Pelacarsen and Cardiovascular Outcomes in Patients with High Lipoprotein(a)

BackgroundPelacarsen, an antisense oligonucleotide, reduces serum levels of lipoprotein(a). However, the effect of pelacarsen on cardiovascular outcomes remains uncertain. MethodsWe conducted an international, randomized, placebo-controlled trial involving patients with preexisting cardiovascular disease and a lipoprotein(a) level of at least 70 mg per deciliter. Patients were randomly assigned in a 1:1 ratio to receive subcutaneous pelacarsen (80 mg) administered monthly or matching placebo. The primary end point was a major adverse cardiovascular event, defined as a composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or urgent coronary revascularization. ResultsA total of 8350 patients underwent randomization, with 8322 included in the efficacy analysis; 4157 patients were assigned to receive pelacarsen, and 4165 to receive placebo. The mean age of the patients was 59.7 years, and 27.0% were women. The median lipoprotein(a) level at baseline was 236 nmol per liter. At 12 months, the lipoprotein(a) level was 64.4 nmol per liter in the pelacarsen group and 233.4 nmol per liter in the placebo group. The median follow-up was 4.7 years. A primary end-point event occurred in 511 patients (12.3%) in the pelacarsen group and in 503 (12.1%) in the placebo group (hazard ratio, 1.02, 95% confidence interval [CI], 0.90 to 1.15, P=0.76). Among patients with a baseline lipoprotein(a) level of at least 90 mg per deciliter, a primary end-point event occurred in 402 of 3266 patients (12.3%) in the pelacarsen group and in 403 of 3274 (12.3%) in the placebo group (hazard ratio, 1.00; 95% CI, 0.87 to 1.15; P=0.99). Serious adverse events occurred in 1553 of 4166 patients (37.3%) who received pelacarsen and in 1709 of 4154 (41.1%) who received placebo. ConclusionsPelacarsen did not result in a lower risk of major adverse cardiovascular events than placebo at a median follow-up of 4.7 years. (Funded by Novartis; Lp[a]HORIZON ClinicalTrials.gov number, NCT04023552.)See also in NEJM Evidence: Extended Analyses of Pelacarsen and Cardiovascular Outcomes in Patients with High Lipoprotein(a)