Physicians' Academy for Cardiovascular Education

Similar risk reductions in MACE with achieved LDL-c <25 mg/dL and 25-50 mg/dL with PCSK9i

Clinical Efficacy and Safety of Alirocumab after Acute Coronary Syndrome According to Achieved Level of Low-Density Lipoprotein Cholesterol: A Propensity Score-Matched Analysis of the ODYSSEY OUTCOMES Trial

Literature - Schwartz GG, Steg PG, Bhatt DL, et al. - Circulation. 2021. doi: 10.1161/CIRCULATIONAHA.120.049447

Introduction and methods

The ECS/EAS guidelines recommend lipid lowering therapy (LLT) that achieves LDL-c levels of <55 mg/dL for patients at very high risk for MACE and <40 mg/dL in those who have had a recurrent MACE within the previous 2 years [1]. It remains uncertain whether additional benefits exist from achieving LDL-c levels significantly below these goals. Prior analyses relating achieved LDL-c to MACE may be confounded by baseline characteristics, such as lower or higher baseline and lifetime levels of LDL-c and/or Lp(a). In addition, lower achieved LDL-c may be related to lower LLT adherence. Most of the prior analyses from LLT studies have not or incompletely accounted for differences in baseline characteristics and adherence in patients [2-7].

This prespecified analysis of the ODYSSEY OUTCOMES trial assessed the risk of MACE and safety in three achieved LDL-c strata from patients with recent ACS receiving the PCSK9 inhibitor alirocumab or placebo. To control for potential confounders, propensity score matching was applied to compare patients in the placebo group to alirocumab treated patients with similar baseline characteristics and medication adherence.

The ODYSSEY OUTCOMES trial was a multinational, double-blind, placebo-controlled trial that included patients with recent ACS who were hospitalized 1 to 12 months before randomization. Patients had LDL-c ≥70 mg/dL, or non-HDL-c of ≥100 mg/dL, or apolipoprotein B levels of ≥80 mg/dL, while receiving atorvastatin 40-80 mg daily, rosuvastatin 20-40 mg daily, or the maximum tolerated dose of one of these statins. Patients were randomized (1:1) to 75 mg of alirocumab or placebo, subcutaneously every 2 weeks. The primary outcome of MACE was the composite of coronary heart disease death, nonfatal myocardial infarction, hospitalization for unstable angina, or fatal or nonfatal ischemic stroke. Patients provided a diary with dates of medication injections to assess therapy adherence. The safety analysis focused on increased risk of neurocognitive events, hemorrhagic stroke and new-onset diabetes in patients with two consecutive measurements of <15 mg/dL achieved LDL-c. In this subanalysis, patients who had not experienced a primary outcome before month 4 were selected for analysis. Patients treated with alirocumab were stratified according to achieved LDL-c concentrations at month 4: <25 mg/dL (n=3357), 25-50 mg/dL (n=3692), and >50 mg/dL (n=2197). Propensity score matching was used to match each patient in the alirocumab group to a patient in the placebo group with similar baseline characteristics and adherence. Median follow-up after month 4 assessment was 2.4 years (IQR 1.9-3.0).

Main results


This subanalysis of the ODYSSEY OUTCOMES trial showed that, after accounting for differences in baseline characteristics in patients with recent ACS, alirocumab decreased the risks for MACE in a similar way in individuals with achieved LDL-c levels of <25 mg/dL and 25-50 mg/dL. Patients who achieved an LDL-c of >50 mg/dL had poorer adherence accompanied by a smaller risk reduction of MACE compared to the other two LDL-c strata.


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