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 with alirocumab from baseline mean 92 mg/dL to ~40 mg/dL at 4 months (ITT; on-treatment nadir 38 mg/dL), rising to ~66 mg/dL by 48 months (ITT) — sustained but attenuating reduction over 2.8 years.
- Greatest absolute benefit in patients with baseline LDL-C ≥100 mg/dL (P<0.001 for interaction between treatment and baseline LDL; NNT 16 over 4 years) — supporting the 'lower is better' LDL hypothesis and identifying the highest-yield population.
- All-cause mortality: 3.5% vs 4.1% (HR 0.85, 95% CI 0.73–0.98). The paper does NOT report a P value because hierarchical testing was stopped after death from CHD was nonsignificant (P=0.38), so the nominal all-cause mortality result cannot be declared significant.
- Ischemic stroke reduced (1.2% vs 1.6%, HR 0.73, 95% CI 0.57–0.93; no P value reported as this was an 'other' end point not adjusted for multiplicity) — relevant for stroke neurologists as it suggests PCSK9 inhibitors' cerebrovascular protection.
- Innovative dose-titration design: alirocumab adjusted (75 or 150 mg) under blinded conditions to target LDL-C 25–50 mg/dL; blinded substitution to placebo if sustained LDL-C <15 mg/dL — 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 excess in neurocognitive disorder (1.5% alirocumab vs 1.8% placebo) despite very low LDL-C levels — allaying a major theoretical safety 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 death from coronary heart disease, nonfatal MI, fatal or 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 as a mortality trial and hierarchical testing was stopped after CHD death was nonsignificant (P=0.38), so the nominal all-cause mortality benefit (HR 0.85, 95% CI 0.73–0.98) cannot be claimed as significant.
- 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 blinded switch to placebo at sustained 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.