Effect of Alirocumab on Mortality After Acute Coronary Syndromes
Philippe Gabriel Steg1,2, Michael Szarek3, Deepak L Bhatt4
1Assistance Publique-Hôpitaux de Paris, Hôpital Bichat, Université de Paris, FACT (French Alliance for Cardiovascular Trials), INSERM U1148, Paris, France (P.G.S.).
Insights
Alirocumab significantly reduced all-cause death in patients after acute coronary syndrome, especially with longer treatment durations or lower LDL cholesterol levels. This PCSK9 inhibitor offers a potential mortality benefit for high-risk cardiovascular patients.
Area of Science:
- Cardiology
- Pharmacology
- Clinical Trials
Background:
- Previous proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitor trials showed reduced cardiovascular events but not mortality.
- The ODYSSEY OUTCOMES trial investigated alirocumab's effect on death following an acute coronary syndrome (ACS).
Purpose of the Study:
- To evaluate the impact of alirocumab on all-cause mortality and its components in patients post-ACS.
- To assess the relationship between achieved low-density lipoprotein cholesterol (LDL-C) levels and mortality benefit.
Main Methods:
- A double-blind, randomized trial involving 18,924 patients with recent ACS and elevated LDL-C on statin therapy.
- Alirocumab dosage was titrated to achieve LDL-C between 25-50 mg/dL; outcomes were compared against placebo.
- Log-rank testing and joint semiparametric models were used to analyze death and cardiovascular events.
Main Results:
- Alirocumab reduced all-cause death (HR 0.85, P=0.03) over a median 2.8-year follow-up.
- A significant mortality benefit was observed in a prespecified analysis of patients with ≥3 years follow-up (HR 0.78, P=0.01).
- Greater mortality reduction was seen in patients with baseline LDL-C ≥100 mg/dL and with achieved LDL-C levels around 30 mg/dL.
Conclusions:
- Alirocumab, when added to intensive statin therapy, may reduce mortality post-ACS.
- Treatment duration of ≥3 years, baseline LDL-C ≥100 mg/dL, and achieving low LDL-C levels enhance the mortality benefit.
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.
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