PDF: FOURIER
(2017)Objective
Determine whether evolocumab reduces cardiovascular events in patients with atherosclerotic cardiovascular disease receiving statin therapy.
Study Summary
• In patients with ASCVD on statin therapy, adding evolocumab significantly lowered LDL-C by 59% and reduced the risk of major cardiovascular events. Benefits emerged after the first year, with no excess in serious adverse events.
Intervention
Evolocumab 140 mg every 2 weeks or 420 mg monthly vs. placebo, added to background statin therapy. 27,564 patients with ASCVD and LDL ≥70 mg/dL randomized. Median follow-up 2.2 years.
Study Design
Arms: Array
Outcome
• Primary: CV death, MI, stroke, hospitalization for unstable angina, or coronary revascularization — 9.8% vs. 11.3%; HR 0.85 (95% CI 0.79–0.92); p<0.001
• Key secondary: CV death, MI, or stroke — 5.9% vs. 7.4%; HR 0.80 (95% CI 0.73–0.88); p<0.001
• MI — 3.4% vs. 4.6%; HR 0.73; p<0.001
• Stroke — 1.5% vs. 1.9%; HR 0.79; p=0.01
• Coronary revascularization — 5.5% vs. 7.0%; HR 0.78; p<0.001
• No difference in CV death or all-cause mortality
• Adverse events: injection-site reactions slightly more common (2.1% vs. 1.6%)
• Key secondary: CV death, MI, or stroke — 5.9% vs. 7.4%; HR 0.80 (95% CI 0.73–0.88); p<0.001
• MI — 3.4% vs. 4.6%; HR 0.73; p<0.001
• Stroke — 1.5% vs. 1.9%; HR 0.79; p=0.01
• Coronary revascularization — 5.5% vs. 7.0%; HR 0.78; p<0.001
• No difference in CV death or all-cause mortality
• Adverse events: injection-site reactions slightly more common (2.1% vs. 1.6%)
Bottom Line
Adding evolocumab to statin therapy significantly reduced the risk of cardiovascular events compared to placebo, without a significant increase in adverse events.
Major Points
- Landmark PCSK9 inhibitor cardiovascular outcomes trial — first to demonstrate that adding a PCSK9 inhibitor to statin therapy reduces cardiovascular events. Established the 'lower is better' LDL paradigm below previously imagined thresholds.
- 27,564 patients with stable ASCVD on optimized statin therapy (99.8% on statins, 69% on high-intensity) — the largest PCSK9 inhibitor trial.
- LDL-C reduced dramatically: median 92 → 30 mg/dL (59% reduction), with 42% achieving LDL <15 mg/dL. This was the first large trial to demonstrate safety at such extreme LDL levels.
- Primary composite (CV death, MI, stroke, hospitalization for unstable angina, coronary revascularization): 9.8% vs 11.3% (HR 0.85, 95% CI 0.79–0.92, p<0.001). NNT 67 over median 2.2 years.
- Key secondary (CV death, MI, stroke): 5.9% vs 7.4% (HR 0.80, p<0.001). Stroke specifically: 1.5% vs 1.9% (HR 0.79, p=0.01) — a 21% relative stroke reduction.
- Benefits emerged after approximately 12 months and continued to accrue — the time-dependent benefit suggested even larger effects with longer treatment.
- No increase in neurocognitive adverse events (0.3% both groups) despite very low LDL levels — directly addressed the concern that extreme LDL lowering could affect brain function (brain needs cholesterol for myelin).
- No increase in new-onset diabetes (8.1% both groups), injection-site reactions, or myalgia — reassuring safety profile for a biologic agent.
- 19.4% had prior stroke — the stroke subgroup benefited comparably to the overall population.
- Led to FDA approval of evolocumab for ASCVD risk reduction and informed 2018 ACC/AHA cholesterol guidelines recommending PCSK9 inhibitors when LDL remains ≥70 mg/dL despite maximally tolerated statin + ezetimibe.
Study Design
- Study Type
- Randomized, double-blind, placebo-controlled trial
- Randomization
- Yes
- Blinding
- Double-blind
- Sample Size
- 27564
- Follow-up
- Median 2.2 years
- Centers
- 1242
- Countries
- Worldwide
Primary Outcome
Definition: Composite of cardiovascular death, MI, stroke, hospitalization for unstable angina, or coronary revascularization
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 11.3% | 9.8% | 0.85 (0.79–0.92) | <0.001 |
Limitations & Criticisms
- Median follow-up of 2.2 years may underestimate long-term benefits — the benefit curve was still diverging at trial end, suggesting larger effects with longer treatment.
- Absolute risk reduction was modest (1.5% for primary outcome) given the high cost of evolocumab (~$14,000/year initially, later reduced) — cost-effectiveness was initially unfavorable.
- No significant reduction in cardiovascular mortality (HR 1.05, p=0.62) or all-cause mortality (HR 0.88, p=0.10) — a key limitation for a secondary prevention trial.
- Industry-sponsored (Amgen) — manufacturer of evolocumab funded the trial and participated in design, data collection, and analysis.
- Injectable biologic with adherence challenges — subcutaneous injection every 2 weeks or monthly may reduce real-world compliance compared to oral medications.
- The trial excluded patients within 4 weeks of an acute event — does not address the early post-ACS or post-stroke 'vulnerable period' where aggressive lipid lowering may have the most benefit.
- No comparison with ezetimibe add-on therapy (tested in IMPROVE-IT) — unclear if the benefit over statin alone is incremental to or independent of other lipid-lowering agents.
- 5.2% were on ezetimibe at baseline — suggesting most patients had not been optimized on oral therapy before starting a biologic, raising step-therapy concerns.
- The very low LDL levels achieved (median 30 mg/dL) raised theoretical concerns about steroid hormone synthesis and fat-soluble vitamin absorption, though no safety signals were detected.
Citation
Sabatine MS, et al. N Engl J Med. 2017;376:1713–1722.