Effect of Alirocumab on Mortality After Acute Coronary Syndromes

Abstract

Background: Previous trials of PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibitors demonstrated reductions in major adverse cardiovascular events, but not death. We assessed the effects of alirocumab on death after index acute coronary syndrome.

Methods: ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) was a double-blind, randomized comparison of alirocumab or placebo in 18 924 patients who had an ACS 1 to 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. We examined the effects of treatment on all-cause death and its components, cardiovascular and noncardiovascular death, with log-rank testing. Joint semiparametric models tested associations between nonfatal cardiovascular events and cardiovascular or noncardiovascular death.

Results: 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; 95% CI, 0.73 to 0.98; P=0.03, nominal P value). This resulted from nonsignificantly fewer cardiovascular (240 [2.5%] vs 271 [2.9%]; HR, 0.88; 95% CI, 0.74 to 1.05; P=0.15) and noncardiovascular (94 [1.0%] vs 121 [1.3%]; HR, 0.77; 95% CI, 0.59 to 1.01; P=0.06) deaths with alirocumab. In a prespecified analysis of 8242 patients eligible for ≥3 years follow-up, alirocumab reduced death (HR, 0.78; 95% CI, 0.65 to 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 cardiovascular and noncardiovascular deaths. A post hoc analysis found that, compared to patients with lower LDL-C, patients with baseline LDL-C ≥100 mg/dL (2.59 mmol/L) had a greater absolute risk of death and a larger mortality benefit from alirocumab (HR, 0.71; 95% CI, 0.56 to 0.90; Pinteraction=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 acute coronary syndrome, particularly if treatment is maintained for ≥3 years, if baseline LDL-C is ≥100 mg/dL, or if achieved LDL-C is low.

Clinical trial registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01663402.

Keywords: PCSK9 protein; acute coronary syndrome; alirocumab; cholesterol; mortality.

Figures

Figure 1.

All-cause, cardiovascular, and noncardiovascular death (intention-to-treat population) shown as Kaplan-Meier curves (left panel) and in a forest plot (right panel). CV indicates cardiovascular; and HR, hazard ratio.

Figure 2.

Prespecified all-cause death subgroup analysis.A, All patients. B, Patients eligible for ≥3 years of follow-up. HR indicates hazard ratio.

Figure 3.

All-cause death by baseline low-density lipoprotein cholesterol subgroup. ARR indicates absolute risk reduction; HR, hazard ratio; and RRR, relative risk reduction.

Figure 4.

All-cause death spline analysis of continuous intention-to-treat month-4 LDL-C for alirocumab-treated* patients. *Hazard ratio (dashed lines indicate upper and lower bounds of the 95% confidence interval) is relative to median month-4 LDL-C (31 mg/dL [0.80 mmol/L]), adjusted for age, sex, geographic region, diabetes status, and baseline LDL-C. Degree = 3, 3 knots located at month-4 LDL-C quartiles (0.52, 0.80, and 1.27 mmol/L [20, 31, and 49 mg/dL]), P value for month 4 spline effect = 0.0169. LDL-C indicates low-density lipoprotein cholesterol.