Pelacarsen did not result in a lower risk of major adverse cardiovascular events compared with placebo in patients with preexisting cardiovascular disease and high lipoprotein(a) (Lp(a)) over a median follow-up period of approximately five years, based on findings from the Lp(a) HORIZON trial presented at AHA 2026 and simultaneously published in NEJM.

The international trial randomized approximately 8,300 patients to subcutaneous pelacarsen (80 mg administered monthly) or matching placebo. The average patient age was about 60 years and 27% were women. All participants had a Lp(a) level of at least 70 mg per deciliter at baseline, with the average being 236 nmol per liter.

According to the study findings, pelacarsen resulted in a 78.4% reduction in Lp(a) levels after 12 months of treatment and to a time-averaged percentage change from baseline of −73.9% over an average of five years. However, it did not lead to lower risk of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or urgent coronary revascularization. Overall, a primary endpoint event occurred in approximately 12% of patients in both the pelacarsen and placebo groups (503 vs. 511 patients, respectively).

Similarly, in a subgroup of patients with a baseline Lp(a) level of at least 90 mg per deciliter, rates of primary endpoint events regardless of pelacarsen or placebo were the same – 12.3% in both groups. Researchers also noted that pelacarsen was associated with treatment-limiting adverse events and rare hypersensitivity reactions compared with placebo.

In presenting the findings, Steven E. Nissen, MD, MACC, said the study had several limitations including that it was limited to only patients with prior cardiovascular events. As a result, effects in a primary prevention population were not studied. The results are also only applicable to pelacarsen and siRNA therapeutics may reduce Lp(a) to a greater extent and be better tolerated, he said.

Separate extended analyses also presented at AHA 2026 and published in NEJM Evidence as part of the HORIZON Outcomes trial, looked at on-treatment analysis; uninterrupted treatment (completed trial with no interruption of treatment >60 days); analysis of total events; and subgroups of patients by baseline characteristics including Lp(a), LDL-C and hsCRP. According to Nissen, these analyses are intended to complement the primary analyses and may help to inform ongoing and future trials.

“Although these results are disappointing, they provide scientific insights that help inform future research efforts,” he said. “The Lp(a) HORIZON trial is not the end of the story. Ongoing trials are studying different populations. A single trial does not provide definitive evidence of a lack of benefit of lowering Lp(a) as a strategy to reduce the cardiovascular risk.”

Clinical Topics: Dyslipidemia, Prevention, Advanced Lipid Testing, Lipid Metabolism, Nonstatins

Keywords: AHA Annual Scientific Sessions, AHA26, C-Reactive Protein, Cholesterol, LDL, Myocardial Infarction, Primary Prevention, Lipoprotein(a), Stroke, RNA, Small Interfering