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
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 . 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).
- There was a gradient in baseline LDL-c in the three strata of achieved LDL-c , with median levels of 79 mg/dL, 88 mg/dL, and 99 mg/dL in the <25 mg/dL, 25-50 mg/dL, and >50 mg/dL strata, respectively. Other differences in baseline characteristics were observed in Lp(a) concentrations, intensity of statin therapy, adherence, as well as demographic, medical history, biometric, and laboratory parameters.
- 99.3% Of patients in the <25 mg/dL stratum and 81.3% in the 25-50 mg/dL stratum had LDL-c reductions of at least 50% after 4 months of treatment with alirocumab. In contrast, among patients in the alirocumab group with achieved LDL-c levels of >50 mg/dL, 26.4% had an increase in LDL-c from baseline with 5.6% with an increase of at least 50%. Only 18.2% showed a decrease of at least 50% from baseline.
- Adherence to alirocumab at month 4 was highest among patients in the <25 mg/dL LDL-c stratum followed by those in the 25-50 mg/dL stratum (97.3% and 95.3%, respectively, P<0.001). Poorer adherence was reported by patients with >50 mg/dL achieved LDL-c levels (77.2%, P<0.001 for >50 mg/dL vs. other strata).
- The relative and absolute risk reductions for MACE in patients treated with alirocumab, compared to placebo, were similar in the <25 mg/dL (HR 0.74, 95% CI: 0.62-0.89; ARR 0.92 per 100 patient-years) and 25-50 mg/dL (HR 0.74, 95% CI: 0.64-0.87; ARR 1.05 per 100 patient-years) achieved LDL-c strata. The risk reductions for MACE with alirocumab were less in the achieved LDL-c >50 mg/dL stratum (HR 0.87, 95% CI: 0.73-1.04; ARR 0.62 per 100 patient-years).
- A spline analysis of continuous time-weighted moving average (TWMA) LDL-c in the alirocumab group showed a linear decreasing risk of MACE at LDL-c levels >50 mg/dL and between 25-50 mg/dL. There was no indication of decreased risk reductions below LDL-c levels down to ~23 mg/dL . However, a broad confidence interval was found at TWMA LDL-c values <20 mg/dL.
- No safety concerns like hemorrhagic stroke, neurocognitive disorders or new-onset diabetes were associated in patients who achieved LDL-c levels of <15 mg/dL for a median period of 6.8 months before being switched blindly to placebo.
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.