Lower rate of ischemic events with alirocumab in patients with atherosclerotic cardiovascular disease but without prior acute ischemic events

Abstract Background ODYSSEY OUTCOMES showed a significant reduction in cardiovascular events, including mortality, in patients with recent acute coronary syndromes, randomized to alirocumab vs. placebo, for lowering low-density lipoprotein cholesterol (LDL-C). However, the trial did not evaluate patients without a prior history of acute events. Purpose To evaluate the potential benefit of alirocumab on acute ischemic events and mortality in patients with atherosclerotic cardiovascular disease (ASCVD) but without prior history of myocardial infarction or stroke. Methods Patients with ASCVD but without prior acute ischemic events were identified from the Optum Research Database (January 2016–December 2022). Patients initiating alirocumab were matched 1:2 with no-PCSK9i (mAb or siRNA) users based on a propensity score that utilized patients’ baseline characteristics. The primary endpoint was the composite of nonfatal myocardial infarction, nonfatal ischemic stroke, and all-cause mortality. The causal estimands were defined as the relative risk reduction (RRR) and absolute risk reduction (ARR) at 3 years with a per-protocol analysis, meaning sustained treatment over time. Rigorous statistical methods for causal inference were utilized to try to obtain unbiased findings. Targeted maximum likelihood estimation (TMLE) was the primary analysis; parametric G-formula was the secondary analysis. The confounder set in these analyses included all baseline characteristics. Results A total of 3,301 patients receiving alirocumab 75mg or 150 mg and 6,602 matched no-PCSK9i users were included. Baseline characteristics were well-balanced. Mean age was 66.8 years; 45.9% were male; 69.4%, 7.6%, and 16.3% had coronary, cerebrovascular, or peripheral artery disease, respectively; 30.5% had diabetes and 8.5% had chronic kidney disease stage 3 or higher. Mean LDL-C was 129.4 mg/dL (3.3 mmol/L) and baseline statin use was 52.2%. TMLE-generated survival curves demonstrated a 3-year event rate of 7.3% (95% confidence interval CI: 5.2%–9.4%) for alirocumab and 15.7% (95% CI: 14.2%–17.1%) for the no-PCSK9i group, resulting in an RRR of 53.3% (p0.001) and an ARR of 8.3% (p0.001) (Figure 1). With the parametric G-formula, the 3-year event rate was 7.8% (95% CI: 5.9%–9.1%) for alirocumab and 15.4% (95% CI: 14.2%–16.5%) for the no-PCSK9i group, resulting in an RRR of 49.3% (p0.001) and an ARR of 7.6% (p0.001) (Figure 2). Conclusions Alirocumab therapy in ASCVD patients without prior acute ischemic events was associated with a significantly lower rate of the composite of non-fatal ischemic events or mortality.