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

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.¹ 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.^{2 - 3} 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 single-antibody 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,^{4 - 5} particularly those undergoing percutaneous coronary intervention,⁴ and in patients undergoing coronary artery bypass graft surgery^{6 - 7} prompted the evaluation of pexelizumab in 2 large phase 3 studies: The Assessment of Pexelizumab in Acute Myocardial Infarction (APEX AMI) trial,⁸ 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and Mortality in Coronary Artery Bypass Graft Surgery (PRIMO CABG-II) study,⁹ which has been presented but is, as yet, unpublished.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.¹⁰ First, initial sample-size 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.¹⁰ 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.¹⁰ 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 clinical trials and avoid performing PCI in the highest-risk patients.¹¹ Despite intensive efforts by the APEX AMI steering committee to target a high-risk patient group, the trial enrolled a relatively low-risk population based on age (median, 61 years), heart rate (median, 75/min), blood pressure (median systolic blood pressure, 133 mm Hg), and Killip class (89% Killip class I).

Notwithstanding the low event rates and low statistical power in the APEX AMI study, the lack of benefit of pexelizumab for any of the efficacy outcomes examined is disappointing. The previously completed phase 2 Complement Inhibition in Myocardial Infarction treated with Angioplasty (COMMA) trial⁴ suggested a greater than 50% reduction in mortality at 90 days among patients treated with pexelizumab, and a meta-analysis of published pexelizumab studies involving a combined total of 5916 patients with STEMI (n = 1903) or undergoing CABG surgery (n = 4013) indicated a 30% reduction in mortality at 30 days with no statistical evidence of heterogeneity between the AMI and CABG groups.¹² Even after the results of the PRIMO CABG II study⁹ were included in the meta-analysis, there was a 24% reduction in mortality.¹⁰ The patient population in the APEX AMI trial was similar to that in the COMMA study,⁴ the same bolus and infusion doses of pexelizumab were used, and similar outcomes were measured. There are, however, many previous examples of large trials that did not confirm the promising results of preliminary research. Relatively small studies, such as the COMMA trial, that are performed in patient settings, in which modest treatment effects are expected and multiple hypotheses are being tested, increase the likelihood of producing false-positive results.¹³ It is also possible that failure to include unpublished pexelizumab studies with less favorable results in the meta-analyses may have upwardly biased estimates of the expected benefit of pexelizumab on mortality.

What are the implications of the APEX AMI trial results for clinical practice and future research? Despite the promising results of the early pexelizumab trials, it seems unlikely that this drug provides any major benefit in preventing reperfusion injury when it is used as an adjunct to primary PCI in patients with STEMI. Furthermore, commercial realities make it unlikely that additional trials will be conducted with this drug in the future. The revised statistical analysis plan for the APEX AMI trial, developed in consultation with the US Food and Drug Administration,¹⁰ details plans for a meta-analysis of all 6 completed pexelizumab studies. Even if the meta-analysis reports a significant benefit of pexelizumab, it is unclear whether the Food and Drug Administration will approve the drug or require an additional study. Despite the disappointing results of the pexelizumab trials, the central hypothesis, that modulating inflammatory mediators may improve clinical outcomes by reducing reperfusion injury, remains worthy of further study. Anti-inflammatory therapies that target other aspects of the complement pathway and that target leukocytes, inflammatory mediators (eg, leukotriene B₄), and C-reactive protein^{3 ,14} are currently under investigation.

The APEX AMI trial also highlights the delicate balance between independent clinical investigation and commercial reality. Trials can be legitimately stopped for reasons related to efficacy, safety, or feasibility.¹⁵ However, the safety of pexelizumab and feasibility of the study were never in question, and the study was not stopped because of futility. Although the decision by the sponsor to delay discontinuation of the study until an agreed number of events had accumulated represents a more balanced approach than has been taken in the past by some sponsors of trials that were stopped for commercial reasons,¹⁵ the final outcome leaves questions concerning the efficacy of pexelizumab unresolved and certainly is unsatisfactory for patients (especially those who participated in the study), clinicians, and the research community.