Effect of Alirocumab on Mortality After Acute Coronary Syndromes

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, allcause
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.