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 (<50 mg/dL). These findings require further validation in the ongoing prospective ODYSSEY OUTCOMES trial.
- Risk reduction
- low-density lipoprotein cholesterol
- cardiovascular events
- Received July 22, 2016.
- Revision received September 9, 2016.
- Accepted October 6, 2016.
Circulation is published on behalf of the American Heart Association, Inc., by Wolters Kluwer. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial-NoDervis License (http://creativecommons.org/licenses/by-nc-nd/3.0/), which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited, the use is noncommercial, and no modifications or adaptations are made.