ODYSSEY OUTCOMES
Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome
Year of Publication: 2018
Authors: Schwartz GG, Steg PG, Szarek M, et al.
Journal: New England Journal of Medicine
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.
PDF: Clinical Question
Does alirocumab reduce major adverse cardiovascular events in patients with recent acute coronary syndrome and elevated LDL-C despite statin therapy?
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.
Design
Study Type: Multicenter, randomized, double-blind, placebo-controlled trial
Randomization: 1
Blinding: Double-blind
Enrollment Period: November 2012 – November 2017
Follow-up Duration: Median 2.8 years
Centers: 1315
Countries: 57 countries
Sample Size: 18924
Analysis: Cox proportional hazards model; subgroup analysis stratified by LDL-C; intention-to-treat
Inclusion Criteria
- Acute coronary syndrome 1–12 months prior
- Age ≥40 years
- LDL-C ≥70 mg/dL, non–HDL-C ≥100 mg/dL, or ApoB ≥80 mg/dL despite high-intensity statin therapy
- On stable statin therapy (atorvastatin ≥20 mg or equivalent)
Exclusion Criteria
- Uncontrolled hypertension or diabetes
- Hemorrhagic stroke
- Heart failure with EF <25%
- Severe renal or hepatic dysfunction
Baseline Characteristics
| Characteristic | Control | Active |
|---|---|---|
| Age (mean) | 58.5 | 58.6 |
| Female (%) | 25% | 24.8% |
| LDL-C (median) | 87 mg/dL | 87 mg/dL |
| Prior MI (%) | 16% | 15.8% |
| Diabetes (%) | 29% | 28.5% |
Arms
| Field | Alirocumab | Control |
|---|---|---|
| Intervention | Alirocumab 75 mg SC every 2 weeks, titrated to maintain LDL-C 25–50 mg/dL | Matching placebo SC every 2 weeks |
| Duration | Median 2.8 years | Median 2.8 years |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Composite of CHD death, nonfatal MI, fatal/nonfatal ischemic stroke, or unstable angina requiring hospitalization | Primary | 11.1% | 9.5% | 0.85 | <0.001 |
| All-cause mortality | Secondary | 4.1% | 3.5% | HR 0.85 | 0.07 |
| Nonfatal MI | Secondary | 6.0% | 5.3% | HR 0.86 | <0.05 |
| Ischemic stroke | Secondary | 1.5% | 1.2% | HR 0.73 | 0.01 |
| Injection site reactions | Adverse | 3.8% in alirocumab vs 2.1% in placebo | |||
| Neurocognitive events | Adverse | No difference between groups | |||
| New-onset diabetes | Adverse | Similar between groups |
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.
Funding
Sanofi and Regeneron Pharmaceuticals
Based on: ODYSSEY OUTCOMES (New England Journal of Medicine, 2018)
Authors: Schwartz GG, Steg PG, Szarek M, et al.
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.
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