ODYSSEY OUTCOMES Trial Summary: Alirocumab for LDL-Cholesterol Management After Acute Coronary Syndrome
In post-ACS patients with LDL-C ≥70 mg/dL despite high-intensity statins, alirocumab 75 mg titrated to 150 mg every two weeks reduced major cardiovascular events by 15% and all-cause mortality by 15%, with the greatest absolute benefit in patients with baseline LDL-C ≥100 mg/dL. 1
Trial Design and Patient Population
ODYSSEY OUTCOMES enrolled 18,924 patients aged ≥40 years who had experienced an acute coronary syndrome 1–12 months prior (median 2.6 months) and maintained elevated LDL-C despite maximally tolerated statin therapy. 2, 1
Baseline lipid levels: Median LDL-C was 92 mg/dL across both treatment arms, with 88.8% of patients on high-intensity statins, 8.7% on low/moderate-intensity statins, and 2.4% on no statin due to documented intolerance. 2, 3
Inclusion criteria required LDL-C ≥70 mg/dL, non-HDL-C ≥100 mg/dL, or apolipoprotein B ≥80 mg/dL despite intensive statin treatment (atorvastatin 40–80 mg or rosuvastatin 20–40 mg daily, or maximum tolerated dose). 2, 4
Alirocumab Dosing Regimen and Titration Strategy
Starting dose: Alirocumab 75 mg subcutaneously every 2 weeks, with protocol-driven titration to 150 mg every 2 weeks at week 12 if LDL-C remained ≥70 mg/dL at week 8. 1
Target LDL-C range: The trial aimed for achieved LDL-C between 25–50 mg/dL during treatment. 2, 1
Dose adjustments: 27.7% of patients required up-titration to 150 mg; conversely, 7.7% had alirocumab temporarily discontinued (switched to placebo) when two consecutive LDL-C measurements fell below 15 mg/dL on the 75 mg dose. 1
LDL-Cholesterol Reduction Achieved
Alirocumab produced a 48% reduction in LDL-C at 12 months (median LDL-C 48 mg/dL with alirocumab versus 96 mg/dL with placebo), with persistent effects through 48 months. 2, 1
Absolute LDL-C reduction: Mean reduction of 52.9 mg/dL in patients on high-intensity statins, 56.7 mg/dL in those on low/moderate-intensity statins, and 86.1 mg/dL in statin-intolerant patients. 3
42% of alirocumab-treated patients achieved LDL-C <25 mg/dL without safety concerns. 2, 1
Primary Cardiovascular Outcomes and Statistical Significance
Primary composite endpoint (coronary heart disease death, nonfatal MI, ischemic stroke, or unstable angina requiring hospitalization) occurred in 9.5% of alirocumab patients versus 11.1% of placebo patients over median 2.8 years follow-up. 2, 1
Hazard ratio 0.85 (95% CI 0.78–0.93; P <0.001), representing a 15% relative risk reduction, 1.6% absolute risk reduction, and number-needed-to-treat of 63 over 2.8 years. 2, 1
All-cause mortality was reduced by 15%: 3.5% with alirocumab versus 4.1% with placebo (HR 0.85; 95% CI 0.73–0.98; P=0.03), yielding an absolute risk reduction of 0.6% and NNT of 167. 2, 1, 5
Subgroup Analyses: Populations with Greatest Benefit
Patients with baseline LDL-C ≥100 mg/dL experienced the largest absolute benefit: In this highest tertile, alirocumab reduced death with HR 0.71 (95% CI 0.56–0.90; P for interaction=0.007), though relative benefit remained consistent across LDL-C strata. 2, 5
Diabetes subgroup: Among the 28.8% of patients with diabetes, alirocumab provided an absolute risk reduction of 2.3% (95% CI 0.4–4.2) for the primary endpoint, compared to 1.2% in prediabetes and normoglycemic patients. 2, 1
Polyvascular disease: Patients with coronary plus peripheral artery or cerebrovascular disease had placebo event rates of 22.2% (2-bed disease) and 39.7% (3-bed disease), with absolute risk reductions of 1.9% and 13.0%, respectively, though confidence intervals were wide for the 3-bed group. 6
Statin-intolerant patients (2.4% of cohort): Placebo MACE rate was 26.0% versus 10.8% in high-intensity statin users; alirocumab reduced events with HR 0.65 (95% CI 0.44–0.97), yielding an absolute risk reduction of 7.97%. 3
Patients eligible for ≥3 years follow-up: In a prespecified analysis of 8,242 patients, alirocumab reduced death with HR 0.78 (95% CI 0.65–0.94; P=0.01), demonstrating greater benefit with longer treatment duration. 5
Total Event Reduction Beyond First Events
Alirocumab prevented 385 total nonfatal cardiovascular events or deaths (including first and subsequent events) compared to 190 first events prevented, demonstrating that total event reduction was twice the first-event reduction. 7
Total nonfatal cardiovascular events were reduced by 13% (HR 0.87; 95% CI 0.82–0.93) in the presence of a strong association between nonfatal events and subsequent death risk. 7
Safety Profile Over 2.8 Years
No increase in serious adverse events, muscle-related events, liver function test elevations, or neurocognitive disorders compared to placebo. 2, 1
Injection-site reactions occurred in 3.8% with alirocumab versus 2.1% with placebo (HR 1.82), but were generally mild and did not lead to discontinuation. 2, 1
Very low LDL-C levels (<25 mg/dL) were not associated with safety concerns: No excess cognitive impairment, hemorrhagic stroke, or impairment of steroid-hormone synthesis was observed. 1
Clinical Significance and Guideline Context
The 2025 ACC/AHA guideline recommends adding a PCSK9 inhibitor when LDL-C remains ≥70 mg/dL despite maximally tolerated statin plus ezetimibe in very high-risk patients (those with recent ACS within 1–12 months). 2
ODYSSEY OUTCOMES provides Class I, Level A evidence that alirocumab reduces both cardiovascular events and mortality when added to intensive statin therapy in the post-ACS population. 1
The trial's titration-to-target strategy (aiming for LDL-C 25–50 mg/dL) supports individualized dosing rather than fixed-dose administration, distinguishing it from the FOURIER trial of evolocumab. 2, 1
Mortality benefit emerged with achieved LDL-C levels: All-cause death declined linearly with achieved LDL-C at 4 months down to approximately 30 mg/dL (adjusted P=0.017 for linear trend), supporting aggressive LDL-C lowering. 5