Lipoprotein(a) Levels, Risk of Cardiovascular Events, and Benefit of Evolocumab: Findings From the VESALIUS-CV Trial

Abstract

BACKGROUND: Lp(a) (lipoprotein[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 previous myocardial infarction (MI) or stroke. METHODS: From June 2019 to November 2021, the VESALIUS-CV trial (Effect of Evolocumab in Patients at High Cardiovascular Risk Without Prior Myocardial Infarctions or Stroke) enrolled patients with qualifying atherosclerosis or high-risk diabetes without previous 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 (adjusted hazard ratio [HR adjusted ] per 100 nmol/L increase in Lp(a), 1.15 [95% CI, 1.05–1.26]; P =0.004), particularly for MI (HR adjusted , 1.23 [95% CI, 1.10–1.38]; P <0.001). There was no association between Lp(a) and ischemic stroke (HR adjusted , 1.00 [95% CI, 0.84–1.19]; P =0.99). After 48 weeks, evolocumab reduced LDL-C (low-density lipoprotein cholesterol) by 66.8 mg/dL and Lp(a) by 38.0 nmol/L in patients with baseline Lp(a) >105 nmol/L versus 61.1 mg/dL and 6.0 nmol/L in those with baseline Lp(a) ≤105 nmol/L. The relative reductions in the rate 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 for Lp[a] modeled as continuous variable). The corresponding absolute reductions were 3.7% versus 2.5% ( P -interaction=0.09), corresponding to a number needed to treat of 28 versus 40 to prevent 1 major coronary event at 5 years. CONCLUSIONS: In patients with atherosclerosis or high-risk diabetes but without previous 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). REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03872401.