Clopidogrel Treatment Prior to Percutaneous Coronary Intervention

Abstract

WORLDWIDE, MORE THAN 2 MILLION PATIENTS WILL be treated with a percutaneous coronary intervention (PCI) this year, with approximately half of these performed in the United States. For almost three fourths of these patients, the diagnosis necessitating the procedure will be an acute coronary syndrome (ACS)—eitherunstableanginaoramyocardial infarction(MI). Inhibitors of platelet function are a critical component of peri-PCI pharmacological therapy. Aspirin, although initially viewed as a weak agent with minimal potential to prevent acute thrombotic events, has been shown in a placebocontrolled trial to decrease the incidence of Q-wave MIs by 75% compared with heparin alone during coronary angioplasty. However, with aspirin alone, thrombotic complications following PCI remained unacceptably high. To address this, the platelet glycoprotein (Gp) IIb/IIIa antagonists were developed as a means to effectively prevent platelet aggregation and its associated complications. Abciximab, eptifibatide, and tirofiban were studied in several placebocontrolled trials involving nearly 17 000 patients undergoing nonemergent PCI. In the Evaluation of Platelet IIb/IIIa Inhibitor for Stenting (EPISTENT) and Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy (ESPRIT) trials, randomization of stented patients to receive either abciximab or eptifibatide was found to decrease rates of 30-day death, MI, or urgent target vessel revascularization by 52% and 35%, respectively, compared with placebo. Importantly, this relative risk reduction was similar for patients diagnosed with stable angina or an ACS. Since no other antiplatelet agents were available clinically that prevented platelet aggregation as completely and as quickly as the Gp IIb/IIIa antagonists, it was assumed that no other antiplatelet regimen would be as effective in preventing periPCI thrombotic events. But soon after long-term post-PCI treatment with thienopyridines—initially ticlopidine and then clopidogrel—became standard care in patients receiving stents, limited reports began to emerge suggesting that pretreatment with these agents might also protect patients from periprocedural events. Although a subsequent randomized, placebo-controlled trial failed toconfirmthis benefit, retrospective analysis suggested that adequate durations of pretreatment achieved an approximately 50% relative risk reduction in the incidence of 28-day death, MI, or urgent target vessel revascularization. This level of benefit for clopidogrel pretreatment was consistent with that found in subset analyses in both the PCI-Clopidogrel as Adjunctive Reperfusion Therapy (CLARITY) and PCI-Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trials. These highly suggestive but nondefinitive results regarding the clinical benefit of clopidogrel pretreatment set the stage for a series of influential studies by the Intracoronary Stenting and Antithrombotic Regimen (ISAR) group to establish the optimal antiplatelet regimen in a broad range of patients undergoing PCI. Using a 600-mg clopidogrel loading dose given at least 2 hours prior to a PCI in all patients, the investigators systematically studied the additional benefit of adjunctive abciximab in lowto intermediate-risk patients undergoing PCI, in patients undergoing revascularization of small-diameter ( 2.5 mm) vessels, and in patients with diabetes. In all of these trials, abciximab was not found to provide even a trend toward additional benefit when given in addition to adequate pretreatment with clopidogrel. However, a large and critically important subgroup of patients was excluded from these studies—those presenting with an ACS. Not only do these patients represent the majority of patients treated with a PCI, but they are also a group of patients that most data suggest may derive the greatest benefit from adjunctive therapy with Gp IIb/IIIa antagonists. In this issue of JAMA, the ISAR investigators close this remaining gap. The ISAR-REACT 2 trial is similar in design to the previous ISAR trial, but it enrolled only patients with objective evidence of an ACS as manifest by anginal symptoms at rest or with minimal exertion accompanied by an elevated level of troponin T or by a new ST-segment deviation or bundle-branch block. Just more than half of the 2022 patients enrolled had elevated troponin levels. In contrast to previous ISAR studies, randomization to abciximab was associated with a significant 25% relative risk reduction in the 30-day combined end point of death, MI, or urgent target vessel revascularization. Interestingly, all of this benefit was con-