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FOURIER

Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease

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Year of Publication: 2017

Authors: Sabatine MS, Giugliano RP, Keech AC, et al.

Journal: The New England Journal of Medicine

Citation: Sabatine MS, et al. N Engl J Med. 2017;376:1713–1722.

Link: https://www.nejm.org/doi/full/10.1056/NEJMoa1615664

PDF: https://www.nejm.org/doi/pdf/10.1056/NEJMoa1615664

Clinical Question

Does adding evolocumab to statin therapy reduce cardiovascular events in patients with atherosclerotic cardiovascular disease?

Study Overview

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 fasting LDL-C ≥70 mg/dL or non-HDL cholesterol ≥100 mg/dL despite optimized lipid-lowering therapy randomized. Median follow-up 2.2 years.

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% of evolocumab patients achieving LDL ≤25 mg/dL at 48 weeks. 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 (1.6% evolocumab vs 1.5% placebo) despite very low LDL levels — directly addressed the concern that extreme LDL lowering could affect brain function.
No increase in new-onset diabetes (8.1% vs 7.7%, HR 1.05, 95% CI 0.94–1.17), or myalgia — reassuring safety profile for a biologic agent; injection-site reactions were nominally more frequent (2.1% vs 1.6%).
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.

      

Design

Study Type: Randomized, double-blind, placebo-controlled trial

Randomization: 1

Blinding: Double-blind

Enrollment Period: February 2013 – June 2015

Follow-up Duration: Median 2.2 years (26 months, IQR 22–30)

Centers: 1242

Countries: 49 countries worldwide

Sample Size: 27564

Analysis: Intention-to-treat

Inclusion Criteria

Age 40–85 years.
Clinically evident ASCVD: prior MI, prior non-hemorrhagic stroke, or symptomatic peripheral artery disease.
Fasting LDL-C ≥70 mg/dL or non-HDL cholesterol ≥100 mg/dL despite optimized lipid-lowering therapy.
On a stable dose of statin ± ezetimibe (preferably high-intensity, at least atorvastatin 20 mg daily or equivalent).
Additional characteristics placing them at higher cardiovascular risk.

Exclusion Criteria

New York Heart Association class III or IV heart failure
Recent MI or stroke within 4 weeks
eGFR <20 mL/min/1.73 m² or dialysis
Active liver disease

Baseline Characteristics

Characteristic	Control	Active
Age (mean)	62.5 ± 8.9	62.5 ± 9.1
Female (%)	24.5	24.6
LDL-C (mg/dL)	92 (IQR 80–109)	92 (IQR 80–109)
HDL-C (mg/dL)	44 (IQR 37–53)	44 (IQR 37–53)
Triglycerides (mg/dL)	133 (IQR 99–181)	134 (IQR 101–183)
Diabetes (%)	36.5	36.7
Hypertension (%)	80.1	80.1
Current smoker (%)	28.5	28.0
Prior MI (%)	81.3	80.9
Prior stroke (%)	19.2	19.5
Peripheral artery disease (%)	12.9	13.5
Statin use (%)	99.8	99.8
Ezetimibe use (%)	5.2	5.3

Arms

Field	Evolocumab	Control
Intervention	Evolocumab (Repatha) subcutaneous injection: patient choice of 140 mg every 2 weeks or 420 mg once monthly (3 injections of 140 mg). Fully human monoclonal antibody targeting PCSK9, preventing LDL receptor degradation and increasing hepatic LDL clearance. Self-administered via prefilled syringe or autoinjector. All patients continued background statin ± ezetimibe therapy.	Matching subcutaneous placebo injections at the same frequency (every 2 weeks or monthly per patient choice). All patients continued background statin ± ezetimibe therapy.
Duration	Median 2.2 years	Median 2.2 years

Outcomes

Outcome	Type	Control	Intervention	HR / OR / RR	P-value
Composite of cardiovascular death, MI, stroke, hospitalization for unstable angina, or coronary revascularization	Primary	11.3%	9.8%	0.85	<0.001
CV death, MI, or stroke	Secondary	7.4%	5.9%	0.8	<0.001
MI	Secondary	4.6%	3.4%	0.73	<0.001
Stroke	Secondary	1.9%	1.5%	0.79	0.01
Coronary revascularization	Secondary	7.0%	5.5%	0.78	<0.001
Safety population	Adverse	Evolocumab N: 13769 · Placebo N: 13756
Serious Adverse Events	Adverse	3404/13,756 (24.7%)	3410/13,769 (24.8%)
Injection site reactions	Adverse	219/13,756 (1.6%)	296/13,769 (2.1%)		<0.001
New-onset diabetes	Adverse	644/8,339 (7.7%)	677/8,337 (8.1%)	1.05
Neurocognitive events	Adverse	202/13,756 (1.5%)	217/13,769 (1.6%)

Subgroup Analysis

Benefit consistent across prespecified subgroups: age (<65 vs ≥65), sex, baseline LDL-C (across quartiles), diabetes status, type of prior ASCVD (MI vs stroke vs PAD), statin intensity (high vs low/moderate), and ezetimibe use. Importantly, patients in the lowest LDL quartile (median 74 mg/dL) benefited comparably to those with higher baseline LDL — supporting 'lower is better' without a floor. Both dosing regimens (140 mg q2wk and 420 mg monthly) showed consistent benefit.

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, 95% CI 0.88–1.25, p=0.62) or all-cause mortality (HR 1.04, 95% CI 0.91–1.19, p=0.54) — 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 head-to-head 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.
Only 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.

Funding

Amgen

Based on: FOURIER (The New England Journal of Medicine, 2017)