The EPIC Investigators Reference

N Engl J Med 1994; 330: 956-961 Abstract

BACKGROUND: Platelets are believed to play a part in the ischemic complications of coronary angioplasty, such as abrupt closure of the coronary vessel during or soon after the procedure. Accordingly, we evaluated the effect of a chimeric monoclonal-antibody Fab fragment (c7E3 Fab) directed against the platelet glycoprotein IIb/IIIa receptor, in patients undergoing angioplasty who were at high risk for ischemic complications. This receptor is the final common pathway for platelet aggregation. METHODS: In a prospective, randomized, double-blind trial, 2099 patients treated at 56 centers received a bolus and an infusion of placebo, a bolus of c7E3 Fab and an infusion of placebo, or a bolus and an infusion of c7E3 Fab. They were scheduled to undergo coronary angio-plasty or atherectomy in high-risk clinical situations involving severe unstable angina, evolving acute myocardial infarction, or high-risk coronary morphologic characteristics. The primary study end point consisted of any of the following: death, non-fatal myocardial infarction, unplanned surgical revascularization, unplanned repeat percutaneous procedure, unplanned implantation of a coronary stent, or insertion of an intraaortic balloon pump for refractory ischemia. The numbers of end-point events were tabulated for 30 days after randomization. RESULTS: As compared with placebo, the c7E3 Fab bolus and infusion resulted in a 35 percent reduction in the rate of the primary end point (12.8 vs. 8.3 percent, p = 0.008), whereas a 10 percent reduction was observed with the c7E3 Fab bolus alone (12.8 vs. 11.5 percent, p = 0.43). The reduction in the number of events with the c7E3 Fab bolus and infusion was consistent across the end points of unplanned revascularization procedures and non-fatal myocardial infarction. Bleeding episodes and transfusions were more frequent in the group given the c7E3 Fab bolus and infusion than in the other two groups. CONCLUSIONS: Ischemic complications of coronary angioplasty and atherectomy were reduced with a monoclonal antibody directed against the platelet IIb/IIIa glycoprotein receptor, although the risk of bleeding was increased.

Summary

Over 2000 patients undergoing high-risk angioplasty (42.5% had acute coronary syndrome, ACS) were randomized to placebo or one of two regimens of c7E3Fab (abciximab) in an attempt to reduce the 10-20% risk of periprocedural ischaemic complications that occur in this group. At 30 days, bolus plus infusion of abciximab was superior to placebo with a 35% reduction in those who reached the primary endpoint. The rates of death, intra-aortic balloon pump (IABP) placement, stent placement, and emergency coronary artery bypass grafting (CABG) were low and not different between groups. The primary endpoint was driven primarily through a decrease in non-fatal myocardial infarction (MI) (8.6% vs. 5.2%, p = 0.013) and the need for emergent repeat percutaneous transluminal coronary angioplasty (PTCA) (4.5% vs. 0.8%, p < 0.001). Major bleeding was higher in the abciximab group compared to placebo (14% vs. 7%, p = 0.001).

Citation Count 1223

Related References

1. The Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) Study Investigators. Inhibition of the platelet glycoprotein IIb/IIIa receptor with tirofiban in unstable angina and non-Q-wave myocardial infarction. N Engl J Med 1998; 338: 1488-1497.

2. The PURSUIT Trial Investigators. Inhibition of platelet glycoprotein IIb/IIIa with eptifibatide in patients with acute coronary syndromes. N Engl J Med 1998; 339: 436-443.

3. GUSTO IV-ACS Investigators. Effect of glycoprotein IIb/IIIa receptor blocker abciximab on outcome in patients with acute coronary syndromes without early coronary revascularisation: the GUSTO IV-ACS randomised trial. Lancet 2001; 357: 1899-1900.

4. Boersma E, Akkerhuis KM, Théroux P, Califf RM, Topol EJ, Simoons ML. Platelet glycoprotein IIb/IIIa receptor inhibition in non-ST-elevation acute coronary syndromes: early benefit during medical treatment only, with additional protection during percutaneous coronary intervention. Circulation 1999; 100: 2045-2048.

Key message

In the balloon angioplasty era, abrupt vessel closure was related to a variety of factors, including local platelet activation and thrombus formation at the site of balloon injury. Profound inhibition of platelet function using an antibody against the IIb/IIIa inhibitor in patients at high risk for acute closure (including unstable angina) was associated with improved periprocedural ischaemic complications, but at a cost of increased bleeding.

Why it's important

This article heralded a phase of progressively more aggressive platelet inhibition during angio-plasty as a mechanism to improve the results of coronary intervention. Patients with ACS were frequent targets of these therapies, because the pathophysiology was thought to include activated platelets and because of the relatively high event rates. This class of medications has had a profound effect on the way in which patients with ACS are managed; these insights were first obtained in this study involving patients undergoing angioplasty, many of whom had ACS.

Strengths

The study was successful in enrolling a group of patients at high risk for serious ischaemic complications of coronary angioplasty: the placebo arm had almost a 13% event rate. In patients with unstable angina, the benefit was the greatest, with a 62% reduction in primary endpoint at 30 days. At 6 months, mortality was reduced from 6.6% in placebo to 1.8% (p = 0.018) in this group, indicating that prevention of creatine kinase (CK) release with this medication did have a favourable effect on intermediate term mortality.

Weaknesses

A significant proportion of the combined endpoint was non-fatal MI (elevation of the creatinine phosphokinase (CPK)-MB). The cutoff for definition of non-fatal MI was elevation of CK-MB greater than three times normal; had less liberal definitions been used the benefit may have been larger.

Relevance

Careful observational and laboratory study had led to the understanding of the importance of platelets in the acute complications of angioplasty. Logical design of a drug to dramatically inhibit platelet function led to abciximab. In a single study of the first drug in this class, the EPIC trial dramatically changed the practice of angioplasty in patients considered to be at "high risk". Future studies of these medications focused almost exclusively on patients with ACS, many of whom had percutaneous intervention. The largest benefits for IIb/IIIa inhibitors appear to be in patients undergoing angioplasty while hospitalized for ACS.

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