Advances in the Treatment of Chronic Angina

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Advances in the Treatmentof Chronic Stable Angina


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Release Date: February 1, 2008 Expiration Date: February 28, 2010FACULTY:

Nicole K. Brogden, PharmDPGY1 Pharmacy Resident, University of

Kentucky HealthCare, Lexington, Kentucky

Steven P. Dunn, PharmD, BCPSCardiology Clinical Specialist, Department ofPharmacy Services and Division ofCardiovascular Medicine, Gill Heart InstituteAdjunct Assistant Professor, University ofKentucky College of PharmacyLexington, Kentucky

Tracy E. Macaulay, PharmD, BCPSCardiology Clinical Specialist, Department ofPharmacy Services and Division ofCardiovascular Medicine, Gill Heart InstituteAdjunct Assistant Professor, University ofKentucky College of PharmacyLexington, Kentucky

FACULTY DISCLOSURE STATEMENTS:

Drs. Brogden, Dunn, and Macaulay have no actual or potential conflicts of interest in relationto this program.U.S. Pharmacist does not view the existence of relationships as an implication of bias or thatthe value of the material is decreased. The content of the activity was planned to be balanced,objective, and scientifically rigorous.Occasionally, authors may express opinions that represent their own viewpoint. Conclusions

drawn by participants should be derived from objective analysis of scientific data.

ACCREDITATION STATEMENT:PharmacyPostgraduate Healthcare Education, LLC is accredited by the Accreditation Council forPharmacy Education as a provider of continuing pharmacy education.Program No.: 430-000-08-003-H01-P; 430-000-08-003-H01-TCredits: 2.0 hours (0.20 ceu)

Exam processing inquiries and booklet orders to:CE Customer Service Manager (800) 825-4696

Direct educational content inquiries to:CE Director (800) 331-9396

DISCLAIMER:

Participants have an implied responsibility to use the newly acquired information to enhancepatient outcomes and their own professional development. The information presented in thisactivity is not meant to serve as a guideline for patient management. Any procedures,medications, or other courses of diagnosis or treatment discussed or suggested in this activity


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Angina is the most frequent symptom of coronary artery disease (CAD), prompting the majority ofpatients with CAD to seek medical attention.1 Angina is classically characterized as substernaldiscomfort, and patients often describe their pain using terms such as squeezing, suffocating, orpressure-like.2 A diagnosis of chronic stable angina (CSA) includes left anterior chest discomfortthat is predictable and reproducible after emotional stress and/or physical activity; the associated

anginal symptoms are typically relieved by either sublingual nitroglycerin or cessation of theexacerbating circumstances. Symptoms are typically worse in cold conditions or followingmeals.2,3 When a patient presents with chest pain, the initial evaluation should include a detailedhistory, physical examination, and other appropriate tests in order to determine the patientsprobability of having significant CAD versus acute myocardial infarction (MI).2 A detailed history ofthe pain should be elicited from the patient, including the nature of the pain, precipitating factors,duration, and relief with rest or nitroglycerin.3,4

A patient presenting with acute onset of angina should also be evaluated for acute coronarysyndrome. The following discussion will focus only on the treatment of CSA.

Pathophysiology of Chronic Stable Angina

Symptoms originate from regional myocardial ischemia that arises from inadequate coronaryperfusion. This type of angina is typically, although not always, caused by increased myocardialoxygen requirements.3,4 An increase in myocardial oxygen demand is created during increasedactivity or stress, leading to a supply-demand mismatch and resulting in ischemia. Progression ofatherosclerosis in the coronary arteries can lead to plaque deposition external to the lumen,ultimately intruding into the lumen, causing obstruction, and, therefore, angina (FIGURE 1).4

Classification of Angina

Stable angina can be described as classic (typical), atypical, nonanginal, and noncardiac; eachtype of angina presents with distinct symptoms.2-4 Classic or typical angina involves three distinctcharacteristics: 1) substernal chest discomfort or pain that has a characteristic quality andduration, which is 2) brought on by emotional stress or physical activity, and is 3) usually relievedby either rest or nitroglycerin. Atypical angina presents as chest pain that contains two out of thethree characteristics of stable angina and is more common in women, elderly patients, and
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patients with diabetes. Noncardiac angina meets one or none of the characteristics of classicangina, and the differential diagnosis should include gastroesophageal reflux disease (GERD),peptic ulcer disease, mitral valve prolapse, and biliary disease.2-4

The Canadian Cardiovascular Society (CCS) classification of angina, proposed in 1976, is awidely used mechanism for characterizing angina based on an assessment of disability resulting

from the anginal symptoms.1,4

The classification system is described in TABLE 1. It is important tonote that Sangareddi et al demonstrated in 2004 that there is no statistically significant correlationbetween the CCS angina class and the severity of CAD as determined by coronaryangiography.1,3

Table 1

Canadian Cardiovascular Society Angina Grading Scale

AnginaClassification

Accompanying Symptoms

Class I Normal physical activity (e.g., climbing stairs or walking) doesnot cause anginal symptoms; angina occurs primarily withstrenuous, extended, or rapid physical activity or recreation

Class II Angina poses a slight limitation on ordinary activity andtypically occurs with the following types of activities:

Quickly walking or climbing stairs

Uphill walking

Walking/stair climbing after meals

Windy or cold weather

Emotional stress

Within the first few hours after waking

Walking more than two blocks or climbing more than

one flight of stairs at a normal pace (under normalconditions)

Class III Anginal symptoms impose marked limitation on physicalactivity; angina occurs upon walking one to two blocks orclimbing one flight of stairs at a normal pace (under normalconditions)

Class IV Symptoms of angina may be present at rest; physical activitycannot be carried out without discomfort

Source: Reference 1.

Treatment of Chronic Stable Angina
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The American College of Cardiology (ACC)/American Heart Association (AHA) guidelines for themanagement of adult patients with CSA were updated in 2002, thus providing the most currentstandards for the medical management of patients with CSA.5 The pharmacologic management ofpatients with CSA is multifaceted but can be classified into two general areas: antianginal/anti-ischemic therapies (i.e., beta-blockers, calcium channel antagonists, and nitrates) andvasculoprotective agents (i.e., lipid-lowering therapies and antiplatelet agents).3 This discussionwill focus primarily on the antianginal and anti-ischemic therapies.

In addition to the pharmacologic options and standards of care described by the 2002 ACC/AHAguidelines, ranolazine was approved in January 2006 by the FDA as a novel treatment option forCSA in patients who have not achieved adequate control of angina symptoms with standardtherapies.6 (These pharmacologic treatments are summarized in TABLE 2.) Nonpharmacologicinterventions for CSA, such as percutaneous coronary intervention and lifestyle modifications,remain central to the overall management of the patient and will be discussed as well.

Antianginal and Anti-ischemic Drugs

Beta-blockers: Beta-adrenergic blockers (beta-blockers) produce their antianginal effectsprimarily through a decrease in myocardial oxygen demand that results from a reduction in heart

rate, myocardial contractility, and blood pressure. According to the ACC/AHA 2002 guidelines,beta-blockers are considered to be initial first-line therapy for CSA in all patients withoutcontraindications, including the elderly, those with a history of previous MI, and those who haveundergone a previous revascularization.5,7 Beta-blockers are especially appealing in patients withconcurrent cardiovascular risk equivalents, as previous data have demonstrated that beta-blockers are able to decrease the incidence of cardiac events and improve survival in patientswho are hypertensive and post-MI.8

Despite differing amounts of alpha- and beta-blocking properties, all of the beta-blockers areessentially thought to be equally effective for the treatment of CSA, although not all are FDAapproved for this indication.7 The beta-blockers exert their antianginal effects in a dose-dependentmanner; thus, therapy must be titrated to goal, which is a resting heart rate of 50 to 60 beats perminute (bpm) and an exercise heart rate of less than 100 bpm.4

There are several absolute contraindications to beta-blocker therapy, including sick sinussyndrome, severe bradycardia or atrioventricular block, and unstable heart failure (TABLE 2).Relative contraindications to beta-blockers include asthma, peripheral vascular disease, anddepression.7 General side effects of this class include fatigue, exercise intolerance, brady-cardia,hypotension, altered glucose metabolism, and worsening claudication.5,7

Calcium Channel Blockers: In general, the calcium channel antagonists (commonly known ascalcium channel blockers, or CCBs), are equally effective in the management of stable angina.9-12

These agents exert their antianginal effects via inhibition of calcium entry into myocardial tissue,resulting in dilation of both systemic and coronary arteries that leads to an increase in coronaryblood flow and thus decreases myocardial oxygen consumption.3,4

The CCBs should be considered first-line therapy in situations when beta-blocker therapy is notindicated, including when patients have absolute contraindications to beta-blockers or are unableto tolerate therapy because of adverse events.5 CCBs can also be used as add-on therapy inpatients with inadequate control of anginal symptoms on monotherapy with a beta-blocker.5 Ingeneral, the short-acting dihydropyridine CCBs should not be used for the treatment of anginabecause of their potential to produce ischemia through rebound activation of the sympatheticnervous system.13
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Generally, all CCBs cause similar adverse events, including peripheral edema, worsening of heartfailure, hypotension, and constipation (TABLE 2). Various CCBs have agent-specific adverseevents due to differences in pharmacology (dihydropyridine versus nondihydropyridine), whichinclude excessive reflex tachycardia (e.g., nifedipine) and bradyarrhythmias (e.g., diltiazem andverapamil). Due to differences in the adverse-effect profiles and peripheral and centralhemodynamic effects, the initial choice of a calcium channel blocker should be carefullyconsidered.

Nitrates: Nitrates provide an exogenous source of the endogenous endothelium-independentvasodilator nitric oxide. It is well known that in the presence of atherosclerosis there is impairedproduction of nitric oxide; thus, nitrates can be given to improve symptoms of angina by reducingboth myocardial ischemia and improving coronary blood flow. Once converted to nitric oxideinside the vessel wall, the enzyme guanylate cyclase is stimulated to produce cyclic guanosinemonophosphate (cGMP). This results in a decrease in calcium in the vascular myocyte, causingvasodilation. Nitrates are better vasodilators of veins than of arteriole; therefore, dose-limitingblood pressure-lowering effects occur, but generally only at higher doses or with combinationtherapy.

There are many different nitrate preparations, most of which are FDA approved for the treatment

of angina (TABLE 2). The most commonly utilized agent is sublingual nitroglycerin, which has anelimination half-life of only a few minutes and is the treatment of choice to halt acute anginalepisodes. The instability of nitroglycerin tablets makes nitroglycerin spray an attractive alternativefor more active individuals or those with chronically dry mouth. In vivo, nitroglycerin isextrahepatically converted rapidly to longer-acting dinitrates, which are biologically active.14

However, when isosorbide dinitrate is administered orally, it must be converted by the liver intoactive mononitrates. Isosorbide dinitrate given sublingually has an antianginal effect lasting aboutone hour and, when ingested, will last up to six hours. The longest-acting oral preparation is thebiologically active formulation isosorbide mononitrate, which is also available in a sustained-release (SR) preparation.

Unlike beta-blockers, nitrates have not demonstrated the ability to reduce MIs or death. However,studies have shown increased exercise duration with isosorbide mononitrate 120 to 240 mg daily

and isosorbide dinitrate 15 to 120 mg administered several times a day.15,16

Nitrates are also idealwhen used in combination with beta-blockers, which may prevent the nitrate adverse effect ofreflex tachycardia.17 Whenused in combination with calcium channel blockers, hypotension maybe more profound, but this combination has also demonstrated positive effects on exercisetolerance. Other important interactions causing profound hypotension include concomitant use ofphosphodiesterase inhibitors (sildenafil, tadalafil, and vardenafil), a combination that should beavoided for up to 24 hours after administration of sildenafil or vardenafil, and 48 hours after long-acting tadalafil.18

However, there is a potentially beneficial drug interaction with hydralazine, which lessens nitratetolerance by decreasing nitric oxide degradation.19 Nitrate tolerance was first noticed by Bruntonand published in the Lancetin 1867.20 Tachyphylaxis is the primary reason for therapy failure withlonger-acting preparations, but it can be circumvented by providing a 10-to 12-hour nitrate-freeinterval or by concurrent administration with hydralazine.21 With so many options foradministration, nitrates are ideal to treat angina in patients without compelling indications forpreviously discussed classes or as adjunct therapy.

Ranolazine

On January 1, 2006, the FDA approved ranolazine as a new treatment option for patients withCSA. Its mechanism of action remains unknown, although the antianginal effects are producedwithout any significant changes in hemodynamic properties such as heart rate and bloodpressure.6
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Despite some uncertainty regarding the exact mechanism of action, ranolazine is thought to exertits effects by altering the production of adenosine triphosphate (ATP) away from oxidation of fattyacids, thus favoring the more oxygen-efficient oxidation of carbohydrates.22 During myocardialischemia, the levels of fatty acids rise suddenly, thus promoting their uptake and oxidation in themyocardial tissue.22 Thephosphorylation of ATP during the oxidation of fatty acids requires moreoxygen than carbohydrate oxidation, ultimately leading to an inefficient use of the availableoxygen supply. A shift in metabolism from fatty acid to carbohydrate oxidation theoreticallypromotes more efficient use of oxygen and would potentially lessen ischemia.22,23 In addition,ranolazine has been shown to inhibit the late phase of the inward sodium current duringrepolarization of cardiac tissue, which may also reduce myocardial ischemia and controlsymptoms of angina.24 Fatty acid metabolism by myocytes also produces potentially harmfulbyproducts, thereby suggesting a potential role for ranolazine in reducing harmful cardiac events.

Ranolazine undergoes significant metabolism in the liver and gut, with a half-life of approximatelyseven hours.6 Nearly 75% of the drug is excreted in the urine, while the remainder is excreted viafeces. Ranolazine is currently contraindicated in patients with preexisting long QT syndrome(irregular electrical activity of the heart that places patients at risk for ventricular arrhythmias) or inthose receiving QT-prolonging drugs. Ranolazine is also contraindicated in patients receivingconcurrent therapy with CYP3A inhibitors (including diltiazem) and in patients with severe hepaticimpairment. No cases of torsades de pointes (a rare form of ventricular tachycardia) have beenreported to date.6

Ranolazine is available as an SR oral tablet that can be taken with or without regard to meals(TABLE 2). Therapy is initiated at 500 mg bid and titrated up to 1,000 mg bid, based on clinicalsymptoms (maximum dose is 1,000 mg bid). In general, concurrent therapy with other antianginaltreatments is well tolerated.6

To date, four major trials have been published describing the efficacy and safety of ranolazine:the Monotherapy Assessment of Ranolazine in Stable Angina (MARISA) trial,22 the CombinationAssessment of Ranolazine in Stable Angina (CARISA) trial,23the Efficacy of Ranolazine inChronic Angina (ERICA) trial,25 and the Metabolic Efficiency with Ranolazine for Less Ischemia inNon-ST Elevation Acute Coronary Syndrome Thrombolysis in Myocardial Infarction 36 (MERLIN-

TIMI 36) trial.24

A brief description of each of these trials is included in the following paragraphs.

Table 2

Pharmacologic Treatments for Chronic Stable Angina

DrugClass

Mechanismof Action

Place inTherapy

Specific Agents(Dosing)

SideEffects

Contraindications

Beta-blockers Decreasedmyocardial

oxygen demand,resulting from areduction inheartrate, myocardialcontractility, andblood pressure

First-linein allpatientswithoutcontraindi-cations

Atenolol: 25-200 mgqdMetoprolol tartrate:100-450mg/day in 2 to 3divided dosesPropranolol:80-320mg/day individed doses (2 to 4times/day);Long-actingformulation:80-320 mg qd

Bradycardia,hypotension,glucoseintolerance,fatigue, exerciseintolerance,worseningclaudication

Absolute: severebradycardia, sick sinussyndrome, AV block,unstable heart failureRelative: asthma,depression, peripheralvascular disease
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Calciumchannelblockers

Dilation ofsystemicand coronaryarteries,leading to anincrease

in coronaryblood flowanddecreasingmyocardialoxygenconsumption

First-linein patientswithcontraindi-cations tobeta-

blockers andin patientswithunacceptableadverseeventsorinadequatesymptomcontrol onmonotherapywith beta-blockers

Amlodipine: 5-10mg/day(5 mg/day in elderlypatients)Diltiazem: ER capsule:120-180 mg qd (max

dose 480 mg/day);ER tablet: 180-360mg/day;IR tablet: 180-360mg/dayin divided dosesFelodipine: 2.5-10 mgqdNifedipine: IR capsule:10-30 mg tid; SRtablet:30-60 mg qdVerapamil: 240-480mg/dayin 3 to 4 divided doses(40 mg tid in elderlypatientsand those with smallframes)

Bradycardia,hypotension,constipation,worsening ofheartfailure,

peripheraledema, agent-specific events,prolongation ofQT-interval(bepridil),AV-block(verapamil,diltiazem),excessive heartrate elevation(nifedipine)

DHP: hypersensitivityNon-DHP: acute MIwith pulmonarycongestion, WolfParkinson-Whitesyndrome, AV block,

hypersensitivity,symptomatic hypotension,sick sinussyndrome, cardiogenicshock, heart failure(verapamil)

Nitrates Vasodilation ofperipheral veinsand arteries,thusdecreasingmyocardialoxygen demandthrough areductioninpreload

Treatment ofangina inpatientswithoutcompellingindicationsforotherantianginaltherapies, orasadjuncttherapy

Isosorbide dinitrate:Oral (IR): 5-40 mg 4times/day;Oral (SR): 40 mgevery 8-12 h;Sublingual: 2.5-5 mgevery 5-10min (max 3 doses in15-30 min),can also be used asprophylaxis15 min prior toactivities thatprovoke anginaIsosorbidemononitrate:Regular tablet: 5-20mg bid, withat least 12 hseparating doses;

ER tablet: initiatetherapy at30-60 mg as a singledose in themorning, then titrateupwardevery 3 days asneeded to maxdaily single dose of

Headache,dizziness,hypotension

Hypersensitivity tonitrates, concurrent useof PDEs (sildenafil,tadalafil, vardenafil),increased intracranialpressure, symptomatichypotension


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240 mgTranslingual spray: 0.4mg/spray,q5 min (max 3 dosesin 15 min)

Ranolazine Mechanism ofactionnotclear; possibleshiftin the productionofATP away fromoxidationoffatty acids, thusfavoring themore

oxygen-efficientoxidationof carbohydrates

Combinationtherapy withamlodipine,nitrates,or beta-blockersin patientsnotwellcontrolledwithmonotherapyon these

agents

Initiate at 500 mg bid;titrate up to max doseof1,000 mg bid

Dizziness,headache,constipation,nausea

Severe hepatic dys-function, concurrent useof QT-interval-prolongingagents or preexisting QTinterval prolongation atbaseline, concurrenttherapy with CYP3A

AV: atrioventricular; ER: extended-release; max: maximum; IR: immediate-release: SR: sustained-release; DHP: dihydropyridine;MI: myocardial infarction; PDEs: phosphodiesterase inhibitors; ATP: adenosine triphosphate.Source: References 3, 6.

MARISA: The MARISA trial was the first placebo-controlled trial to examine ranolazine SR asmonotherapy in patients with chronic angina. All subjects had at least a three-month history ofexertional angina that was responsive to beta-blockers, CCBs, and/or long-acting nitrates. Theprimary end point of the trial was total exercise duration at trough of ranolazine plasmaconcentrations. The authors concluded that doses of 500 to 1,500 mg of ranolazine improvedexercise performance significantly and delayed or prevented the ECG evidence and symptoms ofmyocardial ischemia (during exercise tests of patients with CSA). These effects occurred withminimal or no effects on heart rate and blood pressure.22

CARISA: The CARISA trial was a double-blind, three-group parallel trial designed to assess theantianginal and anti-ischemic effects of ranolazine in patients with anginal symptoms despitestandard treatment with atenolol, diltiazem, or amlodipine. The primary end point of the trial wasto compare the effects of placebo versus ranolazine with regard to exercise duration whenranolazine levels were at a trough (i.e., 12 hours after administration of the dose). Subjectsdiscontinued all antianginal drugs except those required for background therapy (atenolol,amlodipine, or diltiazem), and the subjects were randomized to receive ranolazine or placebo.The trial met the primary end point, as the duration of exercise in those patients taking ranolazinewas increased over placebo.23

ERICA: The ERICA trial was a prospective, randomized, double-blind trial of patientsexperiencing three or more anginal attacks per week despite maximal therapy with amlodipine.Frequency of angina episodes during the six-week treatment period was the primary end point;efficacy was assessed by the consumption of nitroglycerin per week and the Seattle AnginaQuestionnaire. The results of the trial displayed a significant reduction in the frequency of anginaepisodes and consumption of nitroglycerin in the ranolazine group. Patients who experiencedmore frequent angina displayed a more profound treatment effect.25


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MERLIN-TIMI 36: The MERLIN-TIMI 36 trial was a randomized, controlled trial of hospitalizedpatients with non-ST elevation acute coronary syndrome. The primary objective of the study wasto evaluate the effect of ranolazine (compared to placebo) on the composite of recurrent ischemicevents or cardiovascular death; ECG measurements were used to assess the incidence ofclinically significant arrhythmias. The results of the MERLIN-TIMI 36 trial failed to meet theprimary end point. However, ranolazine did demonstrate non-significant decrease in the incidenceof sudden cardiac death when compared to placebo. Of note, treatment with ranolazine alsoappeared to have some antiar-rhythmic properties, reducing events seen on ambulatorymonitoring. While these results demonstrate that ranolazine does not reduce clinical events, theydo suggest that ranolazine appears to be safe and effective when used as long-term antianginaltherapy, and that it may have some antiarrhythmic effects. Further studies are required toexamine the future of ranolazine as an antiarrhythmic agent.24

Nonpharmacologic Management

Although aggressive medical management and invasive intervention are indicated to treat CSA,significant lifestyle modifications should also be encouraged to avoid MI and worsening ofdisease. Many such interventions revolve around controlling known risk factors for cardiovasculardisease and include smoking cessation, increasing physical activity, and involvement in a weight-

management program to reduce obesity. Beyond these basic lifestyle modifications, severalnonpharmacologic strategies aimed at the improvement of angina symptoms are available,including exercise training, surgical revascularization, enhanced external counterpulsation(EECP), and surgical laser transmyocardial revascularization (TMR).

Exercise training or cardiac rehabilitation has shown remarkable efficacy in increasing exercisetolerance,26,27with more limited data showing improvement in symptomatology.26,28 Several studieshave also shown decreases in objective measures of ischemia, such as ST-segment depressionand myocardial perfusion imaging.26,28

While there are only limited data linking exercise programs to improvement in diseaseprogression and patho-physiology, exercise programs likely benefit the patient, and manypractitioners believe that these programs also entitle the patient to an improved sense of well-

being. In addition, exercise has been positively associated with improved control of knowncardiovascular risk factors such as hypertension, hyperlipidemia, and diabetes, and thus shouldbe enthusiastically recommended to all patients with CSA.

Two well-established forms of coronary revascularization existcoronary artery bypass grafting(CABG) and percutaneous coronary intervention (PCI). Coronary bypass surgery involves amedian sternotomy and surgical grafting of the coronary arteries, whereas PCI is primarilyperformed via balloon angioplasty and coronary stent placement.


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For the most part, PCI has emerged as the nonpharmacologic treatment of choice for CSA due toits relative simplicity and decreased recovery time for the patient when compared to CABG.However, CABG is still preferred for patients with difficult coronary anatomy, as well as for thosewith high-risk features such as multivessel coronary disease, left main disease, or decreased leftventricular ejection fraction.5 PCI is also not completely without long-term complications, ascoronary stent restenosis and now stent thrombosis with drug-eluting stents have beenproblematic to manage. PCI has been compared to CABG in multiple studies, the results of which

have been mixed and serve to define which subgroups of patients should receive one therapyover the other.24,25 It should also be noted that PCI has recently been shown not to offer a survivaladvantage to patients receiving the procedure when compared with aggressive medicalmanagement.29 However, many patients crossed over into the PCI group by the end of the follow-up period, implying more frequent treatment failure with patients receiving aggressive medicaltherapy. While the long-term impact of this study and its effect on consensus-based guidelinesremains to be seen, it seems reasonable that PCI could be deferred or omitted if a patientresponds to aggressive antianginal medication therapy.

Several alternative nonpharmacologic methods for relieving angina are also recommended byACC/AHA guidelines, although primarily for refractory disease.5 EECP is a technique using cuffsto compress a patients lower extremities during diastole, thereby forcing vascularcounterpulsation and increasing coronary artery blood flow. This procedure has been evaluated in

a placebo-controlled trial in which patients were randomized to receive EECP (35 hours) versusinactive EECP over a four- to seven-week period. The results of the study demonstrated thatEECP reduced angina frequency and increased exercise time when compared with placebo.30

EECP has also been analyzed in the International EECP Patient Registry in comparison withpatients undergoing surgical revascularization (i.e., PCI or CABG), showing decreased frequencyof angina, MI, and hospitalizations at six months.31

TMR is an advanced surgical technique for patients with refractory angina. It can be performedpercutaneously or via surgical creation of transmural endomyocardial channels designed to
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improve myocardial circulation. In general, these techniques have been shown to offer short-termrelief of angina symptoms, but few data exist describing long-term outcomes of the procedures.32,33

Conclusion

According to the ACC/AHA updated guidelines for the management of adult patients with CSA,

the central treatments continue to include beta-blockers, calcium channel blockers, and nitrates.However, since the release of these guidelines in 2002, ranolazine has received FDA approval asanother potential treatment option in patients not receiving adequate control of anginal symptomson standard therapy, although it is not currently considered a first-line treatment option.

Several factors should be considered when selecting therapy for a patient newly diagnosed withstable angina, including other comorbid conditions, concurrent medication use, and the cost oftherapy. Ranolazine is currently only available as a brand name product; therefore, monotherapymay be significantly more expensive than combination therapy with generic options from the othertherapeutic classes (i.e., beta-blockers, calcium channel blockers, and nitrates). In terms ofimprovement of anginal symptomatology, few data purport superiority of one medication overanother. However, given the fact that angina suggests active CAD and increased risk of MI, beta-blockers should be considered the monotherapeutic treatment of choice. Other agents may be

considered in lieu of, or in combination with, beta-blockers, but offer no survival advantage.

Nonpharmacologic therapies remain a cornerstone in the treatment of CSA. While PCI is likelythe overall treatment of choice for uncomplicated coronary disease, there is no survival benefitoffered to patients receiving the procedure. Advanced therapies are available for refractorydisease, but few long-term data exist. Overall, aggressive pharmacotherapeutic management ofthe patient with CSA remains critically important for first-line stabilization of CAD.

REFERENCES

1. Sangareddi V, Chockalingam A, Gnanavelu G, et al. Canadian Cardiovascular Society classification of effortangina: an angiographic correlation. Coron Artery Dis. 2004;15:111-114.2. Williams SV, Fihn SD, Gibbons RJ. Guidelines for the management of patients with chronic stable angina:diagnosis and risk stratification.Ann Intern Med. 2001;135:530-547.3. Abrams J. Clinical practice. Chronic stable angina. N Engl J Med. 2005;352:2524-2533.4. DiPiro JT. Pharmacotherapy. 5th ed. New York, NY: McGraw-Hill; 2002.5. Gibbons RJ, Abrams J, Chatterjee K, et al. ACC/AHA 2002 guideline update for the management of patientswith chronic stable anginasummary article: a report of the American College of Cardiology/American Heart

Association Task Force on practice guidelines (Committee on the Management of Patients With Chronic StableAngina).J Am Coll Cardiol.2003;41:159-168.6. Ranexa (ranolazine extended-release tablets) package insert. Palo Alto, CA: CV Therapeutics Inc; December2007.7. Fihn SD, Williams SV, Daley J, Gibbons RJ. Guidelines for the management of patients with chronic stableangina: treatment.Ann Intern Med. 2001;135:616-632.8. Psaty BM, Smith NL, Siscovick DS, et al. Health outcomes associated with antihypertensive therapies used asfirst-line agents. A systematic review and meta-analysis.JAMA. 1997;277:739-745.9. Heidenreich PA, McDonald KM, Hastie T, et al. Meta-analysis of trials comparing beta-blockers, calciumantagonists, and nitrates for stable angina.JAMA. 1999;281:1927-1936.10. Dargie HJ, Ford I, Fox KM. Total Ischaemic Burden European Trial (TIBET). Effects of ischaemia and treatmentwith atenolol, nifedipine SR and their combination on outcome in patients with chronic stable angina. The TIBET

Study Group. Eur Heart J. 1996;17:104-112.11. Rehnqvist N, Hjemdahl P, Billing E, et al. Treatment of stable angina pectoris with calcium antagonists andbeta-blockers. The APSIS study. Angina Prognosis Study in Stockholm. Cardiologia (Rome, Italy).1995;40(suppl1):301.12. von Arnim T. Medical treatment to reduce total ischemic burden: Total Ischemic Burden Bisoprolol Study

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Advances in the Treatment of Chronic Angina