Complement C5 inhibition with eculizumab or ravulizumab is associated with increased cardiovascular and thromboembolic risk after ST-elevation myocardial infarction: a propensity-matched global retrospective cohort study

Complement-mediated myocardial and vascular injury is a hallmark of ST-elevation myocardial infarction (STEMI). Dysregulated activation of complement component C5 has been implicated in endothelial dysfunction, exacerbated inflammatory responses, and progressive vascular damage during acute ischemia. Experimental data suggest that antagonizing the C5a–C5aR1 axis may attenuate these effects, but clinical evidence regarding the impact of established C5 inhibitors during STEMI remains limited. To investigate real-world cardiovascular and thromboembolic outcomes associated with C5 inhibition during STEMI, a propensity score-matched retrospective cohort study using the TriNetX Global Collaborative Network was performed. 174 patients with STEMI who had received Eculizumab or Ravulizumab for pre-existing complement-mediated disorders (paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, neuromyelitis optica, or myasthenia gravis) prior to the index event were compared with 174 matched patients without C5-inhibitor exposure. Outcomes were assessed at 30 days and 365 days after STEMI and included all-cause mortality, stroke or transient ischemic attack (TIA), arrhythmia, thrombotic disorders, major adverse circulatory events (MACE), acute kidney injury (AKI), and cardiomyopathy. At 365 days, C5-inhibited patients demonstrated significantly higher risks of death (21.7% vs. 15.8; p < 0.05), stroke/TIA (12.9% vs. 6.8%; p < 0.05), thrombotic disorders (23.8% vs. 11.3%; p < 0.001), MACE (36.8% vs. 22.8%; p < 0.001), and AKI (61.1% vs. 22.5%; p < 0.001). Cardiomyopathy rates were comparable between groups. Arrhythmia occurred less frequently in the C5-inhibition cohort (30.3% vs. 37.4%; p < 0.05). Similar patterns were observed at 30 days, with significantly increased risks for thrombotic disorders, MACE, and AKI in the C5-inhibited group. Hazard ratios confirmed elevated risks for most cardiovascular and thromboembolic outcomes at both time points. In this global real-world cohort, prior treatment with Eculizumab or Ravulizumab was associated with increased mortality and heightened cardiovascular and thromboembolic risk following STEMI. These findings underscore the need for careful clinical consideration of ongoing C5-inhibitor therapy in the acute management of STEMI and highlight the importance of prospective studies to clarify the mechanistic and clinical implications of complement blockade in acute myocardial ischemia.