What were the inclusion criteria, dosing regimen, baseline LDL‑C levels, and cardiovascular outcomes of the FOURIER trial evaluating evolocumab (PCSK9 inhibitor) in patients with established atherosclerotic cardiovascular disease on maximally tolerated statin therapy?

FOURIER Trial: Evolocumab for LDL-C Management in High-Risk ASCVD

Drug and Dosing Regimen

Evolocumab (Repatha®) was administered at 140 mg subcutaneously every 2 weeks OR 420 mg monthly, with 86% of participants using the every-2-week regimen throughout the trial. 1, 2

• Both dosing schedules provide comparable LDL-C reduction: 64% reduction with 140 mg every 2 weeks and 58% reduction with 420 mg monthly 3
• Patients could choose either regimen based on preference, as both demonstrated equivalent efficacy 2

Study Population and Inclusion Criteria

The trial enrolled 27,564 patients aged 40-85 years with clinically evident atherosclerotic cardiovascular disease (ASCVD) and additional risk factors. 1

Specific Inclusion Requirements:

• Prior cardiovascular events: 81% had prior myocardial infarction (median 3.3 years before enrollment), 20% had prior non-hemorrhagic stroke, or 13% had symptomatic peripheral arterial disease 1
• LDL-C threshold: Fasting LDL-C ≥70 mg/dL OR non-HDL-C ≥100 mg/dL despite maximally tolerated statin therapy 1
• Background statin therapy: 69% on high-intensity statin, 30% on moderate-intensity statin, and 5% also taking ezetimibe 1, 2
• Exclusion criteria: MI or stroke within 4 weeks before enrollment 1

Baseline Characteristics:

• Mean age 63 years (45% ≥65 years old); 25% women 2
• 85% White, 2% Black, 10% Asian; 8% Hispanic ethnicity 2
• Additional risk factors: 80% hypertension, 37% diabetes mellitus (1% type 1,36% type 2), 28% current smokers, 23% NYHA class I-II heart failure, 6% eGFR <60 mL/min/1.73m² 2

Baseline LDL-C Levels and Lipid Changes

The median baseline LDL-C was 92 mg/dL (mean 98 mg/dL), reduced by 59% to a median of 30 mg/dL at 48 weeks in the evolocumab arm. 1

Additional Lipid Effects:

• Non-HDL-C: reduced by 51% 1
• Lipoprotein(a): reduced by 27% 1
• Triglycerides: reduced by 16% 1
• HDL-C: increased by 8% 1
• Absolute LDL-C reduction: 62 mg/dL from baseline 1

Cardiovascular Outcomes and Clinical Efficacy

Evolocumab reduced the primary composite endpoint by 15% (HR 0.85; 95% CI 0.79-0.92; p<0.001) and the key secondary endpoint by 20% (HR 0.80; 95% CI 0.73-0.88; p<0.001) over a median follow-up of 2.2 years. 1

Primary Composite Endpoint (Time to First Event):

• Evolocumab arm: 9.8% event rate (4.5 events per 100 patient-years) 2
• Placebo arm: 11.3% event rate (5.2 events per 100 patient-years) 2
• Components: cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization 2
• Absolute risk reduction: 1.5%; NNT: 67 patients for 2.2 years 1

Key Secondary Endpoint:

• Evolocumab arm: 5.9% event rate 1
• Placebo arm: 7.4% event rate 1
• Components: cardiovascular death, myocardial infarction, or stroke 1
• Absolute risk reduction: 2.5%; NNT: 40 patients 1

Individual Component Reductions:

• All strokes: reduced by 21% (1.5% vs 1.9%; HR 0.79; 95% CI 0.66-0.95; p=0.01) 1, 4
• Ischemic stroke: reduced by 25% (1.2% vs 1.6%; HR 0.75; 95% CI 0.62-0.92; p=0.005) 1, 4
• Total cardiovascular events (including recurrent events): reduced by 18% (RR 0.82; 95% CI 0.75-0.90; p<0.001), preventing 52 total events per 1000 patients treated for 3 years versus 22 first events 5
• No difference in cardiovascular death or all-cause death 1

Safety Profile

Serious adverse events were comparable between treatment arms (24.8% evolocumab vs 24.7% placebo), with excellent overall tolerability. 1

Specific Safety Findings:

• Injection site reactions: only adverse event more frequent with evolocumab (2.1% vs 1.6%) 1
• No differences in: diabetes mellitus rates, muscle-related events, liver function test elevations 1
• Neurocognitive events: similar rates between groups in overall trial and detailed cognitive testing subgroup 1
• Very low LDL-C (<10 mg/dL): no signal of harm among 10% of participants achieving these levels 1
• Hemorrhagic stroke: no increase (0.21% vs 0.18%; HR 1.16; p=0.59) 4

Key Subgroup Analyses

Patients with Peripheral Arterial Disease:

Similar relative risk reduction with greater absolute risk reduction compared to those without PAD; evolocumab also reduced major limb events. 1

Patients with Elevated C-Reactive Protein:

Greater absolute risk reduction in patients with higher baseline hsCRP due to higher baseline ASCVD risk, though relative risk reduction was consistent across hsCRP strata. 1, 6

• Baseline hsCRP categories (<1-3, >3 mg/L) showed 3-year event rates of 12.0%, 13.7%, and 18.1% for primary endpoint in placebo arm 6
• Absolute risk reductions: 1.6%, 1.8%, and 2.6% across increasing hsCRP strata 6
• Both LDL-C and hsCRP independently predicted cardiovascular risk (p<0.0001 for each) 6

Patients with Baseline LDL-C <70 mg/dL:

Evolocumab was equally effective in the 2,034 patients (7.4%) with baseline LDL-C <70 mg/dL (HR 0.80; 95% CI 0.60-1.07) compared to those with LDL-C ≥70 mg/dL (HR 0.86; 95% CI 0.79-0.92; p=0.65 for interaction). 7

Patients on Maximal-Potency Statins:

Among 7,533 patients (27.3%) on maximal-potency statins (atorvastatin 80 mg or rosuvastatin 40 mg), evolocumab significantly reduced events (HR 0.86; 95% CI 0.75-0.98) to a similar degree as those on submaximal statins (p=0.88 for interaction). 7

Monotonic LDL-C Relationship:

Even at achieved LDL-C <20 mg/dL, there was a continuous relationship between lower LDL-C and lower ASCVD risk, with no threshold effect. 1, 8

Study Quality and Follow-Up

The trial had minimal loss to follow-up (<0.1%) and modest, balanced dropout rates (12-13% in both arms), with 99.2% of patients followed until trial end or death. 1, 2

• Median follow-up: 2.2 years (range 1.8-2.5 years) 2, 6
• Double-blind, randomized, placebo-controlled, event-driven design 2

Clinical Significance and Context

The 20% relative risk reduction in the key secondary endpoint was less than predicted from prior meta-analyses despite a 62 mg/dL LDL-C reduction, though the trial definitively established benefit in very high-risk patients with residual hypercholesterolemia on maximally tolerated statins. 1

• For every 1000 patients treated for 3 years, evolocumab prevented 22 first events and 52 total events (including recurrent events) 5
• Benefits were maintained for up to 4 years of continuous treatment in extension studies 3
• The trial established that PCSK9 inhibition provides incremental cardiovascular benefit beyond high-intensity statin therapy in appropriate secondary prevention populations 1, 8