Pexelizumab Does Not “Complement” Percutaneous Coronary Intervention in Patients With ST-Elevation Myocardial Infarction

Abstract

TIMELY RESTORATION OF CORONARY ARTERY BLOOD flow using thrombolytic therapy, percutaneous coronary intervention (PCI), or coronary artery bypass graft (CABG) surgery salvages threatened myocardium and decreases cardiac morbidity and mortality. Reperfusion of ischemic tissues can, however, be associated with life-threatening reperfusion injury that can cause arrhythmias, myocardial stunning, microvascular dysfunction, and cell death. Accordingly, therapies that modulate reperfusion injury would be expected to enhance the effectiveness of thrombolysis and primary percutaneous coronary intervention for preserving myocardium and reducing mortality in patients with ST-elevation myocardial infarction (STEMI). Complement activation plays a key role in the acute inflammatory response associated with ischemia and reperfusion injury. The anaphylotoxins, C3a and C5a, and the C5b-9 membrane attack complex that are formed during complement activation promote tissue injury by increasing vascular permeability, activating endothelial and inflammatory cells, activating hemostasis, inducing apoptosis, and causing cell lysis. Targeting the complement pathway to reduce inflammation and subsequent tissue injury in patients undergoing reperfusion therapy is thus an attractive therapeutic strategy. Pexelizumab is a recombinant humanized singleantibody chain fragment that targets and binds to the human C5 complement component with high affinity, thereby blocking generation of the C5a anaphylotoxin and the formation of the C5b-9 terminal membrane attack complex. Impressive results of early studies in patients with STEMI undergoing reperfusion therapy, particularly those undergoing percutaneous coronary intervention, and in patients undergoing coronary artery bypass graft surgery prompted the evaluation of pexelizumab in 2 large phase 3 studies: The Assessment of Pexelizumab in Acute Myocardial Infarction (APEX AMI) trial, reported in this issue of JAMA, and the Pexelizumab for Reduction in Myocardial Infarction and Mortality in Coronary Artery Bypass Graft Surgery (PRIMO CABG-II) study, which has been presented but is, as yet, unpublished. The APEX AMI trial investigators planned a large, simple trial to investigate the efficacy of pexelizumab for preventing death in 8500 patients with STEMI presenting within 6 hours of symptom onset and undergoing primary percutaneous coronary intervention (PCI). The trial was designed to have 80% power to detect a 24% reduction in all-cause mortality at 90 days. However, recruitment was subsequently curtailed to 5745 patients, resulting in a markedly underpowered trial that did not demonstrate a significant effect of pexelizumab on mortality or any other efficacy outcome. Two factors were central to the decision to stop the APEX AMI trial before originally planned. First, initial samplesize calculations were based on a predicted 6.5% mortality rate in the placebo group at 90 days. At the time of the first interim analysis (September 2005), the overall mortality rate at 90 days was much lower than expected and it was estimated that the sample size would have to be increased to more than 11 000 patients to maintain study power. Second, it was reported in November 2005 that the parallel phase 3 trial, the PRIMO-CABG II trial of Pexelizumab in CABG surgery, did not achieve its primary objective. The latter results together with the lower-than-expected event rates observed in the APEX AMI trial reportedly led the steering committee, in conjunction with the study sponsors, to formulate a revised study plan to discontinue the study after half of the anticipated number of events was accumulated. The rationale for targeting one half of the number of anticipated events is unclear, but the revised study plan provided only about 50% power to detect a 24% reduction in mortality at 30 days. The study authors attributed the lower-than-expected event rates observed in the APEX AMI trial to a high standard of care delivery with widespread use of effective therapies. Indeed, a very high proportion of patients did receive evidence-based treatments, both in hospital and at discharge, and most patients underwent timely reperfusion. However, the lower-than-expected mortality also may be explained by the tendency to enroll low-risk patients in clini-