Alirocumab reduces MACE after ACS regardless of sex
Alirocumab reduced the risk of MACE after ACS compared with placebo regardless of sex, as shown in a prespecified subgroups analysis of ODYSSEY OUTCOMES. The treatment benefit of alirocumab on total CV events was greater at higher baseline Lp(a).
This summary is based on the publication of Bittner VE, Schwartz GG, Bhatt DL, et al. - Alirocumab and cardiovascular outcomes according to sex and lipoprotein(a) after acute coronary syndrome: a report from the ODYSSEY OUTCOMES study. J Clin Lipidol. 2024 Apr 10:S1933-2874(24)00169-7. doi: 10.1016/j.jacl.2024.04.122.
Introduction and methods
Background
A recent statement by the European Society of Atherosclerosis underscores that there are differences in lipids levels between women and men through the life course [1]. For instance, women generally have higher Lp(a) levels compared with men [2]. In ODYSSEY OUTCOMES, the PCSK9 monoclonal antibody alirocumab versus placebo reduced the risk of MACE in patients with recent ACS and persistent elevation of atherogenic lipoproteins despite optimized statin therapy [3-4]. It remains unclear whether sex influences the efficacy of PCSK9 inhibitors in patients with recent ACS, and whether the effect of PCSK9 inhibitors on cardiovascular outcomes in women and men is impacted by Lp(a).
Aim of the study
In a prespecified subgroup analysis of ODYSSEY OUTCOMES, the authors evaluated the efficacy and safety of alirocumab according to sex. Moreover, in a post-hoc analysis of ODYSSEY OUTCOMES, the authors evaluated cardiovascular outcomes according to sex, baseline Lp(a), and treatment.
Methods
The ODYSSEY OUTCOMES trial was a double-blind, placebo-controlled trial in which 18,924 patients (4762 females and 14.162 males) with recent ACS (1–12 months prior) and elevated levels of atherogenic lipoproteins (LDL-c ≥70 mg/dL, non-HDL-c ≥100 mg/dL or apoB ≥80 mg/dL) despite high-intensity or maximum-tolerated statin therapy were randomized to alirocumab 75 mg subcutaneously every 2 weeks or placebo. The median follow up period was 2.8 years.
Outcomes
The primary outcome was MACE (defined as the first event in a composite of death from coronary heart disease (CHD), non-fatal MI, fatal or non-fatal ischemic stroke, or unstable angina requiring hospitalization). Secondary outcomes were total CV events (which included first and subsequent components of MACE, CV mortality, hemorrhagic stroke, HF hospitalizations, PAD events, and VTE), non-cardiovascular mortality, and all-cause mortality.
Main results
Efficacy according to sex
- Compared with placebo, alirocumab reduced the risk of MACE in women (HR: 0.90; 95%CI: 0.76-1.07) and men (HR: 0.83; 95%CI: 0.75-0.92) (P for interaction=0.40).
- The treatment effects of alirocumab versus placebo on CHD death or non-fatal MI, ischemic stroke, all-cause mortality, first CV events, and total CV events were similar in both sexes (all P for interactions>0.05).
- Women had a higher number of total CV events compared with men (12.7 vs. 11.2 per 100 patient-years in the placebo group; and 10.3 vs 9.7 per 100 patient-years in the alirocumab group). This was caused by a higher incidence of subsequent events in women compared with men, whereas the rate of first events were similar between the sexes.
Safety according to sex
- The rate of adverse events and serious adverse events were similar between the placebo group and alirocumab group in women.
- The rate of adverse events and serious adverse events were lower in alirocumab-treated men compared with placebo-treated men (P=0.02). However, there was no interaction of sex (P for interaction=0.24).
Total CV events by sex, treatment group, and baseline Lp(a)
- In the placebo group, Lp(a) concentrations were related to the risk of CV events in both women and men. There was interaction of sex and baseline Lp(a) (P for interaction=0.95).
- The absolute risk reduction with alirocumab was greater in patients with higher baseline Lp(a) in both sexes. There was a trend that the treatment effect size was more dependent on Lp(a) levels in women compared with men (3-way interaction of sex, Lp(a), and treatment, P=0.08).
Conclusion
In this analysis of ODYSSEY OUTCOMES among patients with recent ACS, alirocumab reduced the risk of MACE compared with placebo in both sexes without safety signals. Patients with higher baseline Lp(a) benefited the most from treatment with alirocumab in both sexes, but the dependance of the treatment effect size on Lp(a) was greater in women than men.
References
- Roeters van Lennep JE, Tokgozoglu LS, Badimon L, et al. Women, lipids, and atherosclerotic cardiovascular disease: a call to action from the European Atherosclerosis Society. Eur Heart J. 2023. doi:10.1093/ eurheartj/ehad472.
- 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(39):3925–3946. doi:10.1093/eurheartj/ehac361.
- Schwartz GG, Steg PG, Szarek M, et al. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med. 2018;379(22):2097–2107. doi:10.1056/NEJMoa1801174.
- Steg PG, Szarek M, Bhatt DL, et al. Effect of alirocumab on mortality after acute coronary syndromes. Circulation. 2019;140(2):103–112. doi:10.1161/CIRCULATIONAHA.118.038840.