ST-Segment Elevation Myocardial Infarction:What Role for Anticoagulants and Antiplatelet Agents?

The goal of treatment in acute coronary syndromes is the restoration and maintenance of myocardial perfusion. To this end, numerous pharmacological agents are available, as well as percutaneous coronary intervention (PCI) (Table).

In an earlier article, we reviewed the recommended uses of antiplatelet agents and anticoagulants in the treatment of non-ST-segment elevation myocardial infarction (NSTEMI) and unstable angina. In this article, we review recommendations for the use of antiplatelet and anticoagulant medications in the treatment of ST-segment elevation myocardial infarction (STEMI); we also summarize the evidence for these recommendations.

TREATMENT OF STEMI: PCI OR FIBRINOLYSIS??

STEMI represents acute thrombotic occlusion of an epicardial coronary artery and signifies ischemic injury to myocardial tissue. Therapy is directed toward restoration of blood flow; its timing is critical.

Figure – A meta-analysis of 23 trials comparing percutaneous transluminal coronary angioplasty (PTCA) with thrombolytic therapy for acute ST-segment elevation myocardial infaction showed that PTCA was better than thrombolytic therapy at reducing death, nonfatal reinfarction, and stroke in affected patients. This was true regardless of the type of thrombolytic agent used and whether patients were transferred for primary PTCA. PCU, peructaneous coronary intervention; MI, myocaridal infaction; SHOCK, SHould we emergently revascularize Occluded Coronaries for cardiogenic shocK? [trial]; CVA, cerebrovascular accident.  

In a meta-analysis of 23 randomized clinical trials that compared fibrinolysis with emergent PCI for the treatment of STEMI, an early invasive strategy was superior to thrombolysis not only with respect to mortality but also with respect to stroke, reinfarction, recurrent ischemia, and major hemorrhage (Figure).¹ In addition, fibrinolytic therapy has been shown to have limited efficacy in patients with STEMI who have had previous coronary artery bypass grafting (CABG) and in those who are in shock.²

In addition to initial pharmacological therapy, the most important determinant of outcome in patients with STEMI is timely transportation to a high-volume PCI facility that has an experienced operator and team (door-to-balloon time, less than 90 minutes).³ However, in hospitals without access to PCI-either locally or by rapid transport-thrombolysis is indicated. Current guidelines recommend a fibrinolytic agent such as alteplase, reteplase, streptokinase, or tenecteplase. Thus, in the following review of antiplatelet and antithrombotic therapies for patients with STEMI, we have included recommendations for both patients being treated with PCI and those receiving fibrinolysis.

ANTIPLATELET THERAPY?

Aspirin. Aspirin significantly reduces morbidity and mortality in patients with STEMI. We recommend immediate administration of 4 chewable 81-mg non-enteric-coated aspirin followed by daily maintenance with 75 to 162 mg (325 mg if a coronary stent is implanted). Aspirin is recommended for both patients treated with PCI and those treated with fibrinolysis.

Clopidogrel in PCI. If primary PCI is anticipated, we recommend administration of clopidogrel in a loading dose of 600 mg followed by maintenance with 75 mg/d. In the ISAR-CHOICE trial (acronyms for all trials mentioned in this article are expanded in the Box), which compared 300-mg, 600-mg, and 900-mg doses of clopidogrel before PCI, 600 mg resulted in more rapid platelet inhibition (within 2 hours) than did 300 mg (more than 6 hours).⁴ There was no added benefit with the 900-mg dose. Although some experts recommend delaying clopidogrel administration until the coronary anatomy has been defined, we feel this approach denies early antiplatelet treatment to the vast majority of patients in order to reduce the bleeding risk in the rare patient with STEMI who proceeds directly to the operating room. Most patients with STEMI who have severe coronary artery disease requiring surgical revascularization usually have their "culprit" artery treated with PCI and are stabilized; they then proceed to elective CABG at a later date, dependent on their clinical course and coronary anatomy.

Clopidogrel (75 mg/d) should be continued for a minimum of 1 month if a bare metal stent is used. However, current guidelines recommend that clopidogrel therapy be continued for 12 months in patients with bare metal stents who are not at increased risk for bleeding. If a drug-eluting stent is placed, it is vital that dual antiplatelet therapy with aspirin and clopidogrel be continued for a minimum of 12 months. This recommendation is based on the results of the BASKET-LATE trial, in which patients received clopidogrel for only 6 months following stent placement. There was a significant increase in cardiac death and MI in the year following discontinuation of clopidogrel in patients who received drug-eluting stents compared with those who received bare metal stents.⁵

The ideal duration of clopidogrel therapy in patients who receive drug-eluting stents is currently unknown. Numerous case series have reported stent thrombosis in patients with drug-eluting stents significantly later than 1 year after implantation. The decision to extend clopidogrel therapy beyond 12 months should be done on a case-by-case basis. Input from the interventional cardiologist may be helpful. Factors that may influence the decision to prolong treatment with clopidogrel include:

• The complexity of the intervention.
• Placement of multiple drug-eluting stents.
• Bifurcation lesion stenting.
• The quantity of myocardial tissue at risk should stent thrombosis occur.
• The risk of bleeding while receiving dual antiplatelet therapy.
• Concomitant medications and comorbidities.

Clopidogrel in fibrinolysis. In patients with STEMI treated with fibrinolysis, administer a loading dose of 300 mg of clopidogrel followed by maintenance with 75 mg/d. In the CLARITY TIMI-28 trial, 3491 patients who presented within 12 hours of the onset of STEMI and were scheduled to receive standard fibrinolytic therapy in addition to aspirin were randomly assigned to receive either placebo or a loading dose of 300 mg of clopidogrel followed by 75 mg/d. Treatment with clopidogrel was associated with a decrease in the composite end point of cardiovascular death, MI, or recurrent ischemia leading to urgent revascularization at 30 days. In the COMMIT/CCS-2 clopidogrel trial, there were also significant reductions in mortality and in the composite of death, MI, or stroke with clopidogrel, 75 mg/d, compared with placebo.^6,7 In patients not at increased risk for bleeding, continue therapy with clopidogrel for 12 months.

Glycoprotein IIb/IIIa inhibitors in PCI. Abciximab is the most studied agent in patients with STEMI treated with PCI. It is the glycoprotein (GP) IIb/IIIa inhibitor recommended in the American College of Cardiology/American Heart Association guidelines for the treatment of STEMI in patients who undergo PCI.¹

Results of multiple trials (TITAN TIMI-34, TIGER-PA, and ADMIRAL)^8-10 have indicated that when STEMI is treated with PCI, early administration of a GP IIb/IIIa inhibitor is associated with faster reperfusion rates. However, the recent ACUITY Timing trial, which involved patients with STEMI, showed that the net ischemic benefit of early treatment with a GP IIb/IIIa inhibitor was realized only in patients in whom stents were placed and was achieved at the risk of increased rates of minor bleeding.¹¹ The CADILLAC trial demonstrated a significant reduction in the primary composite end point of death, reinfarction, ischemia-driven target vessel revascularization, or stroke at 6 months when abciximab was used in conjunction with aspirin, unfractionated heparin, an intravenous -blocker, and clopidogrel.¹²

GP IIb/IIIa inhibitors in fibrinolysis. Based on the results of the GUSTO-IV ACS trial, which showed increased mortality with GP IIb/IIIa use in patients with STEMI treated with fibrinolysis, GP IIb/IIIa inhibitors should not be used in this setting.¹³

ANTICOAGULANT THERAPY?

Unfractionated heparin in PCI. The role of unfractionated heparin in the treatment of STEMI is well established. In a patient undergoing PCI, give a bolus of 50 U/kg (maximum, 5000 U) and transport the patient directly to the catheterization laboratory. We recommend not starting a drip.

Unfractionated heparin in fibrinolysis. Give a bolus of 50 U/kg (maximum, 5000 U) followed by a 7 U/kg/h drip. No additional heparin boluses are recommended; simply adjust the drip rate as needed to bring the activated partial thromboplastin time into the target range.

Enoxaparin in PCI. Although enoxaparin has been shown to be beneficial in patients with NSTEMI, there are no current data on its use in patients with STEMI who are treated with an invasive strategy.

Enoxaparin in fibrinolysis. In the ExTRACT-TIMI 25 trial of patients presenting with STEMI, those who were treated with fibrinolysis and who received enoxaparin had a significant reduction in death and MI at 30 days compared with those who received unfractionated heparin (9.9% vs 12.0%; P < .001). They also experienced fewer deaths at 48 hours than did the patients who received unfractionated heparin (5.3% vs 6.1%). However, the rate of major bleeding was significantly higher in patients who received enoxaparin than in those who received unfractionated heparin (2.1% vs 1.4%; P < .001).¹⁴ In any event, a difference in the duration of treatment in the 2 groups (patients received unfractionated heparin for 48 hours, while enoxaparin was given for the duration of hospitalization) may make interpretation of the results of this study difficult.

Fondaparinux in PCI. In the OASIS-6 trial, fondaparinux and placebo were compared in patients undergoing PCI for STEMI. In both groups, patients were stratified based on their need for unfractionated heparin. The trial showed a reduction in death or MI at 30 days in patients who received fondaparinux; however, this result was driven largely by the group that did not receive unfractionated heparin.¹⁵ More data are needed before fondaparinux can be routinely recommended for patients undergoing PCI for STEMI.

Fondaparinux in fibrinolysis. No current data are available on the use of fondaparinux with fibrinolytic agents.

NEW AGENTS ON THE HORIZON?

Two antiplatelet medications are currently in clinical trials. Both agents are adenosine 5'-diphosphate (ADP) antagonists and are designed to replace clopidogrel, which, despite its successful use in thousands of patients, fails to fully inhibit platelet aggregation in 15% to 30% of healthy human subjects.¹⁶ AZD6140 is a reversible, oral ADP antagonist. A phase 3 trial (PLATO) now in preparation will compare the safety and efficacy of AZD6140 and clopidogrel in the treatment of patients with NSTEMI and STEMI. A similar agent, prasugrel, which is also an ADP antagonist, is currently being investigated in a phase 3 trial (TRITON TIMI-38) that compares it with clopidogrel in patients undergoing PCI.

References:

REFERENCES:1. Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review of 23 randomised trials. Lancet. 2003;361:13-20.
2. Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction-executive summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (writing committee to revise the 1999 guidelines for the management of patients with acute myocardial infarction). J Am Coll Cardiol. 2004;44:671-719.
3. Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction-executive summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to revise the 1999 guidelines for the management of patients with acute myocardial infarction). J Am Coll Cardiol. 2004;44:671-719.
4. Von Beckerath N, Tauberet D, Pogatsa-Murray G, et al. Absorption, metabolization, and antiplatelet effects of 300-, 600-, and 900-mg loading doses of clopidogrel. Results of the ISAR-CHOICE trial. Circulation. 2005;112:2946-2950.
5. Pfisterer M, Brunner-La Rocca HP, Buser PT, et al; the BASKET-LATE Investigators. Late clinical events after clopidogrel discontinuation may limit the benefit of drug-eluting stents: an observational study of drug-eluting versus bare-metal stents. J Am Coll Cardiol. 2006;48:2584-2591.
6. Chen ZM, Jiang LX, Chen YP, et al. Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomized placebo-controlled trial. Lancet. 2005;366:1607-1621.
7. Sabatine MS, Cannon CP, Gibson CM, et al. Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation. N Engl J Med. 2005;352:1179-1189.
8. Gibson CM. Time to Integrellin Therapy in Acute Myocardial Infarction (TITAN - TIMI 34). Slides presented at: the Texas Heart Symposium; November 2005; Dallas.
9. Lee DP, Herity NA, Hiatt BL, et al. Adjunctive platelet glycoprotein IIb/IIIa receptor inhibition with tirofiban before primary angioplasty improves angiographic outcomes. Results of the TIrofiban Given in the Emergency Room before Primary Angioplasty (TIGER-PA) Pilot Trial. Circulation. 2003;107:1497-1501
10. Montalescot G, Barragan P, Wittenberg O, et al. Platelet glycoprotein IIb/IIIa inhibition with coronary stenting for acute myocardial infarction. N Engl J Med. 2001;344:1895-1903.
11. Stone GW. Acute Catheterization and Urgent Intervention Triage Strategy Timing Trial (ACUITY Timing Trial). Presented at: the i2 Summit Annual Scientific Session; March 2006; Atlanta.
12. Stone GW, Grines CL, Cox DA, et al. Comparison of angioplasty with stenting, with or without abciximab, in acute myocardial infarction. N Engl J Med. 2002;346:957-966.
13. Simoons ML; GUSTO IV-ACS Investigators. Effect of glycoprotein IIb/IIIa receptor blocker abciximab on outcome in patients with acute coronary syndromes without early revascularisation: the GUSTO IV-ACS randomized trial. Lancet. 2001;357:1915-1924.
14. Antman EM, Morrow DA, McCabe CH, et al. Enoxaparin versus unfractionated heparin with fibrinolysis for ST-elevation myocardial infarction. N Engl J Med. 2006;354:1477-1488.
15. Yusuf S, Mehta SR, Chrolavicius S, et al. Effects of fondaparinux on mortality and reinfarction in patients with acute ST-segment elevation myocardial infarction: the OASIS-6 randomized trial. JAMA. 2006;295:1519-1530.
16. Wiviott SD, Antman EM. Clopidogrel resistance: a new chapter in a fast-moving story. Circulation. 2004;109:3064-3067.

Therapeutic Agents in This Article

Abciximab (ReoPro)
Alteplase (Activase)
Aspirin* (Genprin, Ecotrin, Heartline,others)
AZD6140
Clopidogrel (Plavix)
Enoxaparin (Lovenox)
Eptifibatide (Integrillin)
Fondaparinux (Arixtra)
Heparin*
Prasugrel
Reteplase (Retavase)
Streptokinase (Streptase)
Tenecteplase (TNKase)
Tirofiban (Aggrastat)

*Available in generic formulations.