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

BACKGROUND: Pelacarsen is an antisense oligonucleotide that reduces serum levels of lipoprotein(a). In a randomized placebo-controlled trial in patients with established cardiovascular disease, pelacarsen did not reduce the risk of major adverse cardiovascular events compared to placebo. We further investigated the association of pelacarsen treatment with cardiovascular outcomes. METHODS: We report the association of pelacarsen treatment with a primary composite end point of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or urgent coronary revascularization. Analyses included on-treatment, uninterrupted treatment, total primary end point events (first and recurrent events), landmark analyses classified by changes in and achieved lipoprotein(a) at 3 months, and key subgroups including baseline lipoprotein(a), low-density lipoprotein (LDL) cholesterol, high-sensitivity C-reactive protein (CRP), and time from qualifying event to enrollment. RESULTS: For participants on treatment, a primary end point occurred in 434 participants (10.4%) randomly assigned to placebo and 380 participants (9.1%) assigned to pelacarsen (hazard ratio, 0.98; 95% confidence interval [CI], 0.85 to 1.12). When evaluating participants with uninterrupted treatment, a primary end point event occurred in 167 participants (11.0%) in the pelacarsen group and 204 participants (10.1%) in the placebo group (hazard ratio, 1.09; 95% CI, 0.89 to 1.34). When evaluating total primary end point events, there were 644 events in the pelacarsen group and 646 events in the placebo group (rate ratio, 1.00; 95% CI, 0.87 to 1.14). In landmark analyses evaluating participants alive and free of the composite end point at 3 months, when compared to placebo there was no association between pelacarsen treatment and the primary end point either in participants with reduction in lipoprotein(a) greater than or equal to the median (170 nmol/l) (hazard ratio, 1.09; 95% CI, 0.92 to 1.29) or in participants who achieved lipoprotein(a) lower than or equal to the median (69.5 nmol/l) (hazard ratio, 1.10; 95% CI, 0.93 to 1.29). There was also no association between pelacarsen treatment and the primary end point in any of the evaluated key subgroups including classification by median baseline lipoprotein(a), LDL cholesterol, high-sensitivity CRP, or time from qualifying cardiovascular disease to enrollment. CONCLUSIONS: Pelacarsen was not associated with a reduction in major adverse cardiovascular events when evaluated by treatment exposure, changes in or achieved lipoprotein(a) levels at 3 months, considering total events, or within subgroups of baseline lipoprotein(a), LDL cholesterol, or high-sensitivity CRP levels.