November 7, 2026NEJM Evidence
Extended Analyses of Pelacarsen and Cardiovascular Outcomes in Patients with High Lipoprotein(a)
Steven E. NissenLeslie ChoSeth FrndakKathy WolskiJing WangBrian ManningEran LeitersdorfUlf LandmesserJackie McCluskeyMichael J. BlahaA. Michael LincoffZiqiang ZhaoBjorn Mueller-EdenbornT NuehrenbergSotirios TsimikasAnastasia LesogorHui CaoVidyasagar KalahastiU LaufsSeth J. BaumEric S. StroesMichael D. ShapiroBørge Grønne NordestgaardStephen J Nicholls
Key result
Pelacarsen did not reduce major adverse cardiovascular events compared to placebo in on-treatment analysis (9.1% vs 10.4%; HR 0.98, 95% CI 0.85-1.12) or across total events and landmark analyses.
Why the study?
After pelacarsen did not reduce major adverse cardiovascular events in patients with established cardiovascular disease and high lipoprotein(a), extended analyses were conducted to further investigate its association with cardiovascular outcomes across treatment exposures, achieved lipoprotein(a) levels, and key subgroups.
Does pelacarsen reduce the composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or urgent coronary revascularization in patients with established cardiovascular disease and high lipoprotein(a) across extended analyses of treatment exposure, achieved lipoprotein(a) levels, and subgroups?
Key Points
- To investigate whether pelacarsen reduces cardiovascular events in extended analyses assessing treatment exposure, achieved lipoprotein(a) reductions, total events, and key clinical subgroups.
- Secondary extended analysis of a randomized placebo-controlled trial in patients with established cardiovascular disease.
- Assessed a primary composite end point of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or urgent coronary revascularization across on-treatment, uninterrupted treatment, total events, and 3-month landmark subgroups.
- In on-treatment analyses, primary events occurred in 9.1% (380) of pelacarsen participants versus 10.4% (434) receiving placebo (hazard ratio, 0.98; 95% CI, 0.85 to 1.12), and in 11.0% (167) versus 10.1% (204) during uninterrupted treatment (hazard ratio, 1.09; 95% CI, 0.89 to 1.34).
- Total primary events showed no difference between groups, with 644 events for pelacarsen versus 646 for placebo (rate ratio, 1.00; 95% CI, 0.87 to 1.14).
- Three-month landmark analyses revealed no risk reduction for participants with lipoprotein(a) reductions of at least 170 nmol/l (HR, 1.09; 95% CI, 0.92 to 1.29) or achieved levels below 69.5 nmol/l (HR, 1.10; 95% CI, 0.93 to 1.29), with no benefits observed across any evaluated baseline subgroups.
Study Design
Type
RCT
Blinding
Placebo-controlled
Randomization
Randomized
Structured PICO
Does pelacarsen reduce the composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or urgent coronary revascularization in patients with established cardiovascular disease and high lipoprotein(a) across extended analyses of treatment exposure, achieved lipoprotein(a) levels, and subgroups?
P
Population
Patients with established cardiovascular disease and high lipoprotein(a) enrolled in a randomized placebo-controlled trial.
I
Intervention
Pelacarsen (an antisense oligonucleotide that reduces serum levels of lipoprotein(a))
C
Comparator
Placebo
O
Outcome
Composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or urgent coronary revascularizationcomposite
Main Result
Hazard Ratio: 0.98 (95% CI 0.85–1.12)
Absolute Event Rate: 9.1% vs 10.4%
Ask about this paper
Answers are grounded in this paper and cite their sources.
Key expert perspectives
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“A single trial does not provide definitive evidence of a lack of benefit of lowering lipoprotein(a) as a strategy to reduce cardiovascular risk. We have to be humble about what our trial did show, what it didn’t show. We’ve got more work to do.”
“I cannot avoid the disappointing conclusion: it didn't work,”
“I cannot avoid the disappointing conclusion: it didn't work.”
Implication
Extended analyses of a randomized trial demonstrate that lowering lipoprotein(a) with pelacarsen does not reduce major adverse cardiovascular events regardless of treatment adherence, magnitude of lipoprotein(a) reduction, or baseline risk subgroups.
Abstract
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.
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Cite This Study
Nissen et al. (2026) conducted an RCT in Established cardiovascular disease and high lipoprotein(a). Pelacarsen vs. Placebo was evaluated on Composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or urgent coronary revascularization (HR 0.98, 95% CI 0.85-1.12). Pelacarsen did not reduce major adverse cardiovascular events compared to placebo in on-treatment analysis (9.1% vs 10.4%; HR 0.98, 95% CI 0.85-1.12) or across total events and landmark analyses.