Abstract and Introduction
Background: Recent trials evaluating the C5 complement inhibitor, pexelizumab, have shown that modulation of inflammation during ischemia/reperfusion in patients with acute myocardial infarction (MI) or undergoing coronary artery bypass graft (CABG) surgery may improve clinical outcomes.
Methods: We performed a systematic overview of individual patient data from all completed randomized controlled trials of pexelizumab to evaluate the effect on all-cause mortality at 30 and 180 days after treatment. We used a random effects model and included all 5916 patients randomized in 4 clinical trials. Patients received placebo, pexelizumab bolus only or pexelizumab bolus followed by a 24-hour infusion.
Results: A significant reduction in mortality at 30 days was observed in patients treated with bolus plus infusion (n = 2476) compared with placebo (n = 2492) (2.9% vs 4.2%; relative risk [RR], 0.70; 95% confidence interval [CI], 0.52-0.95; P = .02), with no interaction according to disease state of CABG or acute MI (P for interaction .33). A trend toward a reduction in mortality was observed in patients who received bolus plus infusion or bolus only (n = 3429) compared with placebo (n = 2476) (3.5% vs 4.2%; RR, 0.85; 95% CI, 0.66-1.0975; P = .215), but not in patients who received bolus only (n = 937) compared with placebo (n = 937) (5.2% vs 5.4%; RR, 0.96; 95% CI, 0.66-1.41; P = .918). The mortality benefit with bolus plus infusion compared with placebo persisted through 180 days (P = .05).
Conclusions: Pexelizumab reduced 30-day mortality in this systematic evaluation. Bolus plus infusion dose is being studied in ongoing trials in acute MI and CABG populations.
In the United States, more than 1.5 million patients undergo coronary artery bypass graft (CABG) surgery or suffer acute myocardial infarction (MI) each year. Despite advances in technology and pharmacological therapies, these patients still suffer significant morbidity and mortality. Myocardial ischemia and reperfusion injury are common consequences of acute ST-segment elevation MI and CABG. In both settings, complement-mediated inflammation plays a role in the insult resulting from both ischemia and reperfusion. In acute MI, inhibition of complement reduces myocardial damage, as well as apoptosis, in ischemia-reperfusion animal models.[1,2,3,4,5,6] Similarly, during cardiopulmonary bypass (CPB), the systematic production of proinflammatory complement byproducts facilitated by exposure of blood to bioincompatible surfaces, endotoxin, and reperfusion of ischemic tissues has been associated with perioperative morbidity and mortality.[7,8,9]
Complement activation may contribute to myocardial cell death through various mechanisms that have important roles in the ischemia/reperfusion setting, including activating leukocytes and endothelial cells, causing direct cellular damage, up-regulating genes involved in cytokine production, stimulating inducible nitric oxide synthase activity, and directly causing cellular injury and apoptosis.[5,10,11,12,13,14] Modulation of complement offers a promising therapeutic modality in patients experiencing ischemia/reperfusion injury.
Pexelizumab is a single-chain fragment of a humanized monoclonal antibody that binds to complement component C5 and has been studied in 4 multicenter placebo-controlled randomized trials of 5916 patients in the setting of CABG and acute ST-elevation MI. We performed a systematic overview to more precisely evaluate the treatment effect of pexelizumab on mortality in these 2 clinical settings of myocardial ischemia and reperfusion.
Am Heart J. 2006;151(2):291-296. © 2006 Mosby, Inc.
Cite this: Effect of Pexelizumab on Mortality in Patients With Acute Myocardial Infarction or Undergoing Coronary Artery Bypass Surgery: A Systematic Overview - Medscape - Aug 01, 2006.