 24 hours of chest pain, for 30 days. Patients received placebo within 24 hours of chest pain, for 30 days.

Risk Of Bias: Sequence Generation: UNCLEAR - No information about the sequence generation process. Allocation Concealment: UNCLEAR - Author states allocation concealment maintained, but methods not described. Blinding: LOW - Investigators blinded to results – trial analysis and management by an independent committee. Incomplete Outcome Data: LOW - Missing outcomes were balanced no differences in the rate or reason; Low LTFU (<2%); In both groups ~13 of randomized patients were withdrawn from tx after confirmation of eligibility, but were included in ITT analysis. Selective Outcome Reporting: LOW - The study protocol was not available, but adequate detail given to specification of outcome. Other Sources of Bias: LOW – No other issues identified



References (1) Berkman LF, Blumenthal J, Burg M, Carney RM, Catellier D, Cowan MJ et al. Effects

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