Pexelizumab fails to inhibit assembly of the terminal complement complex in patients with ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention. Insight from a substudy of the Assessment of Pexelizumab in Acute Myocardial Infarction (APEX-AMI) trial.
BACKGROUND: Reasons for pexelizumab lack of benefit in ST-elevation myocardial infarction patients undergoing primary percutaneous coronary intervention remain unclear. In a substudy of the APEX-AMI trial, we explored the hypothesis that early complement activation preceding drug administration explained the failure. METHODS: A panel of terminal complement complex proteins and fragments and biomarkers of inflammation, apoptosis, and high-risk features were assessed in serum obtained before and 24 hours after administration of placebo or pexelizumab and primary percutaneous coronary intervention (n = 356) and in human umbilical vein endothelial cell cultures coincubated with serum (n = 45). RESULTS: In the placebo group, C5a and sC5b-9 levels increased by 37% (7.9-14.2 ηg/mL, P = .007) and 96% (442-845 ηg/mL, P < .0001), respectively, during the first 24 hours. Pexelizumab prevented the increase in C5a (P = .01 vs placebo), but not that of sC5b-9 (502-1,157 ηg/mL, not significant vs placebo). Levels of C-reactive protein, interleukin (IL) 6, IL-1ß, Regulated on Activation, Normal T Cell Expressed and Secreted (RANTES) or Chemokine C-C motif ligand 5 (CCL5), and N-terminal probrain natriuretic peptide increased significantly in both groups; those of IL-10, IL-12, IL-1ra, and Interferon gamma-induced protein 10 (IP-10) or C-X-C motif chemokine 10 (CXCL10) decreased. Pexelizumab halved the increase in IL-6 (+92% vs 156%, P = .01) without effects on other markers, including C-reactive protein and N-terminal probrain natriuretic peptide. In cell culture, pexelizumab inhibited C5a, sC5b-9, and membrane-bound C5b-9 by 92%, 75%, and 78%, respectively (all P < .0001), without influencing cytokine levels and cell apoptosis. CONCLUSIONS: The blockage of both C5a and terminal complement in cell culture, but of C5a only in vivo with minimal effects on inflammation and risk biomarkers, supports the hypothesis that late administration of pexelizumab after the ischemia/reperfusion insult precluded adequate myocardial protection, resulting in a negative trial.
Martel, C; Granger, CB; Ghitescu, M; Stebbins, A; Fortier, A; Armstrong, PW; Bonnefoy, A; Theroux, P
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