Clopidogrel Treatment Prior to Percutaneous Coronary Intervention: Title and subTitle BreakWhen Enough Isn't Enough

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.¹ For almost three fourths of these patients, the diagnosis necessitating the procedure will be an acute coronary syndrome (ACS)—either unstable angina or a myocardial infarction (MI).²

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 placebo-controlled trial to decrease the incidence of Q-wave MIs by 75% compared with heparin alone during coronary angioplasty.³ 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 placebo-controlled trials involving nearly 17 000 patients undergoing nonemergent PCI. In the Evaluation of Platelet IIb/IIIa Inhibitor for Stenting (EPISTENT)⁴ and Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy (ESPRIT)⁵ 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 peri-PCI 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.^{6 - 7} Although a subsequent randomized, placebo-controlled trial failed to confirm this benefit,⁸ 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.⁹ 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)¹⁰ and PCI-Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE)¹¹ 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 low- to intermediate-risk patients undergoing PCI,¹² in patients undergoing revascularization of small-diameter (≤2.5 mm) vessels,¹³ and in patients with diabetes.¹⁴ 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.¹⁵ 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 confined to the 1049 patients with elevated troponin levels, in whom abciximab decreased the occurrence of the primary end point by 29%. Troponin-negative patients experienced substantially lower and almost identical event rates, irrespective of randomized therapy. These results are consistent with those from the troponin substudy of the c7E3 Fab AntiPlatelet Therapy in Unstable Refractory Angina (CAPTURE) trial.¹⁶

The results of the ISAR-REACT 2 trial and the previous ISAR trials examining the role of abciximab in patients pretreated with clopidogrel prior to undergoing PCI provide compelling evidence that Gp IIb/IIIa antagonists offer no additional protection from peri-PCI thrombotic events in a wide range of patients in whom pretreatment with 600 mg of clopidogrel at least 2 hours prior to the PCI is feasible. The only, but critically important, exception are those patients with a primary non–ST-segment elevation MI documented by an abnormal elevation of troponin level. While the terms ACS and non–ST-segment elevation MI are frequently used interchangeably in both clinical practice and clinical trials, the difference is not trivial. Elevation of troponin level, serving as a marker for an unstable thrombotic lesion with distal embolization, indicates an increased risk for adverse outcomes. It is also one of very few markers shown to effectively guide many therapeutic interventions, including low-molecular-weight heparin,¹⁷ Gp IIb/IIIa antagonists,¹⁶ and an invasive treatment approach.¹⁸ The findings of the current study are consistent with this pattern.

Recognition that troponin status should strongly influence treatment strategies has important implications for resource utilization, as only approximately one third of patients admitted with a diagnosis of ACS have elevated troponin levels.¹⁹ Of concern, data from the Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the ACC/AHA Guidelines (CRUSADE) registry²⁰ suggest a long way to go to achieve this, at least in the United States, because troponin status has only a small influence on the use of antithrombotic therapies and an early invasive approach.

This brief moment of clarity regarding the optimal antiplatelet therapy in patients undergoing PCI, thanks in part to the ISAR investigators, is an important contribution. Given current evidence, all heparin-treated patients undergoing PCI for treatment of ACS with elevated troponin levels should receive adjunctive Gp IIa/IIIb antagonists, irrespective of whether the patient has also received adequate pretreatment with clopidogrel. Whether there is additional clinical benefit to administering clopidogrel in addition to a Gp IIa/IIIb antagonist, as has been suggested by previous post hoc analysis,^{9 ,11} remains to be prospectively studied. Still, the current treatment options of aspirin, clopidogrel, and the Gp IIb/IIIa antagonists may soon be joined by new agents. Ongoing or soon-to-begin trials of new thienopyridines (prasugrel), reversible oral (AZD6140) and parenteral (cangrelor) P2Y12 inhibitors, as well as platelet thrombin receptor inhibitors (SCH530348) may cloud the picture again but at the same time may also lead to continued improvements in the care of patients with acute coronary disease.