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Synopsis: Eptifibatide treatment in patients with recent acute coronary syndrome referred for coronary artery bypass graft results in significant reduction in death or MI rates through six months of follow-up without an increase in bleeding complications.
Source: Marso SP, et al. Circulation 2000;102:2952-2958.
The use of glycoprotein (GP) IIb/IIIa antagonists has significantly improved outcomes for patients with coronary artery disease, most notably higher risk subgroups including those with acute coronary syndromes (ACS) or those undergoing percutaneous coronary revascularization. A small, but significant number of these patients will ultimately be referred for coronary artery bypass grafting (CABG), often in the urgent or emergent setting, which places them at higher risk for adverse cardiac events in the peri-operative period. Despite accumulating data supporting the safety of GP IIb/IIIa antagonists in the setting of CABG, concerns about potential bleeding complications associated with their use persist. More importantly, little is known about the potential role that GP IIb/IIIa antagonists might play in reducing morbidity and mortality in the peri-operative period, as they have in the catheterization laboratory and the coronary care unit. Therefore, Marso and colleagues reviewed death, myocardial infarction, and bleeding complication rates in the 1558 ACS patients referred for CABG during the index hospitalization in the Platelet Glycoprotein IIb-IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial.
PURSUIT, the largest trial of GP IIb/IIIa inhibition in ACS, was designed to evaluate a relatively unselected group of 10,948 patients with UA and non-ST elevation myocardial infarction (MI). Patients received aspirin or ticlopidine, and heparin, and were randomized to receive a bolus and infusion of eptifibatide (Integrilin) or placebo for up to 72 hours. The eptifibatide-treated group experienced a 14.2% reduction the primary end point of death or nonfatal myocardial infarction at 30 days (14.2% vs 15.7%; P = 0.04). Eptifibatide treatment was associated with reduced rates of reinfarction and of large MI (CK-MB elevation > 5-fold) and event rates were significantly reduced in patients undergoing PCI.
In the PURSUIT trial, 1558 patients underwent CABG during the index hospitalization. Of these, 866 received eptifibatide and 692 received placebo. The main substudy end point was death or MI at 30 days. MI was defined as CK or CK-MB = 5 times the upper limit of normal, or new Q-waves in two contiguous leads. In addition, bleeding events were characterized using the TIMI bleeding scale. Minor bleeding was defined as observed bleeding with drop in hematocrit of 10%, or hemoglobin of 3 g/dL. Major bleeding was defined as any intracranial bleeding or observed bleeding with drop in hematocrit of 15%, or hemoglobin of 5 g/dL.
While the baseline characteristics suggest that the patients receiving in-hospital surgery in PURSUIT represent a relatively high-risk cohort, these characteristics were well matched between patients receiving eptifibatide and those receiving placebo. The urgency of referral for CABG and the extent of coronary disease were also comparable between groups.
There was a significant 15.6% reduction in death or MI at 30 days in the eptifibatide-treated group relative to the placebo-treated group (26.1% vs 30.8%; P = 0.041). This difference was evident within seven days, and persisted out to six months of post-CABG follow-up (27.6% for eptifibatide vs 32.7% for placebo; P = 0.029). When peri-operative MIs were excluded from the analysis, the reduction in events for eptifibatide-treated patients persisted. When time from discontinuation of the study drug to surgery was evaluated, benefit was limited to only those patients undergoing surgery within 72 hours of discontinuation of eptifibatide. In addition, multivariate analysis showed additional benefit when eptifibatide administration was continued closer to the time of surgery. There were no differences in major or minor bleeding events or stroke rates between the eptifibatide and placebo-treated groups.
Marso et al conclude that eptifibatide treatment in patients with recent ACS referred for CABG results in significant reduction in death or MI rates through six months of follow-up without an increase in bleeding complications. They acknowledge the limitation that this was not a prespecified substudy of PURSUIT and that referral for CABG was not randomized. They outline the importance of platelet activation that can persist for several days in patients with ACS, and postulate that plaque passivation may be especially important when these patients undergo CABG because of the additional platelet activation precipitated by the initiation of cardiopulmonary bypass. They further suggest that evaluation of prophylactic GP IIb/IIIa inhibitor administration as a strategy to prevent platelet activation while on bypass warrants further evaluation.
Overall, the need for CABG is probably reduced in patients who have received GP IIb/IIIa antagonists. However, when these patients are referred for CABG, they often represent a particularly high-risk group because of the refractory ischemia and/or hemodynamic instability that often accompanies unstable coronary syndromes, high-risk coronary anatomy (such as left main or severe multivessel disease) or unsuccessful PCI procedures. Unfortunately, these higher risk patients also have higher rates of adverse perioperative events such as MI or bleeding complications, though in all likelihood, many of these complications occur independent of preoperative GP IIb/IIIa antagonist administration. At the same time, data continue to accumulate with regard to their efficacy both in the medical therapy and in the prevention of ischemic complications due to PCI, and in study after study, it has been shown that the highest risk patients derive the greatest benefit from GP IIb/IIIa antagonist administration. Therefore, it becomes progressively more difficult for the clinical cardiologist to justify witholding these agents in patients hospitalized with coronary artery disease, simply because referral for urgent or emergent CABG may eventually become necessary.
Prior to this report, the largest published experience of CABG in patients receiving GP IIb/IIIa antagonists comes from the EPIC trial1 in which 2099 patients were randomized to receive abciximab or placebo during PCI for acute coronary syndromes. In EPIC, 56 patients (2.7%) were referred for CABG surgery within 24 hours of receiving abciximab. There were no differences in rates of peri-operative myocardial infarction or death between the groups. While major bleeding occurred at high rates in all treatment groups in EPIC, including placebo, there were no differences in bleeding or transfusion rates between the abciximab and placebo-treated groups. Thus, EPIC data suggested that emergent CABG surgery could be performed in abciximab-treated patients with acceptable mortality and complication rates. Up until now, the remainder of published data regarding outcomes of CABG surgery for patients who have received GP IIb/IIIa antagonists comes from even smaller, retrospective series and case reports.
Recently published data from the PURSUIT trial now suggest that outcomes in patients undergoing CABG may, in fact, be improved by eptifibatide administration, and that, once again, bleeding rates for CABG patients who have received GP IIb/IIIa antagonists are equivalent to placebo. These data should make the decision to initiate GP IIb/IIIa antagonist therapy a little easier, though the intricacies of which agent and which concomitant therapy in which clinical scenario remain to be elucidated. In addition, these data are also supported by the theoretically appealing and feasible postulated mechanism of passivation of ACS and CPB mediated platelet activation, and suggest that the outcomes of patients undergoing CABG could conceivably be further improved by the routine use of GP IIb/IIIa antagonists in the future. While not a randomized trial specifically designed to test the safety and efficacy of short-acting GP IIb/IIIa antagonists in all patients referred for CABG, the results of this substudy should be reassuring, if not compelling, to practicing cardiologists and their surgical colleagues.
1. The Epic Investigation. N Engl J Med 1994;330: 956-961.