Eptifibatide did not significantly reduce the rate of adverse events in patients undergoing percutaneous coronary revascularization

weight-adjusted heparin. Abciximab was administered as a bolus of 0.25 mg/kg followed by an infusion of 0.125 gg/kg/min for 12 h. Main outcome measures The primary efficacy outcome was a composite of death, MI or reinfarction, or severe myocardial ischemia requiring further revascularization within 30 d of randomization. Bleeding events were classified as major or minor according to the rules of the Thrombolysis in Myocardial Infarction Study Group. Main results The trial was terminated early since the pre-specified stopping rule was met.

11.7% of patients in the placebo group reached the composite end-point at 30 d compared to 5.2% receiving abciximab with low-dose heparin (hazard ratio 0.43: 95% CI 0.30-0.60; P < 0.001) and 5.4% receiving abciximab with standarddose heparin (hazard ratio 0.45; 95% CI 0.32-0.63; P < 0.001). At 6 months, the composite end-point was reached by 25.8% of patients in the placebo group, 22.8% in the abciximab with low-dose heparin group (11.7% relative risk reduction; P = 0.07), and 22.3% in the abciximab with standard-dose heparin group (13.7% relative risk reduction; P = 0.04). There was no significant difference in the incidence of major bleeding events (3.1 vs 2.0 vs 3.5% in

Eptifibatide did not significantly reduce the rate of adverse events in patients undergoing percutaneous coronary revascularization The IMPACT-II Investigators. Randomised placebo-controlled trial of effect of

eptifibatide on complications of percutaneous coronary intervention: IMPA CT-H. Lancet 1997; 349:1422-1428

Objective To assess the effects of eptifibatide, 0 platelet glycoprotein IIb/IIIa receptor inhibitor, on iscbemic complications in patients undergoing percutaneous coronary intervention. Design Randomized, double-blind, placebocontrolled trial. Setting 82 centers in the USA. Patients 4010 patients (75% men; median age 61 years) scheduled for elective, urgent or emergency percutaneous coronary intervention. Intervention All patients received 325 mg aspirin prior to the procedure. Patients were allocated to

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receive eptifibatide (bolus of 135 gg/kg followed by infusion of 0.5 ~tg/kg/min [referred to as 135/0.5]; or bolus of 135 gg/kg followed by infusion of 0.75 p.g/kg/min [referred to as 135/0.75]) or placebo. Heparin was given to maintain an activated clotting time of 300--350 s. Main outcome measures The primary end-point was death, MI or urgent or emergency percutaneous revascularization or CABG within 30 d. The principal safety end-points were major bleeding (as defined by the Thrombolysis in Myocardial Infarction Study), blood transfusion and stroke. Main results By 30 d, the primary end-point was reached by 11.4% of patients in the placebo group compared to 9.2% in the eptifibafide 135/0.5 group (OR 0.79; 95% CI 0.61-1.0l; P = 0.063) and 9.9% in the

EV/DENCE-BASED CARDIOVASCULAR MEDICINE

the placebo, abciximab with low-dose heparin, and abciximab with standarddose heparln groups) although minor bleeding events occurred more frequently with the standard-dose (3.7 vs 4.0 vs 7.4%, respectively; P < 0.001 for comparison of placebo and abciximab with standard-dose heparin). Conclusion Abciximab with low-dose heparin reduced the rate of short-term ischemic complications following percutaneous coronary revascularization and was associated with fewer hemorrhagic complications than abciximab with standard-dose heparin.

eptifibatide 135/0.75 group (OR 0.86; CI 0.67-1.10; P = 0.22). Most primary events occurred within 6 h. The treatment effect observed at 30 d was not affected by patient characteristics or baseline risk category. Comparing the placebo group to all patients who received any study drug, eptifibatide 13510.5 produced a significant reduction in the number of events (9.1 vs 11.6%; OR 0.76; CI 0.59-0.98; P = 0.035). Similarly, 10.0% of patients receiving any eptifibatide 135/0.75 experienced a primary outcome event (P = 0.18). At 24 h, primary end-points were reached by 9.3% of patients in the placebo group compared to 6.8% in the 135/0.5 group (P = 0.017) and 7.0% in the 135/0.75 group (P = 0.026). There was no clustering of events in the 24-48 h period after cessation of treatment. At 6 months, there was no difference in the rates of primary events between groups. There were significant differences in the rates of abrupt vessel closure during the procedure (5.1% in placebo group vs 2.8% in eptifibatide 135/0.5 group [OR 0.53; CI 0.35-0.80; P = 0.002] vs 3.7% in the eptifibatide 135/0.75 group [OR 0.72; CI 0.49-1.05; P = 0.08 l]). Rates of major bleeding events were similar in all three groups (4.8 vs 5.1 vs 5.2% in the placebo group, eptifibatide 13510.5 and 13510.75 groups, respectively). Conclusion Eptifibatide did not significantly reduce the rate of adverse events in an intentionto-treat analysis among patients undergoing percutaneous coronary revascularization.

DECEMBER 1997

Commentary Why do we need more potent and specific platelet receptor antagonists? Among patients undergoing elective or urgent PTCA, approximately one-quarter experience death, MI or the need for urgent revascularization during the succeeding 6 months. Most of these events occur within the first 6 h after the procedure. Despite heparin and aspirin treatment, 72% of the events occurred within these first 6 h in the IMPACT-II trial (in the heparin, aspirin and placebo arm). Thus, there is a strong clinical rationale for more effective pharmacological measures following urgent or elective PTCA. The rationale for more potent and specific platelet receptor antagonists is based upon the relatively weak effects of aspirin on ADP-induced aggregation of platelets and the potential for potent stimuli to overcome the relatively weak effects of aspirin. What do the trials have in common? The three trials test glycoprotein IIb/IIIa receptor antagonists as more potent inhibitors of the final common pathway of platelet activation. These receptors (up to 80 000 per platelet) are expressed on activated platelets and megakaryocytes and the most abundant ligand is fibrinogen. In the presence of a potent thrombogenic stimulus (as induced by angioplasty in unstable coronary syndromes) it appears necessary to inhibit at least 70% of platelets. However, since initiation of the IMPACT-II trial, there is evidence that the biological activity of ebtifibatide may only have achieved 30-50% of platelet inhibition.~ What are the key findings? The most important and consistent finding of the CAPTURE, EPILOG and IMPACTII trials is in the effective reduction in coronary events during the administration of the study drug. Similar findings have been seen with other Ilb/IIIa receptor antagonists provided that they achieve effective platelet inhibitory concentrations during drug administration. Thus, the magnitude of inhibition of coronary events was similar for abciximab and eptifibatide over the course of the first 48 h. However, thereafter the results show important

DECEMBER 1997

differences. Higher concentrations of eptifibatide were achieved by the bolus administration in the acute phase (135 ~tg/ kg) than during the continuous infusion of 0.5 or 0.75 gg/kg/min. At 24 h (the limit of infusion of eptifibatide) there were highly significant differences on the composite event rates between treatment and placebo group (placebo group 9.3% vs 6.8% in the 135/0.5 group and 7.0% in the 135/0.75 group). Thereafter, although no clear rebound was detected, the benefits were attenuated and were not statistically significant at 30 d or at 6 months. In contrast to the IMPACT-II study, the CAFI'URE and EPILOG trials employed abciximab, which is less specific and has a much lower dissociation constant. CAPTURE and EPILOG had different trials designs: in the former, abciximab was administered for 18-24 h prior to PTCA and 1 h thereafter; in the latter study abciximab was given for 10-60 rain prior to PTCA balloon inflation and 12 h thereafter. Both CAPTURE and EPILOG demonstrate a highly significant reduction in the prespecified 30-day end-point (death, new MI or severe ischemia requiring further revascularization). In contrast to the earlier EPIC study, in IMPACT-II the weightadjusted heparin substantially lowered bleeding events and there was no advantage for the high-dose heparin compared to the low-dose hepafin? Thus, bleeding events appeared to have been reduced by limiting heparin administration, institution of early sheath removal and, perhaps, better puncture site care. What are the limitations? Each of the trials employing IIb/IIIa receptor antagonists demonstrates that provided they achieve at least 70% platelet receptor inhibition (approximately) there is an important reduction in cardiovascular events. The main limitation of the three trials is the fact that the beneficial effects were either eliminated or attenuated by 6 months. This is due to the continuing cardiovascular event rate in patients with unstable angina and to the further revascularizations in the PTCA studies. Thus, unlike thrombolytic treatment for acute MI, unstable angina appears to require continuing anti-platelet and/or anti-thrombin treatment. The continuing rate of cardiovascular events after PTCA (in CAPTURE and EPILOG) suggests that

balloon angioplasty does not provide a definitive solution. The rate of stent implantation was only 12% in the EPILOG trial and it is possible that a higher rate of stent deployment may have reduced the need for a recurrent revascularization. Whether lib/Ilia receptor antagonists provide an advantage over primary stem deployment in unstable angina is unknown, but is currently being tested. Most of the early events prevented in the three trials are non-Q-wave MIs diagnosed by enzyme release. Although the significance of these 'enzyme bump' infarctions has been questioned, evidence suggests that such events are related to the subsequent risk of death, in proportion to the magnitude of enzyme rise/,4 One of the unexpected findings from the CAPTURE trial was the increase in MIs induced within the first 6 h of PTCA (in both arms of the trial) compared to the 24 h prior to the PTCA. This raises concerns about the hazards of PTCA in this type of patient population. In contrast, the data suggests that abciximab may reduce MI events in unstable angina without an intervention and, perhaps, reduce the need, or at least the urgency, for intervention. Perhaps the majority of patients with unstable angina may be managed with an effective anti-thrombotic agent and either no or delayed vascular intervention. In conclusion, the trials demonstrate important gains over current conventional treatment with heparin and aspirin. However, the remaining challenge is to assess the optimal role of PTCA, to maintain the impressive early benefits by means of longer-term platelet inhibitor therapy, anti-thrombintherapy or, perhaps, more complete revasculadzation using stent deployment. Keith A. A. Fox, MS, CH~

University of Edinburgh, Edinburgh, UK Other sources 1. Teheng JE Am J Cardlol 1996; 78 (suppl 3a): 35-40 2. EPIC Investigators. N Engl J Med 1994; 330: 956-961 3. Kong TQ, Davldson C J, Meyers SN, Tauke JT, Parker MA, Bonow RO. JAMA 1997; 277: 461-466 4. Tardiff BE, Califf RM, Tcheng JE et al [abstract]. J Am Coll Cardiol 1996, 27(suppl A)" 83A

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