High tierRandomized Controlled TrialCitation verified
Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome
Gregory G Schwartz, P Gabriel Steg, Michael Szarek, Deepak L Bhatt, ODYSSEY OUTCOMES Committees and Investigators - New England Journal of Medicine, 2018
The second large PCSK9-inhibitor outcomes trial. Alirocumab on top of intensive statins reduced recurrent major ischemic events (HR 0.85). Unlike FOURIER, it showed a possible all-cause mortality signal (HR 0.85), though this was not formally significant under the trial's prespecified hierarchical testing - so it is a hypothesis, not a proven mortality benefit.
Key findings
- Primary composite: 9.5% vs 11.1%; HR 0.85 (95% CI 0.78-0.93, p<0.001).
- Death from any cause: 3.5% vs 4.1%; HR 0.85 (95% CI 0.73-0.98) - not significant under hierarchical testing.
- Adds a second, independent PCSK9 mechanism confirming event reduction.
Effect measures
- Hazard Ratio: 0.85 (primary composite)95% CI 0.78-0.93
- Hazard Ratio: 0.85 (all-cause mortality; not formally significant)95% CI 0.73-0.98
Why this evidence tier (High)
- Risk of bias:
- Very large double-blind randomized placebo-controlled trial.
- Precision:
- Large event count; precise primary estimate. The mortality result is borderline and not formally significant.
- Directness:
- Hard clinical composite; second independent PCSK9 mechanism.
- Consistency:
- Event reduction concordant with FOURIER and the statin/ezetimibe evidence.
- Funding / COI:
- Manufacturer-funded (Sanofi and Regeneron); several authors were employees.
High certainty for event reduction; the all-cause mortality signal is suggestive but not established, so it should not be over-read.
- Population:
- 18,924 patients 1-12 months after an acute coronary syndrome on high-intensity or maximally tolerated statins, randomized to the PCSK9 inhibitor alirocumab vs placebo; median follow-up 2.8 years.
- Conflicts of interest:
- Industry-funded by Sanofi and Regeneron, which co-develop alirocumab. Several co-authors were employees of the sponsors.
- Funding:
- Sanofi and Regeneron (co-developers of alirocumab); NCT01663402.
Limitations
- Mortality signal not formally significant under prespecified testing.
- Short median follow-up (2.8 years); manufacturer-funded.