Reductions in Atherogenic Lipids and Major Cardiovascular Events: A Pooled Analysis of 10 ODYSSEY Trials Comparing Alirocumab to Control

BACKGROUND: -A continuous relationship between reductions in low-density lipoprotein cholesterol (LDL-C) and major adverse cardiovascular events (MACE) has been observed in statin and ezetimibe outcomes trials, down to achieved levels of 54 mg/dL. However, it is uncertain whether this relationship extends to LDL-C levels <50 mg/dL. We assessed the relationship between additional LDL-C, non-high-density lipoprotein cholesterol (non-HDL-C), and apolipoprotein B100 (apoB) reductions and MACE among patients within the ODYSSEY trials that compared alirocumab versus controls (placebo/ezetimibe), mainly as add on to maximally tolerated statin. METHODS: -Data were pooled from 10 double-blind trials (6699 patient-years follow-up). Randomization was to alirocumab 75/150 mg every 2 weeks or control for 24-104 weeks, added to background statin therapy in 8 trials. This analysis included 4974 patients (3182 alirocumab, 1174 placebo, 618 ezetimibe). In a post hoc analysis, the relationship between average on treatment lipid levels and percent reductions in lipids from baseline were correlated with MACE (coronary heart disease death, non-fatal myocardial infarction [MI], ischemic stroke, or unstable angina requiring hospitalization) using multivariable analyses. RESULTS: -Overall, 33.1% of the pooled cohort achieved average LDL-C <50 mg/dL (44.7-52.6% allocated to alirocumab, 6.5% allocated to ezetimibe, and 0% allocated to placebo). In total, 104 patients experienced MACE (median time to event: 36 weeks). For every 39 mg/dL lower achieved LDL-C, the risk of MACE appeared to be 24% lower (adjusted hazard ratio [HR] 0.76, 95% confidence interval [CI]: 0.63-0.91; P=0.0025). Percent reductions in LDL-C from baseline were inversely correlated with MACE rates (HR 0.71 [0.57 to 0.89] per additional 50% reduction from baseline; P=0.003). Materially similar strengths of association to those described for LDL-C were observed with achieved non-HDL-C and apoB levels or percentage reductions. CONCLUSIONS: -In a post hoc analysis from 10 ODYSSEY trials greater percentage reductions in LDL-C and lower on-treatment LDL-C were associated with a lower incidence of MACE, including very low levels of LDL-C (