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

Kausik K Ray, Henry N Ginsberg, Michael H Davidson, Robert Pordy, Laurence Bessac, Pascal Minini, Robert H Eckel, Christopher P Cannon, Kausik K Ray, Henry N Ginsberg, Michael H Davidson, Robert Pordy, Laurence Bessac, Pascal Minini, Robert H Eckel, Christopher P Cannon

Abstract

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, and apolipoprotein B100 reductions and MACE among patients within the ODYSSEY trials that compared alirocumab with controls (placebo/ezetimibe), mainly as add-on therapy to maximally tolerated statin.

Methods: Data were pooled from 10 double-blind trials (6699 patient-years of follow-up). Randomization was to alirocumab 75/150 mg every 2 weeks or control for 24 to 104 weeks, added to background statin therapy in 8 trials. This analysis included 4974 patients (3182 taking alirocumab, 1174 taking placebo, 618 taking 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, nonfatal myocardial infarction, ischemic stroke, or unstable angina requiring hospitalization) in 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, 0.76; 95% confidence interval, 0.63-0.91; P=0.0025). Percent reductions in LDL-C from baseline were inversely correlated with MACE rates (hazard ratio, 0.71; 95% confidence interval, 0.57-0.89 per additional 50% reduction from baseline; P=0.003). Strengths of association materially similar to those described for LDL-C were observed with achieved non-high-density lipoprotein cholesterol and apolipoprotein B100 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.

Clinical trial registration: URL: https://www.clinicaltrials.gov. Unique identifiers: NCT01507831, NCT01623115, NCT01709500, NCT01617655, NCT01644175, NCT01644188, NCT01644474, NCT01730040, NCT01730053, and NCT01709513.

Keywords: apolipoproteins; cardiovascular diseases; cholesterol, LDL; risk.

© 2016 The Authors.

Figures

Figure 1.
Figure 1.
Distribution of achieved levels of low-density lipoprotein cholesterol (LDL-C; A), non–high-density lipoprotein cholesterol (non–HDL-C; B), and apolipoprotein B100 (apoB; C) during treatment stratified by control group. For patients with no postbaseline lipid measurement, baseline values were used. CI indicates confidence interval; and MACE, major adverse cardiovascular event.
Figure 2.
Figure 2.
Distribution of the percentage reductions in low-density lipoprotein cholesterol (LDL-C; A), non–high-density lipoprotein cholesterol (non–HDL-C; B), and apolipoprotein B100 (apoB; C) from baseline during treatment stratified by control group. For patients with no postbaseline lipid measurement, baseline values were used. Two patients with missing baseline LDL-C and 3 patients with missing baseline apoB were excluded from the analysis. CI indicates confidence interval.
Figure 3.
Figure 3.
Relationship between on-treatment lipids and reductions in lipid levels with major adverse cardiovascular events (MACE). A through C show adjusted MACE rate by achieved levels of low-density lipoprotein cholesterol (LDL-C), non–high-density lipoprotein cholesterol (non–HDL-C), and apolipoprotein B (apoB), respectively, during follow-up. Corresponding results for percent reductions are shown in D through F, respectively. Multivariate analysis was adjusted for baseline characteristics (age, sex, diabetes mellitus, history of myocardial infarction/stroke, baseline LDL-C, and smoking status). CI indicates confidence interval.

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