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Effect of Alirocumab on Mortality After ACS: ODYSSEY OUTCOMES Analysis
Study Questions:
Proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors have been shown to reduce major adverse cardiovascular events, but not death. Does alirocumab, the antibody to PCSK9, reduce death after an index acute coronary syndrome (ACS)?
Methods:
The ODYSSEY OUTCOMES trial was a double-blind, randomized comparison of alirocumab or placebo in 18,924 patients who had an ACS 1-12 months previously and elevated atherogenic lipoproteins despite intensive statin therapy. Alirocumab dose was blindly titrated to target achieved low-density lipoprotein cholesterol (LDL-C) between 25 and 50 mg/dl. Outcome variables of all-cause death and its components, cardiovascular and noncardiovascular death, were assessed with log-rank testing. Joint semiparametric models tested associations between nonfatal cardiovascular events and cardiovascular or noncardiovascular death.
Results:
Mean age was 59 years, 25% were female, 79.4% were white, and 88% were on high-intensity statins; 51% were European, 75% were from Canada/United States, Latin America 14%, and Asia 12%. Mean LDL-C at baseline was 86 mg/dl. Median follow-up was 2.8 years. Death occurred in 334 (3.5%) and 392 (4.1%) patients, respectively, in the alirocumab and placebo groups (hazard ratio [HR], 0.85; nominal p value = 0.03). This resulted from nonsignificantly fewer cardiovascular (240 [2.5%] vs. 271 [2.9%]; p = 0.15) and noncardiovascular (94 [1.0%] vs. 121 [1.3%]; p = 0.06) deaths with alirocumab. In a prespecified analysis of 8,242 patients eligible for ≥3 years’ follow-up, alirocumab reduced death (HR, 0.78; 95% CI, 0.65-0.94; p = 0.01). Patients with nonfatal cardiovascular events were at increased risk for cardiovascular and noncardiovascular deaths (p < 0.0001 for the associations). Alirocumab reduced total nonfatal cardiovascular events (p < 0.001) and thereby may have attenuated the number of noncardiovascular deaths. A post-hoc analysis found that, compared to patients with lower LDL-C, patients with baseline LDL-C ≥100 mg/dl had a greater absolute risk of death and a larger mortality benefit from alirocumab (HR, 0.71; 95% CI, 0.56-0.90; p for interaction = 0.007). In the alirocumab group, all-cause death declined with achieved LDL-C at 4 months of treatment, to a level of approximately 30 mg/dl (adjusted p = 0.017 for linear trend).
Conclusions:
Alirocumab added to intensive statin therapy has the potential to reduce death after ACS, particularly if the treatment was maintained for ≥3 years, if baseline LDL-C is ≥100 mg/dl, or if achieved LDL-C is low.
Perspective:
This is an important analytic process and findings are clinically important. Reduction in total mortality only occurred in the group with potential ≥3 years of follow-up, and the number needed to treat to reduce a fatal event is less when LDL-C is >100 mg/dl (e.g., cost-effectiveness). All-cause death declined when the 4-month LDL-C was <30 mg/dl, which implies there may be value in maintaining or intensifying the other lipid-lowering drugs for maximal benefit.
Keywords: Acute Coronary Syndrome, Antibodies, Monoclonal, Cholesterol, LDL, Cost-Benefit Analysis, Dyslipidemias, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hypolipidemic Agents, Primary Prevention, Proprotein Convertases, Subtilisins
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