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Efficacy and Safety of Evolocumab in Reducing Lipids and Cardiovascular Events
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April 2015 NEJM
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Abstract
Background
Evolocumab, a monoclonal antibody that inhibits proprotein convertase subtilisin-kexin type 9 (PCSK9), significantly reduced low-density lipoprotein (LDL) cholesterol levels in short-term studies. We conducted two extension studies to obtain longer-term data.
Methods
In two open-label, randomized trials, we enrolled 4465 patients who had completed 1 of 12 phase 2 or 3 studies ("parent trials") of evolocumab. Regardless of study-group assignments in the parent trials, eligible patients were randomly assigned in a 2:1 ratio to receive either evolocumab (140 mg every 2 weeks or 420 mg monthly) plus standard therapy or standard therapy alone. Patients were followed for a median of 11.1 months with assessment of lipid levels, safety, and (as a prespecified exploratory analysis) adjudicated cardiovascular events including death, myocardial infarction, unstable angina, coronary revascularization, stroke, transient ischemic attack, and heart failure. Data from the two trials were combined.
Results
As compared with standard therapy alone, evolocumab reduced the level of LDL cholesterol by 61%, from a median of 120 mg per deciliter to 48 mg per deciliter (P<0.001). Most adverse events occurred with similar frequency in the two groups, although neurocognitive events were reported more frequently in the evolocumab group. The risk of adverse events, including neurocognitive events, did not vary significantly according to the achieved level of LDL cholesterol. The rate of cardiovascular events at 1 year was reduced from 2.18% in the standard-therapy group to 0.95% in the evolocumab group (hazard ratio in the evolocumab group, 0.47; 95% confidence interval, 0.28 to 0.78; P=0.003).
Conclusions
During approximately 1 year of therapy, the use of evolocumab plus standard therapy, as compared with standard therapy alone, significantly reduced LDL cholesterol levels and reduced the incidence of cardiovascular events in a prespecified but exploratory analysis. (Funded by Amgen; OSLER-1 and OSLER-2 ClinicalTrials.gov numbers, NCT01439880. opens in new tab and NCT01854918. opens in new tab.)
Reduction in low-density lipoprotein (LDL) cholesterol levels has proved to be highly effective in reducing rates of major cardiovascular events in numerous large outcome trials.1-3 For this reason, LDL cholesterol reduction has been incorporated into practice guidelines as a fundamental means of reducing cardiovascular morbidity and mortality.4-7
During the past 3 years, monoclonal antibodies that inhibit proprotein convertase subtilisin-kexin type 9 (PCSK9) have emerged as a new class of drugs that very effectively lower LDL cholesterol levels.8 One of the members of this class is evolocumab, a fully human monoclonal antibody that typically achieves approximately a 60% reduction in LDL cholesterol levels when administered at the doses that were studied in phase 3 trials.9-13
On completing a trial of evolocumab (parent trial), patients could enroll into one of two longer-term extension trials, designated Open-Label Study of Long-Term Evaluation against LDL Cholesterol 1 (OSLER-1), for patients completing phase 2 trials, and OSLER-2, for those completing phase 3 trials. The OSLER-1 and OSLER-2 trials had as their primary goal the gathering of longer-term data on safety, side-effect profile, and LDL cholesterol reduction and also included a prespecified exploratory analysis on adjudicated cardiovascular outcomes. Here, we report on the combined results of the OSLER-1 and OSLER-2 trials.
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