In patients with a recent acute coronary syndrome (ACS) and low‑density lipoprotein cholesterol (LDL‑C) ≥70 mg/dL despite maximally tolerated high‑intensity statin therapy, what were the dosing regimen of alirocumab (Praluent), the study population characteristics, and the cardiovascular outcomes reported in the ODYSSEY OUTCOMES trial?

ODYSSEY OUTCOMES Trial: LDL Management Focus, Drug Details, Population, and Results

Alirocumab 75–150 mg subcutaneously every 2 weeks reduced major adverse cardiovascular events by 15% (HR 0.85; 95% CI 0.78–0.93) and all-cause mortality by 15% (HR 0.85; 95% CI 0.73–0.98) in 18,924 patients with recent acute coronary syndrome and LDL-C ≥70 mg/dL despite maximally tolerated high-intensity statin therapy. 1

Study Drug and Dosing Regimen

Alirocumab (Praluent) was administered with a titration-to-target strategy: 1, 2

• Starting dose: 75 mg subcutaneously every 2 weeks 1
• Up-titration: Increased to 150 mg every 2 weeks at week 12 if LDL-C remained ≥70 mg/dL at week 8; 27.7% of participants required this adjustment 2
• Down-titration: Reduced back to 75 mg if two consecutive LDL-C measurements fell <25 mg/dL; 30.8% of up-titrated patients were subsequently down-titrated 2
• Temporary discontinuation: Switched to placebo if two consecutive LDL-C values were <15 mg/dL on 75 mg dose; 7.7% underwent this protocol-mandated switch 1, 2
• Target LDL-C range: 25–50 mg/dL during the trial 1, 2

This represents a fundamentally different approach from evolocumab in FOURIER, which used fixed dosing without titration. 1

Study Population Characteristics

Inclusion Criteria

• Recent acute coronary syndrome: 1–12 months before enrollment (median 2.6 months) 1
• Persistent dyslipidemia: LDL-C ≥70 mg/dL (≥1.8 mmol/L) or non-HDL-C ≥100 mg/dL (≥2.6 mmol/L) 1
• Background statin therapy: Despite predominantly high-intensity statin treatment (89% on high-intensity statins) 1, 3

Baseline Demographics

• Total enrollment: 18,924 patients randomized 1
• Median baseline LDL-C: 92 mg/dL (2.4 mmol/L) 1
• Statin intensity distribution: 88.8% high-intensity, 8.7% low/moderate-intensity, 2.4% no statin (documented intolerance) 3
• Diabetes prevalence: 28.8% 2
• Polyvascular disease: 1,405 patients (7.4%) had disease in 2 vascular beds; 149 (0.8%) had disease in 3 beds 4
• Median follow-up: 2.8 years 1

The trial specifically targeted a very high-risk population with recent ACS, distinguishing it from FOURIER which enrolled stable ASCVD patients (median 3.3 years post-MI). 1

LDL-C Reduction Achieved

Alirocumab produced a 48% reduction in LDL-C at 12 months, with persistent effects at 48 months: 1

• Median LDL-C at 12 months: 48 mg/dL with alirocumab versus 96 mg/dL with placebo 2
• Absolute reduction: Approximately 52.9 mg/dL in patients on high-intensity statins 3
• Proportion achieving very low LDL-C: 42% reached LDL-C <25 mg/dL 2
• Goal achievement: 94.6% of patients achieved European guideline target of LDL-C <1.4 mmol/L (54 mg/dL) versus only 17.3% with placebo 5

The smaller difference between on-treatment and intention-to-treat LDL-C levels compared to FOURIER was partly attributable to the trial-designed reduction in therapy for those with LDL-C <15 mg/dL. 1

Primary Cardiovascular Outcomes

Primary Composite Endpoint

The primary endpoint (coronary heart disease death, non-fatal MI, ischemic stroke, or unstable angina requiring hospitalization) occurred in: 1

• Alirocumab arm: 9.5%
• Placebo arm: 11.1%
• Hazard ratio: 0.85 (95% CI 0.78–0.93)
• Absolute risk reduction: 1.6%
• Number needed to treat: 63 patients for 2.8 years to prevent one event 1, 2

All-Cause Mortality

Alirocumab significantly reduced all-cause mortality: 1

• Alirocumab arm: 3.5%
• Placebo arm: 4.1%
• Hazard ratio: 0.85 (95% CI 0.73–0.98)
• Absolute risk reduction: 0.6%
• Number needed to treat: 167 1

This mortality benefit was not observed in FOURIER with evolocumab, making ODYSSEY OUTCOMES the first PCSK9 inhibitor trial to demonstrate a survival advantage. 1

Total Events Analysis

When accounting for both first and subsequent events, alirocumab prevented 385 total nonfatal cardiovascular events or deaths compared to 190 first events—twice the benefit captured by traditional first-event analysis: 6

• Total nonfatal cardiovascular events: HR 0.87 (95% CI 0.82–0.93) 6
• Death: HR 0.83 (95% CI 0.71–0.97) in the joint frailty model 6

Subgroup Analyses: Identifying Maximum Benefit

Baseline LDL-C Stratification

Patients in the highest baseline LDL-C tertile (≥100 mg/dL) experienced the greatest absolute risk reduction, though relative benefit was consistent across strata (P for interaction 0.09): 1

• LDL-C <80 mg/dL: Modest absolute benefit
• LDL-C 80–100 mg/dL: Intermediate benefit
• LDL-C ≥100 mg/dL: Greatest absolute risk reduction 1

Diabetes Status

Diabetic patients derived substantially greater absolute benefit: 2

• Diabetes subgroup: 2.3% absolute risk reduction (95% CI 0.4–4.2)
• Pre-diabetes: 1.2% absolute risk reduction
• Normoglycemic: 1.2% absolute risk reduction 2

This finding supports preferential use of alirocumab in diabetic patients with recent ACS. 2

Polyvascular Disease

Patients with polyvascular disease had dramatically higher event rates and larger absolute benefits: 4

• Monovascular (coronary only): 10.0% placebo event rate; 1.4% absolute risk reduction with alirocumab
• 2-bed polyvascular disease: 22.2% placebo event rate; 1.9% absolute risk reduction
• 3-bed polyvascular disease: 39.7% placebo event rate; 13.0% absolute risk reduction (95% CI -2.0% to 28.0%) 4

For mortality in 3-bed polyvascular disease, the absolute risk reduction was 16.2% (95% CI 5.5% to 26.8%). 4

Statin Intolerance

Among the 2.4% of patients unable to tolerate any statin (documented intolerance to ≥2 statins): 3

• Placebo event rate: 26.0% (highest risk subgroup)
• Hazard ratio with alirocumab: 0.65 (95% CI 0.44–0.97)
• Absolute risk reduction: 7.97% (95% CI 0.42–15.51) 3

This demonstrates that PCSK9 inhibition is a critical therapeutic strategy for statin-intolerant patients with ACS. 3

Peripheral Artery Disease Events

Alirocumab reduced PAD events (critical limb ischemia, limb revascularization, or amputation): 7

• Hazard ratio: 0.69 (95% CI 0.54–0.89; P=0.004) 7
• Mechanism: Reduction in PAD events was associated with baseline lipoprotein(a) quartile (P trend=0.03), but not LDL-C corrected for lipoprotein(a) content (P trend=0.50) 7

Safety Profile

Overall Safety

Serious adverse events were comparable between arms over 2.8 years: 1

• Muscle-related events: No difference between alirocumab and placebo 1
• Liver function test elevations: No difference 1
• Neurocognitive disorders: No difference 1
• New-onset diabetes: No adverse impact on HbA1c or fasting glucose 2

Injection-Site Reactions

The only adverse event more common with alirocumab: 1, 2

• Alirocumab: 3.8%
• Placebo: 2.1%
• Hazard ratio: 1.82 2

These reactions were generally mild and did not lead to treatment discontinuation. 1

Very Low LDL-C Safety

Among patients achieving LDL-C <25 mg/dL (42% of alirocumab-treated patients), no safety signals emerged: 1, 2

• No increase in cognitive impairment 1
• No increase in hemorrhagic stroke 1
• No impairment of steroid-hormone synthesis 2

This confirms the safety of achieving very low LDL-C levels with PCSK9 inhibition. 1

Clinical Importance: LDL Management Strategy

ODYSSEY OUTCOMES established that in the highest-risk post-ACS population—those with persistent LDL-C ≥70 mg/dL despite maximally tolerated statins—adding alirocumab with dose titration to achieve LDL-C 25–50 mg/dL reduces both cardiovascular events and mortality. 1 The 15% relative risk reduction was identical to FOURIER, but the absolute benefit and mortality reduction distinguish this trial. 1 The greatest absolute benefits accrue to patients with diabetes, polyvascular disease, statin intolerance, or baseline LDL-C ≥100 mg/dL—precisely the populations who should be prioritized for PCSK9 inhibitor therapy after ACS. 2, 3, 4