PubMed abstract / permitted excerpt

BACKGROUND: Proprotein convertase subtilisin/kexin type 9 inhibition with evolocumab reduced the risk of a first major adverse cardiovascular event (MACE) in patients at high cardiovascular risk with no prior myocardial infarction (MI) or stroke in the VESALIUS-CV (Effect of Evolocumab in Patients at High Cardiovascular Risk Without Prior Myocardial Infarction or Stroke) trial. Recurrent MACE is common and important to patients, clinicians, and health care systems. OBJECTIVES: The purpose of this study was to evaluate the effect of evolocumab on total (first and subsequent) MACE. METHODS: The VESALIUS-CV trial randomized patients with qualifying atherosclerosis or high-risk diabetes, no prior MI or stroke, and a low-density lipoprotein cholesterol ≥90 mg/dL on optimized lipid-lowering therapy to evolocumab or placebo. The dual primary endpoints were a composite of coronary heart disease death, MI, ischemic stroke, or ischemia-driven arterial revascularization (4-point [4-P] MACE) and 3-point (3-P) MACE (not including ischemia-driven arterial revascularization). In this prespecified analysis, all dual primary endpoint events (first and subsequent) were analyzed using negative binomial regression models. RESULTS: Among 12,257 patients followed for a median of 4.6 years, there were 1,654 first 4-P MACE and 1,107 subsequent events (67% more) for 2,761 total events. There were 779 first 3-P MACE and 146 subsequent events (19% more) for 925 total events. Evolocumab reduced the rate of first 4-P MACE by 19% (HR: 0.81; 95% CI: 0.73-0.89; P < 0.0001), was associated with a reduction of subsequent events by 25% (incidence rate ratio [IRR]: 0.75; 95% CI: 0.61-0.91), and reduced total events by 20% (IRR: 0.80; 95% CI: 0.71-0.90; P = 0.0002). Likewise for 3-P MACE, evolocumab reduced the rate of first events by 25% (HR: 0.75; 95% CI: 0.65-0.86; P < 0.0001), was associated with a reduction of subsequent events by 37% (IRR: 0.63; 95% CI: 0.42-0.94) and reduced total events by 27% (IRR: 0.73; 95% CI: 0.63-0.86; P = 0.0001). Based on annualized incidence rate differences over the full follow-up period, evolocumab was projected to prevent 31 first and 24 subsequent 4-P MACE, for 55 total events per 1,000 patients over 5 years (95% CI: for the total-event difference: 36-74). The corresponding estimates for 3-P MACE were 20 first and 5 subsequent events, for 25 total events per 1,000 patients over 5 years (95% CI: for the total event difference: 15-37). Results were consistent across key subgroups, including by statin intensity and presence of qualifying atherosclerosis. CONCLUSIONS: A substantial proportion of patients experiencing a cardiovascular event had more than 1 event. The addition of evolocumab reduced the total number of MACE, providing support for the role of intensive low-density lipoprotein cholesterol lowering to prevent first and subsequent MACE in patients at high cardiovascular risk and no prior MI or stroke. (Effect of Evolocumab in Patients at High Cardiovascular Risk Without Prior Myocardial Infarction or Stroke [VESALIUS-CV]; NCT03872401).