Evolocumab and risk of a first myocardial infarction: a prespecified analysis of the VESALIUS-CV trial

Background Intensive LDL-cholesterol lowering with the PCSK9 inhibitor evolocumab reduces the risk of major adverse cardiovascular (CV) events, but a detailed characterization of the effects on myocardial infarction (MI) in patients at high CV risk but without a prior MI or stroke has not been performed. Purpose To characterize the effect of evolocumab on the incidence of a first MI by type, ECG phenotype, and infarct size, in the VESALIUS-CV trial. Methods VESALIUS-CV randomized 12,257 patients with qualifying atherosclerosis or high-risk diabetes, without a prior MI or stroke, and an LDL-C ≥ 90 mg/dL to evolocumab or placebo on background optimized lipid-lowering therapy. MI was adjudicated and classified according to the Universal Definition (UDMI Types 1–5), ECG phenotype (STEMI/NSTEMI) and infarct size (peak troponin [Tn]) by a blinded clinical events committee. This prespecified analysis evaluated the first MI of a given type in the intention-to-treat population with stratified Cox proportional hazards models in the overall study population and in key subgroups. Results During a median follow-up of 4.6 years (interquartile range, 4.0-5.2), 378 patients experienced MI (3.1%). Type 1 MI was the predominant mechanism (79% of all MIs), followed by Type 2 MI (12%). NSTEMI (69%) was more frequent than STEMI (26%) and unknown ECG phenotype (6%). Patients with MI were more likely to have met inclusion for qualifying coronary disease and to have had a prior coronary revascularization and less likely to be on a high-intensity lipid regimen at baseline. Evolocumab significantly reduced the risk of any MI by 36% compared with placebo (149 [5-Yr Kaplan-Meier, 2.7%] vs 229 [5-Yr Kaplan-Meier, 4.1%]; HR 0.64, 95% CI 0.52–0.79; p<0.0001) (Fig 1). The cumulative incidence curves separated early such that the risk of MI was already significantly lower by 6 months (p<0.01), and the benefit persisted over time. Risk reductions were consistent across UDMI type (Type 1: HR 0.61, 0.48–0.77; Type 2: HR 0.70, 0.39-1.26), ECG phenotype (NSTEMI: HR 0.63, 0.49–0.81; STEMI: HR 0.64, 0.43–0.96), and MI size (Tn≥10x ULN: HR 0.60, 0.46–0.78; Tn<10x ULN: HR 0.77, 0.50–1.20). Results were consistent for the endpoint of first MI across the key subgroups defined according to the baseline variables of LDL-C quartile, statin intensity, presence of diabetes, and presence of qualifying atherosclerosis. Conclusions Among patients without a history of a prior MI or stroke, evolocumab reduced the incidence of a first MI, with a robust early benefit that was maintained over time. These favourable results were observed across subtypes of MI, including for spontaneous Type 1 events, large MIs and both NSTEMI and STEMI. These findings strongly support intensive LDL-C lowering with evolocumab for prevention of a first MI in high-risk patients.