PDF: ODYSSEY OUTCOMES
(2018)Objective
Evaluate whether alirocumab reduces cardiovascular events in patients with recent acute coronary syndrome receiving high-intensity statin therapy.
Study Summary
• In patients with recent acute coronary syndrome and elevated atherogenic lipoproteins despite high-intensity statin therapy, alirocumab significantly reduced the risk of major adverse cardiovascular events compared to placebo. Benefit was more pronounced in patients with baseline LDL ≥100 mg/dL.
Intervention
Alirocumab 75 mg subcutaneous injection every 2 weeks (adjusted to target LDL 25–50 mg/dL) vs. placebo. All patients were on high-intensity statin or maximum tolerated dose. Median follow-up 2.8 years.
Study Design
Arms: Array
Outcome
• Primary composite (CHD death, nonfatal MI, fatal/nonfatal ischemic stroke, unstable angina requiring hospitalization): 9.5% vs. 11.1%; HR 0.85 (95% CI 0.78–0.93); P<0.001
• All-cause mortality: 3.5% vs. 4.1%; HR 0.85 (95% CI 0.73–0.98)
• Nonfatal MI: 6.6% vs. 7.6%; HR 0.86 (95% CI 0.77–0.96)
• Ischemic stroke: 1.2% vs. 1.6%; HR 0.73 (95% CI 0.57–0.93)
• Unstable angina hospitalization: 0.4% vs. 0.6%; HR 0.61 (95% CI 0.41–0.92)
• CHD death: 2.2% vs. 2.3%; HR 0.92 (95% CI 0.76–1.11)
• Injection-site reactions more common with alirocumab (3.8% vs. 2.1%)
• All-cause mortality: 3.5% vs. 4.1%; HR 0.85 (95% CI 0.73–0.98)
• Nonfatal MI: 6.6% vs. 7.6%; HR 0.86 (95% CI 0.77–0.96)
• Ischemic stroke: 1.2% vs. 1.6%; HR 0.73 (95% CI 0.57–0.93)
• Unstable angina hospitalization: 0.4% vs. 0.6%; HR 0.61 (95% CI 0.41–0.92)
• CHD death: 2.2% vs. 2.3%; HR 0.92 (95% CI 0.76–1.11)
• Injection-site reactions more common with alirocumab (3.8% vs. 2.1%)
Bottom Line
In patients with recent ACS and elevated LDL-C despite intensive statin therapy, alirocumab significantly reduced major adverse cardiovascular events, particularly in those with baseline LDL-C ≥100 mg/dL.
Major Points
- Second major PCSK9 inhibitor outcomes trial (after FOURIER): 18,924 post-ACS patients across 1,315 centers in 57 countries — the largest PCSK9 outcomes trial.
- Alirocumab reduced 4-point MACE by 15% (9.5% vs 11.1%, HR 0.85, 95% CI 0.78–0.93, P<0.001) in patients with elevated LDL despite maximum statin therapy.
- LDL-C reduced from median 87 mg/dL to ~30 mg/dL with alirocumab — demonstrated safety and efficacy of very low LDL-C levels over 2.8 years.
- Greatest absolute benefit in patients with baseline LDL-C ≥100 mg/dL (HR 0.76) — confirming the 'lower is better' LDL hypothesis and identifying the highest-yield population.
- All-cause mortality showed a trend toward reduction (HR 0.85, P=0.07) — not statistically significant overall but significant in the LDL ≥100 subgroup, suggesting mortality benefit in highest-risk patients.
- Ischemic stroke specifically reduced by 27% (HR 0.73, P=0.01) — important for stroke neurologists as it demonstrates PCSK9 inhibitors' cerebrovascular protection.
- Innovative dose-titration design: alirocumab adjusted to maintain LDL-C 25–50 mg/dL; if LDL-C fell <15 mg/dL, switched to placebo — addressing safety at very low levels.
- Complementary to FOURIER (evolocumab, 2017): together these two trials established PCSK9 inhibitors as a major secondary prevention tool, particularly post-ACS.
- No increase in neurocognitive events despite very low LDL-C levels — the EBBINGHAUS substudy confirmed cognitive safety, allaying a major theoretical concern.
- Cost-effectiveness concerns initially limited uptake; subsequent price reductions (>60%) and evolving guidelines have expanded use in high-risk post-ACS patients.
Study Design
- Study Type
- Multicenter, randomized, double-blind, placebo-controlled trial
- Randomization
- Yes
- Blinding
- Double-blind
- Sample Size
- 18924
- Follow-up
- Median 2.8 years
- Centers
- 1315
- Countries
- 57 countries
Primary Outcome
Definition: Composite of CHD death, nonfatal MI, fatal/nonfatal ischemic stroke, or unstable angina requiring hospitalization
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 11.1% | 9.5% | 0.85 (0.78–0.93) | <0.001 |
Limitations & Criticisms
- LDL-C levels were not fully blinded after the initial titration period — investigators could infer treatment assignment from dramatic LDL-C reductions, potentially introducing bias.
- Not powered to detect an overall mortality benefit — the P=0.07 for all-cause death suggests a larger trial or longer follow-up might have reached significance.
- Shorter median follow-up (2.8 years) than some other long-term CV outcomes trials — long-term safety and efficacy beyond 3 years not established.
- Industry-sponsored by Sanofi and Regeneron (alirocumab manufacturers) — inherent conflict of interest in trial design and reporting.
- The dose-titration protocol with potential switch to placebo at LDL <15 mg/dL complicates interpretation — some patients in the alirocumab arm received placebo during portions of the trial.
- Cost of alirocumab ($5,850/year at launch, later reduced) initially limited real-world uptake — cost-effectiveness debated despite clear clinical efficacy.
- Post-ACS population only — results may not apply to chronic stable ASCVD (addressed by FOURIER with evolocumab).
- Underrepresentation of women (25%) and certain racial/ethnic groups limits generalizability.
- Injection-based biweekly dosing may limit long-term adherence in real-world practice compared to the controlled trial setting.
Citation
Schwartz GG, Steg PG, Szarek M, et al. Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome. N Engl J Med. 2018;379:2097–2107.