What is a concise summary of the FOURIER trial of the PCSK9 inhibitor evolocumab, including its dosing regimen and the significance of its findings for low‑density lipoprotein cholesterol management?

FOURIER Trial Summary: Evolocumab for LDL-Cholesterol Management

Trial Design and Patient Population

The FOURIER trial enrolled 27,564 adults aged 40–85 years with clinically evident atherosclerotic cardiovascular disease (ASCVD) and additional risk factors, requiring fasting LDL-C ≥70 mg/dL or non-HDL-C ≥100 mg/dL despite maximally tolerated statin therapy. 1

Baseline Characteristics

• 81% had prior myocardial infarction (median 3.3 years before enrollment) 1
• 20% had non-hemorrhagic stroke 1
• 13% had symptomatic peripheral arterial disease 1
• Median baseline LDL-C was 92 mg/dL (mean approximately 98 mg/dL) 1
• 69% were on high-intensity statins, 30% on moderate-intensity statins, and 5% also received ezetimibe 1

Dosing Regimen

Evolocumab was administered as 140 mg subcutaneously every 2 weeks or 420 mg monthly, with 86% of participants using the every-2-week regimen. 1 Both dosing schedules demonstrated comparable efficacy in LDL-C reduction. 1

Lipid-Lowering Efficacy

At 48 weeks, evolocumab reduced LDL-C by 59% from baseline, achieving a median LDL-C of 30 mg/dL. 1 The absolute LDL-C reduction averaged 62 mg/dL. 1 Additional lipid effects included:

• Non-HDL-C decreased by 51% 1
• Lipoprotein(a) fell by 27% 1
• Triglycerides reduced by 16% 1
• HDL-C increased by 8% 1

Cardiovascular Outcomes

Over a median follow-up of 2.2 years, evolocumab reduced the primary composite endpoint (cardiovascular death, myocardial infarction, stroke, unstable angina hospitalization, or coronary revascularization) by 15% (HR 0.85; 95% CI 0.79–0.92; p<0.001). 1

Key Secondary Endpoint

The composite of cardiovascular death, myocardial infarction, or stroke was reduced by 20% (HR 0.80; 95% CI 0.73–0.88; p<0.001). 1

Absolute Risk Reductions

• Primary endpoint: 1.5% absolute risk reduction, NNT = 67 over 2.2 years 1
• Key secondary endpoint: 2.5% absolute risk reduction, NNT = 40 1

Stroke Prevention

All strokes were reduced by 21% (HR 0.79; 95% CI 0.66–0.95; p=0.01) and ischemic strokes by 25% (HR 0.75; 95% CI 0.62–0.92; p=0.005). 1, 2

Mortality

No significant difference was observed in cardiovascular death or all-cause mortality during the trial. 1 This finding is consistent with high-dose versus low-dose statin trials and reflects the short duration of follow-up (2.2 years) against a background of contemporary high-intensity statin therapy. 3 However, long-term follow-up data from FOURIER-OLE demonstrated a 23% reduction in cardiovascular death (HR 0.77; 95% CI 0.60–0.99; p=0.04) with extended treatment up to 8.4 years. 4

Safety Profile

Serious adverse events occurred at similar rates in evolocumab and placebo arms (24.8% vs 24.7%). 1 Key safety findings include:

• Injection-site reactions: 2.1% with evolocumab vs 1.6% with placebo 1
• No increase in new-onset diabetes, muscle-related events, or liver enzyme elevations 1
• Neurocognitive event rates were similar between groups, including in patients achieving very low LDL-C (<10 mg/dL) 1
• No safety signal detected in approximately 10% of participants achieving LDL-C <10 mg/dL 1

Clinical Significance

High-Risk Subgroups

Patients with peripheral arterial disease experienced similar relative risk reduction but larger absolute benefit, including a reduction in major limb events (HR 0.58; 95% CI 0.38–0.88; p=0.0093). 5 Patients with metabolic syndrome showed a 17% relative risk reduction for the primary endpoint (HR 0.83; 95% CI 0.76–0.91) and 24% reduction for the key secondary endpoint (HR 0.76; 95% CI 0.68–0.86). 6

LDL-C Threshold Relationship

A continuous, monotonic relationship between achieved LDL-C levels (down to <20 mg/dL) and ASCVD risk was observed, with no apparent threshold effect. 1 This finding supports the concept that "lower is better" for LDL-C reduction in very high-risk patients.

Trial Duration Context

The trial was event-driven rather than time-driven; the median 26-month duration occurred because the observed event rate was higher than anticipated, allowing accrual of 1,829 key secondary endpoints (exceeding the planned 1,630). 3 The predominant effect was prevention of non-fatal cardiovascular events, mainly driven by myocardial infarction and coronary revascularization, with fatal MI or stroke accounting for only 5–10% of all events. 3

Guideline Integration

The FOURIER trial, together with the SPIRE trials, constituted a key step forward in demonstrating that PCSK9 inhibition provides definitive cardiovascular benefit in patients with very high residual risk despite maximally tolerated statin therapy. 3 The key determinants of clinical benefit are absolute cardiovascular risk, absolute magnitude of LDL-C reduction, and absolute LDL-C level achieved. 3