The 2007 ACC/AHA STEMI GuIdelines: Providing the … · elevATIon MyoCArdIAl InfArCTIon In The ed 11 ... activation through the ADP-mediated pathway. The focused update gives clopidogrel

The 2007 ACC/AhA STeMI GuIdelIneS: ProvIdInG The BeST AnTIPlATeleT And AnTIThroMBIn MAnAGeMenT of ST-SeGMenT

elevATIon MyoCArdIAl InfArCTIon In The ed

9w w w . e m c r e g . o r g

Objectives:1. Participants should be familiar with the 2007 focused update on STeMI and its relationship to the

2004 ACC/AhA guidelines for the treatment of ST-segment elevation MI (STeMI).2. Participants should understand the clinical decision making factors needed to determine the

optimum reperfusion therapy in STeMI.3. Participants should understand the recent clinical trial evidence and rationale behind the use of

clopidogrel, enoxaparin, and bivalirudin in the treatment of STeMI.4. Participants should understand the concept of facilitated PCI, and the clinical trial data supporting

its recommendations in the treatment of STeMI.

Specifically, new clinical

trials data support

the use of clopidogrel,

enoxaparin, and

bivalirudin in STeMI,

while downgrading the

use of facilitated PCI.

iNtRODUctiONST-segment elevation myocardial infarction (STEMI) remains one of the most important disease states for emergency physicians. When minutes count, and time is muscle, we have the opportunity to make a crucial impact on morbidity and mortality by applying appropriate therapy in a very time-efficient manner. The 2004 American College of Cardiology/American Heart Association (ACC/AHA) Guidelines for the treatment of STEMI outline the recommendations for the emergency department (ED) management of STEMI, including anti-ischemic, antithrombotic, and fibrinolytic versus catheter-based reperfusion therapy.1

These guidelines were promulgated in an effort to standardize and optimize the evaluation, diagnosis, and management of patients with STEMI and to provide physicians with a framework for clinical decision-making. They have become the cornerstone of many ED protocols for the

treatment of STEMI which are crucial to providing efficient care in the ED and seamless transitions for our patients to the catheterization lab or CCU. However, within a few months of the ACC/AHA STEMI Guidelines publication, new clinical trials data were released and published which added significantly to our knowledge of the treatment of STEMI, confirmed some of the STEMI Guideline recommendations, and provided valuable adjuncts to “cutting edge care” of STEMI, beyond the Guidelines. These clinical trial results were incorporated in the recommendations included in the Focused Update for STEMI, which was published in December, 20072 (Table 1). This focused update is meant to be a supplement or addendum to the 2004 Guidelines. It lists specific changes in the recommendations of 2004 that are changed based on new clinical trial data. Specifically, new clinical trials data support the use of clopidogrel, enoxaparin, and bivalirudin in STEMI, while downgrading the use of facilitated percutaneous coronary intervention (PCI).



James W. Hoekstra, MDProfessor and Fredrick Glass Chairman of Emergency Medicine

Wake Forest University Health Sciences, Winston Salem, NC

ADVANCING THE STANDARD OF CARE:Cardiovascular and Neurovascular Emergencies


Reperfusion Therapy in STEMIThe pathophysiology of STEMI is initiated by the endothelial rupture of an atherosclerotic coronary artery plaque. Plaque rupture leads to platelet aggregation, platelet activation, fibrin deposition, and downstream myocardial ischemia and necrosis. Downstream necrosis is time dependent, with a wavefront of necrosis developing from the subendocardium and extending to the epicardium (transmural) with time. The longer the period of necrosis, the higher the chance of CHF and death. For every 30 minutes of duration of ischemia, mortality increases 8-10%.3 Reperfusion therapy, with dissolution or removal of the intracoronary thrombosis, provides the best chance for mortality reduction. The focused update gives primary PCI a Class IA recommendation for reperfusion, as long as it can be accomplished with a first medical contact to balloon inflation time of 90 minutes or less. Fibrinolysis,

which is less effective than PCI in head-to-head trials, is given a Class IB rating as an alternative to primary PCI, as long as PCI cannot be accomplished within 90 minutes.

There is a distinct gray zone, however, for patients in whom the choice must be made between timely fibrinolysis versus “minimally delayed” primary PCI. This decision is often made in the context of an interhospital transfer. The emergency physician must decide between fibrinolysis within 30 minutes followed by transfer, versus transfer for PCI, knowing that the chances of a door to balloon time of 90 minutes are remote. In NRMI, the percentage of patients meeting the 90 minute window with a transfer from one hospital to another was less than 4%4. Factors which preclude “waiting for PCI” include young age, anterior MI, and early (<3 hrs of pain) presentation. Factors which make delayed

for every 30 minutes

of duration of

ischemia, mortality

increases 8-10%.

Table 1. Class I Recommended ED Pharmacologic and Reperfusion Therapy in STEMI

• Targeted ED protocol and collaboration

• ASA immediately (325 mg)

• Morphine sulphate, nitrates

• β-blockers by mouth (IV if tachycardia, hypertension)

• Clopidogrel 300 mg by mouth loading dose, then 75 mg daily

• Antithrombin

– Heparin weight-based dosing [60 IU/Kg IV (max 4,000 IU) and 12 IU/kg/hr (max 1,000 IU/hr)]

OR

– Enoxaparin 30 mg IVP, 1 mg/kg subcutaneous (reduced in elderly)

• Fibrinolytics in less than 30 minutes (if chest pain < 3 hours) or percutaneous coronary intervention (PCI) in less than 90 minutes if available

• PCI for rescue or critical lesions post-fibrinolytic therapy




PCI the preferred strategy include contraindications to fibrinolysis, cardiogenic shock, advanced age, inferior MI, and delayed presentation.5 It is clear, from the data, that a “one size fits all” approach may not be adequate, especially if delays to primary PCI are substantial (>120 minutes).

Antiplatelet Therapy in STEMIAntiplatelet agents, including aspirin and glycoprotein IIb/IIIa receptor blockers (GPIs) have all been investigated in this group of patients in large multicenter clinical trials, and these therapies have been incorporated as Class I recommendations in the ACC/AHA Guidelines.1,2 Specifically, aspirin 325 mg po is indicated at patient presentation regardless of the reperfusion strategy, while GPIs are indicated in the catheterization laboratory as an adjunct to primary PCI as a reperfusion strategy.

Clopidogrel in STEMIClopidogrel is an oral antiplatelet agent that binds to platelets at the P2Y

12 site, and inhibits platelet

activation through the ADP-mediated pathway. The focused update gives clopidogrel 75 mg daily a Class IA recommendation for STEMI. The 300 mg load is recommended with fibrinolysis (IIaC) and the 600 mg

load is recommended for primary PCI.6 The recently completed CLARITY trial investigated the effectiveness of a 300 mg loading dose of clopidogrel, in conjunction with fibrinolytic therapy, in the treatment of STEMI.7 The CLARITY trial randomized 3491 STEMI patients to clopidogrel 300 mg load, and 75 mg per day versus placebo, initiated in the ED. The primary outcome of death, MI, and target vessel occlusion at angiography was reduced 36% (p=0.00000036) in the clopidogrel group, offset by only a 0.3% increase in bleeding (figure 1). Death, MI and recurrent ischemia at 30 days were reduced 20% with clopidogrel (p=0.026). In the patients who went on to PCI after their initial fibrinolytic therapy, there was a 46% reduction in death, MI, and stroke in the patients treated with clopidogrel (p=0.008). These results were further supported by the COMMIT trial, which randomized 40,000 STEMI patients (recruited in Asia) who were treated with fibrinolytics or medical management, to 75 mg per day (no loading dose) of clopidogrel versus placebo.8 In the COMMIT trial, clopidogrel was associated with a 9% relative reduction in death, recurrent MI, and stroke (p=0.002). Clopidogrel should be added to the STEMI treatment algorithms in your ED if it has not been already.

Figure 1. Primary Results of the CLARITY Trial: Reduction in Death, MI, and OccludedInfarct Related Artery with Clopidogrel and Fibrinolytic Therapy Initiated in the ED

Adapted with permission from Sabatine MS, Cannon CP, Gibson M, et al. Addition of clopidogrel to aspirin and fibrinolytic therapy for STEMI. N Engl J Med. 2005;352:1179-1189.



Antithrombins in STEMIThe focused update for STEMI recommends the administration of an antithrombin as an adjunct to reperfusion therapy, initiated in the ED, either in conjunction with fibrinolytic therapy or in preparation for primary PCI. The focused update gives unfractionated heparin an IC recommendation, and enoxaparin an IA recommendation. The recently presented EXTRACT TIMI 25 trial compared enoxaparin (30mg IVP, and 1 mg/kg) to unfractionated heparin (weight based dosing) in 20,478 patients treated with a variety of fibrinolytics for STEMI.9 The trial was a double-blind, double-dummy design, carried out mostly in Europe. The primary outcome of death and MI at 30 days was reduced 17% (p<0.0001) in patients treated with enoxaparin versus heparin (figure 2). Bleeding was increased 2% in the enoxaparin treated patients, but the intracranial hemorrhage rate was not significantly different. The new dosing strategy of enoxaparin 0.75 mg/kg subcutaneous in patients greater than 75 years old eliminated any increased risk of intracranial hemorrhage compared to heparin in that population, and appears to be safe and effective in the elderly. EXTRACT shows us that enoxaparin is preferable to unfractionated heparin in STEMI patients treated with fibrinolytic therapy. Conversely, unfractionated heparin has more data than enoxaparin in primary PCI, and remains the antithrombin agent of choice in this country for primary PCI.

Since the focused update was pub-lished, another “antithrombin” has been investigated in the treatment

of STEMI with primary PCI. The recently completed HORIZONS trial10 investigated the use of heparin plus a GP IIb/IIIa inhibitor (GPI) versus bivalirudin with provisional GPI therapy in 3602 STEMI patients undergoing primary PCI. The primary outcome of the trial was the net clinical outcome of death, MI, stroke, or urgent intervention plus major bleeding at 30 days. Bivalirudin monotherapy resulted in no difference in ischemic endpoint, but a significant 40% reduction (8.3% versus 4.9%, p<0.0001) in major bleeding compared to standard therapy (figure 3). Of interest is that the majority of patients in the bivalirudin arm received unfractionated heparin, in the ED, prior to enrollment in the study. As such, the utilization of bivalirudin for primary PCI in the cath lab may not have significant effects on the ED treatment of STEMI patients prior to primary PCI.

Facilitated PCIFacilitated primary PCI, which involves the administration of pharmacologic reperfusion therapy prior to planned primary PCI, has been advocated as a method of enhancing the ease of primary PCI and/or preserving myocardial func-tion while awaiting primary PCI. Half-dose fibrinolytics, full-dose fibrinolytics, or GPIs have all been used for facilitated PCI with variable results, mostly in small studies, sub-analyses, or single-center reports.11-15 This approach of pre-PCI reperfusion therapy is of special interest to emergency physicians, who often find themselves feeling rather helpless, watching a patient infarct while awaiting activation of the cath lab for primary PCI. The focused update significantly downgrades the concept of facilitated

The new dosing

strategy of enoxaparin

0.75 mg/kg

subcutaneous in

patients greater than

75 years old eliminated

any increased risk of

intracranial hemorrhage.

––––––––––––––

The utilization of

bivalirudin for primary

PCI in the cath lab may

not have significant

effects on the ed

treatment of STeMI

patients prior to

primary PCI.




Figure 3. Results From the HORIZONS Trial: No Difference in Ischemic Endpoints But a40% Reduction in Bleeding in Patients Treated With Bivalirudin During Primary PCI

Figure 2. Results of the EXTRACT TIMI 25 Trial: Comparison ofEnoxaparin to UFH, In Conjunction With Fibrinolytic Therapy, In STEMI

*Not related to CABG

**MACE = All cause death, reinfarction, ischemic target-vessel revascularization or stroke



PCI in the treatment of STEMI. The use of full-dose fibrinolytics for facilitated PCI has recently come under scrutiny with the results of the ASSENT 4 trial, which had to be prematurely terminated due to an increased in-hospital mortality (p=0.01) and an increased incidence of strokes in patients treated with full-dose TNK-t-PA prior to primary PCI.16 Fibrinolytic therapy prior to PCI also resulted in an increase in ischemic complications of reinfarction and revascularization. Routine use of full dose fibrinolytics prior to immediate PCI is presently being discouraged. The use of half-dose fibrinolytics or GPIs in facilitated PCI is still given a IIbC recommendation, however, in patients with low bleeding risk, or when the time to primary PCI may be delayed (as with an interhospital transfer). Larger trials are needed, however, to demonstrate more clinically significant benefits on mortality or morbidity with ED GPI administration in STEMI.

A recent investigation brings into question this Class III rating for facilitated PCI between full dose fibrinolytics and PCI in patients undergoing interhospital transfer. In the recently presented TRANSFER

AMI trial,17 patients with STEMI were treated with fibrinolysis at smaller, referral hospitals, and then transferred to a tertiary care hospital with PCI capabilities. Half of the patients were taken to PCI immediately after transfer (average 2 hours post fibrinolytics) and half were admitted and underwent PCI within 48 hours. The patients who were treated immediately with PCI (so-called facilitated PCI) had a 46% reduction in the combined outcome of death, reinfarction, refractory ischemia, and stroke compared to the standard of care arm (figure 4). Bleeding rates were not significantly higher in the facilitated PCI group either. It appears that waiting as little as 2 hours after fibrinolysis may reduce the risk of facilitated PCI, and make interhospital transfers for PCI after fibrinolysis a viable strategy.

The use of half-dose

fibrinolytics or GPIs

in facilitated PCI

is still given a IIbC

recommendation,

however, in patients

with low bleeding risk,

or when the time to

primary PCI may be

delayed (as with an

interhospital transfer).

Figure 4. Results From the TRANSFER AMI Trial: Reduction In CombinedOutcome In Patients Treated With Fibrinolysis, Followed by InterhospitalTransfer to Immediate PCI




sUMMARYThe CLARITY, COMMIT, EXTRACT, HORIZONS, and TRANSFER MI trials are only five examples of the many recent clinical trials involving the care of patients with STEMI. Like many past clinical trials, these recent trials answer some clinical questions, but raise others. They must be interpreted in the light of our practice, with emphasis on their applicability to ED practice. Lessons from these trials may change our practice, or strengthen the data behind our practice patterns. Emergency physicians must remain vigilant to the results of these and other trials, to keep up-to-date and provide cutting edge care for STEMI patients.

ReFeReNces 1. Antman EM, Anbe DT, Armstrong, PW, et al: ACC/AHA guidelines

for the management of patients with ST-elevation myocardial infarction: a report of the task force on practice guidelines: Executive summary. Available at www.circulationaha.org. or www.acc.org/clinical /guidelines/stemi.index.pdf.

2. Antman EM, Hand M, Armstrong PW, et al: Focused Update for STEMI. JACC 2008;51(2): 210-247 or available on line at acc.org.clinical/guidelines/stemi.index.pdf.

3. Pinto DS, Kirtane AJ, Nallamathu BK, et al: Hospital delays in reperfusion for ST-elevation myocardial infarction: implications when selecting a reperfusion strategy. Circulation 2006;114:2019-2025.

4. Nallamothu BK, Bates ER, Heron J, et al: Times to treatment in transfer patients undergoing primary percutaneous coronary intervention in the United States: National Registry of Myocardial Infarction (NRMI)-3/4 analysis. Circulation 2005;111:761–7.

5. Antman EM, Anbe DT, Armstrong PW, et al: 2004 ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction--executive summary. J Am Coll Cardiol. 2004;44:671-719.

6. Smith SC, Feldman TE, Hirschfeld JW, et al: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines ACC/AHA guidelines for percutaneous coronary intervention. Available at www.acc.org/clinical/guidelines/percutaneous/update/index_rev.pdf.

7. Sabatine MS, Cannon CP, Gibson M, et al. Addition of clopidogrel to aspirin and fibrinolytic therapy for STEMI. N Engl J Med. 2005;352:1179-1189.

8. The COMMIT trial investigators: Addition of clopidogrel to aspirin in 45852 patients with AMI: a randomized placebo controlled trial. Lancet 2005;366:1607-1621.

9. Antman EM, Morrow DA, McCabe CH, et al: Enoxaparin versus unfractionated heparin with fibrinolysis for ST elevation MI (EXTRACT TIMI 25 trial). N Eng J Med 2006;354:1477-1488.

10. Stone G, et al: HORIZONS trial, presented at TCT annual meeting, Washington, DC, November, 2007.

11. Ross AM, Coyne KS, Reiner JS, et al: The PACT trial: A randomized trial comparing primary angioplasty with a strategy of short-acting thrombolysis and immediate planned percutaneous coronary angioplasty. Lancet 1988;1:197-203.

12. Simoons ML, Arnold AE, Betrui A, et al. Thrombolysis with TPA in AMI: No additional benefit from immediate percutaneous coronary angioplasty. Lancet 1988;1:197-203.

13. The TIMI Research Group: TIMI II A: Immediate versus delayed catheterization and angioplasty following thrombolytic therapy for AMI. JAMA 1988;260:2849-2858.

14. Montalescot G, Borentain M, Payot L, et al: Early versus late administration of GP IIb/IIIa inhibitors in primary PCI for acute STEMI: A meta analysis. JAMA 2004;292:362-366.

15. Cutlip DE, Ricciardi MJ, Frederick SL, et al: Emergency room administration of eptifibatide before primary angioplasty for STEMI and its effects on coronary blood flow and procedure outcomes. Am J Cardiol 2001;88:62-64.

16. van de Werf F. Primary versus tenecteplase-facilitated PCI in patients with STEMI (the ASSENT-4 Trial). Lancet 2006;367(9510):569-578.

17. Cantor WJ. TRANSFER AMI trial. Presented at ACC scientific sessions, Chicago, March, 2008.

Documents

The 2007 ACC/AHA STEMI GuIdelines: Providing the … · elevATIon MyoCArdIAl InfArCTIon In The ed 11 ... activation through the ADP-mediated pathway. The focused update gives clopidogrel