VESALIUS-CV: Lp(a) voorspelt risico, evolocumab werkt ongeacht uitgangswaarde

BACKGROUND: Lipoprotein(a) [Lp(a)] is a risk factor for coronary heart disease. Whether baseline Lp(a) identifies higher risk patients who derive more benefit from evolocumab is not established in a population without prior myocardial infarction (MI) or stroke. METHODS: From June 2019 to November 2021, the VESALIUS-CV trial enrolled patients with qualifying atherosclerosis or high-risk diabetes, without prior MI or stroke and randomized them to evolocumab or placebo (median follow-up 4.6 years). In a prespecified analysis, Lp(a) was assessed at baseline in 7557 patients. Cox models were used to assess the adjusted risk of cardiovascular events by baseline Lp(a) in the placebo arm, and the efficacy of evolocumab by baseline Lp(a). The primary outcome of interest was the composite of major coronary events (coronary heart disease death, MI or urgent coronary revascularization). RESULTS: Median age was 66 [interquartile range 60-71] years and 42.8% were women; median Lp(a) was 28 (interquartile range 9-132) nmol/L. Higher baseline Lp(a) was associated with an increased risk of major coronary events (HRadjusted per 100 nmol/L increase in Lp(a): 1.15; 95%CI 1.05-1.26; P=0.004), particularly for MI (HR: 1.23; 1.10-1.38; P<0.001). There was no association between Lp(a) and ischemic stroke (HR: 1.00; 0.84-1.19; P=0.99). After 48 weeks, evolocumab reduced LDL-C by 66.8 mg/dL and Lp(a) by 38.0 nmol/L in patients with baseline Lp(a) >105 nmol/L vs. 61.1 mg/dL and 6.0 nmol/L in those with baseline Lp(a) ≤105 nmol/L. The relative reductions in risk of major coronary events were 41% (HR 0.59; 95%CI 0.41-0.83) in those with Lp(a) >105 nmol/L compared with 35% (HR 0.65; 95%CI 0.51-0.82) in those below (P-interaction=0.45; Lp(a) modeled as continuous variable). The corresponding absolute reductions were 3.7% vs. 2.5% (P-interaction=0.09), corresponding to a NNT of 28 versus 40 to prevent one major coronary event at 5 years. CONCLUSIONS: In patients with atherosclerosis or high-risk diabetes but without prior MI or stroke, Lp(a) was independently associated with an increased risk of major coronary events, but not ischemic stroke. Evolocumab reduced the relative risk of major coronary events to a similar degree irrespective of baseline Lp(a), with a numerically greater absolute risk reduction in patients with elevated Lp(a).