Target elevated lipoprotein(a) in patients with acute coronary syndromes
October 2025
Patients with acute coronary syndromes and elevated lipoprotein(a) derive earlier and greater reduction in risk for both major adverse cardiovascular events and adverse limb events with alirocumab: insights from ODYSSEY OUTCOMES.
Ray KK, Szarek M, Bhatt DL, et al. Lipoprotein(a) identifies patients with acute coronary syndromes who derive cardiovascular benefit from alirocumab, particularly for limb events. J Am Coll Cardiol 2025; https://doi.org/10.1016/j.jacc.2025.08.043
STUDY SUMMARY
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Objective |
Previous reports from the ODYSSEY OUTCOMES trial showed that patients with an acute coronary syndrome (ACS) derive greater reduction in major adverse cardiovascular events (MACE) and major adverse limb events (MALE) with alirocumab treatment when lipoprotein(a) [Lp(a)] is elevated. This latest analysis investigated how soon these patients derive benefit after initiation of this therapy.
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Study design |
Post hoc time-to-benefit analysis of the ODYSSEY OUTCOMES trial
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Study population |
ODYSSEY OUTCOMES included 18,924 patients with elevated lipids despite statin treatment (mean age 58 years and 89% on high-intensity statin). Patients were randomized 1-12 months after ACS to alirocumab or placebo administered subcutaneously every 2 weeks.
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Main study variables |
· MACE, a composite of cardiovascular death, myocardial infarction, ischaemic stroke, unstable angina, or ischaemia-driven coronary revascularization. · MALE, a composite of critical limb ischaemia, revascularization, or amputation for ischaemia.
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Methods |
Patients were stratified by baseline Lp(a) concentration as i) ≥30 mg/dL (n=8051) versus <30 mg/dL (n=10,873) or ii) ≥50 mg/dL (n=5709) versus <50 mg/dL (n=13,215). These two Lp(a) thresholds were chosen as 30 mg/dL is considered the lower limit of an interim range for consideration of increased risk (1), and 50 mg/dL as a risk enhancer in current guidelines. Treatment hazard ratios (HR) with 95% confidence interval (CI) were estimated from proportional hazards models with truncated follow-up for consecutive days after randomization. Time-to-benefit was determined as the day after randomization where the treatment HR+95% CI was <1 for all subsequent days without correction for multiple comparisons.
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Key results |
Baseline levels and changes in low-density lipoprotein cholesterol (LDL-C) and Lp(a) concentration are summarized in Table 1. Table 1. Baseline level and reduction in LDL-C and Lp(a) at 4 months, according to Lp(a) category.
Over a median 2.8-years follow-up, there were 2775 MACE and 246 MALE. Treatment HR + 95%CI for MACE were less than 1 (indicative of treatment benefit) from 1.31 years for patients with baseline Lp(a) ≥30 mg/dl and from 1.25 years for patients with Lp(a) ≥50mg/dL. However, for patients with baseline Lp(a) <30 mg/dL or <50mg/dL, treatment HR + 95%CI for MACE exceeded 1 for the duration of follow-up.
Similarly, time-to-event analysis for MALE showed that for patients with Lp(a) ≥30 mg/dL or ≥50 mg/dL, the treatment HR+ 95%CI for MALE was less than 1 from 0.18 and 0.24 years, respectively, but exceeded 1 for the duration of follow-up for patients with lower Lp(a) concentration. |
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Author conclusions |
PCSK9 inhibition with alirocumab was associated with an earlier time-to-benefit for MACE and MALE in patients with elevated lipoprotein(a), observations warranting prospective confirmation. |
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Comment
Patients with ACS remain at very high residual cardiovascular risk, particularly early after discharge (2). The ODYSSEY OUTCOMES trial showed that intensive LDL-C lowering with the PCSK9 inhibitor alirocumab significantly reduced this risk (3). Moreover, Lp(a) appeared to modify the benefit of alirocumab, with greater relative and absolute reductions in the risk of both cardiovascular events and adverse limb events among patients with elevated Lp(a) (4,5). Given the very high risk of recurrent events in ACS patients, it is therefore pertinent to investigate how soon these patients derive benefit from initiation of PCSK9-directed therapy.
The results of this post hoc analysis indicate early benefit from PCSK9 inhibition, especially for reduction in the risk of MALE, for which significant reduction in risk was observed within 3 months. As highlighted in this report, for patients with Lp(a) concentration ≥50 mg/dL, the treatment HR+95% CI for MALE remained <1 from 0.24 years (approximately 3 months). this benefit was also evident among patients with an Lp(a) ≥30 mg/dL from 0.18 years (2.2 months). Based on these findings, the authors conclude that elevated Lp(a) concentration may be a prognostic marker to identify ACS patients at highest risk, who would derive benefit from early initiation of PCSK9 inhibitor treatment. Indeed, clinical guidelines (6-8), highlight elevated Lp(a) as a prognostic risk enhancer in high-and very high-risk patients.
Given the caveats of a post hoc analysis these findings should be viewed as exploratory. However, the early benefit indicated, especially for adverse limb events, warrants further investigation in a prospective trial.
References
- Kronenberg F, Mora S, Stroes ESG, et al. Lipoprotein(a) in atherosclerotic cardiovascular disease and aortic stenosis: a European Atherosclerosis Society consensus statement. Eur Heart J 2022;43:3925–46.
- Steen DL, Khan I, Andrade K, et al. Event rates and risk factors for recurrent cardiovascular events and mortality in a contemporary post acute coronary syndrome population representing 239 234 patients during 2005 to 2018 in the United States. J Am Heart Assoc 2022; 11: https://doi.org/10.1161/JAHA.121.022198
- Schwartz GG, Steg PG, Szarek M et al. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med 2018;379:2097-107.
- Szarek M, Bittner VA, Aylward P et al. Lipoprotein(a) lowering by alirocumab reduces the total burden of cardiovascular events independent of low-density lipoprotein cholesterol lowering: ODYSSEY OUTCOMES trial. Eur Heart J 2020;41:4245-55.
- Schwartz GG, Steg PG, Szarek M et al. Peripheral artery disease and venous thromboembolic events after acute coronary syndrome: role of lipoprotein(a) and modification by alirocumab: prespecified analysis of the ODYSSEY OUTCOMES randomized clinical trial. Circulation 2020;141:1608-17.
- Mach F, Koskinas KC, Roeters van Lennep JE, et al. 2025 Focused Update of the 2019 ESC/EAS Guidelines for the management of dyslipidaemias: Developed by the task force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS) Eur Heart J 2025; https://doi.org/10.1093/eurheartj/ehaf190
- Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk: the task force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and
European Atherosclerosis Society (EAS). Eur Heart J 2020;41:111–88.
- Koschinsky ML, Bajaj A, Boffa MB et al. A focused update to the 2019 NLA scientific statement on use of lipoprotein(a) in clinical practice. J Clin Lipidol 2024;18:e308-e319.
Key words: ODYSSEY OUTCOMES; lipoprotein(a); acute coronary syndrome; time-to-benefit; MACE; MALE
