BACKGROUND
Evolocumab is a monoclonal antibody that inhibits proprotein convertase subtilisin–kexin
type 9 (PCSK9) and lowers low-density lipoprotein (LDL) cholesterol levels by approxi
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mately 60%. Whether it prevents cardiovascular events is uncertain.
METHODS
We conducted a randomized, double-blind, placebo-controlled trial involving 27,564 pa
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tients with atherosclerotic cardiovascular disease and LDL cholesterol levels of 70 mg per
deciliter (1.8 mmol per liter) or higher who were receiving statin therapy. Patients were
randomly assigned to receive evolocumab (either 140 mg every 2 weeks or 420 mg monthly)
or matching placebo as subcutaneous injections. The primary efficacy end point was the
composite of cardiovascular death, myocardial infarction, stroke, hospitalization for un
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stable angina, or coronary revascularization. The key secondary efficacy end point was the
composite of cardiovascular death, myocardial infarction, or stroke. The median duration
of follow-up was 2.2 years.
RESULTS
At 48 weeks, the least-squares mean percentage reduction in LDL cholesterol levels with
evolocumab, as compared with placebo, was 59%, from a median baseline value of 92 mg
per deciliter (2.4 mmol per liter) to 30 mg per deciliter (0.78 mmol per liter) (P<0.001).
Relative to placebo, evolocumab treatment significantly reduced the risk of the primary
end point (1344 patients [9.8%] vs. 1563 patients [11.3%]; hazard ratio, 0.85; 95% confi
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dence interval [CI], 0.79 to 0.92; P<0.001) and the key secondary end point (816 [5.9%] vs.
1013 [7.4%]; hazard ratio, 0.80; 95% CI, 0.73 to 0.88; P<0.001). The results were consistent
across key subgroups, including the subgroup of patients in the lowest quartile for base
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line LDL cholesterol levels (median, 74 mg per deciliter [1.9 mmol per liter]). There was
no significant difference between the study groups with regard to adverse events (includ
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ing new-onset diabetes and neurocognitive events), with the exception of injection-site
reactions, which were more common with evolocumab (2.1% vs. 1.6%).
CONCLUSIONS
In our trial, inhibition of PCSK9 with evolocumab on a background of statin therapy
lowered LDL cholesterol levels to a median of 30 mg per deciliter (0.78 mmol per liter) and
reduced the risk of cardiovascular events. These findings show that patients with athero
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sclerotic cardiovascular disease benefit from lowering of LDL cholesterol levels below
current targets. (Funded by Amgen; FOURIER ClinicalTrials.gov number, NCT01764633.)