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Original Investigation
May 22, 2019

Effect of the PCSK9 Inhibitor Evolocumab on Total Cardiovascular Events in Patients With Cardiovascular Disease: A Prespecified Analysis From the FOURIER Trial

Author Affiliations
  • 1TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, Masschusetts
  • 2Oslo University Hospital, Ullevål and Medical Faculty, University of Oslo, Oslo, Norway
  • 3Department of Internal Medicine, Hypertension and Vascular Diseases, The Medical University of Warsaw, Warsaw, Poland
  • 4Center for Preventive Cardiology, 3rd Internal Medicine Clinic, University General Hospital and Charles University 1st Medical Faculty, Prague, Czech Republic
  • 5National Cardiology Research Center, Moscow, Russia
  • 6Birmingham City and Sandwell Hospitals and the Institute of Cardiovascular Sciences, University of Birmingham, Birmingham, England
  • 7Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands
  • 8First Department of Medicine, University of Pecs, Medical School, Pecs, Hungary
  • 9Folkhälsan Research Center, University of Helsinki, Helsinki, Finland
  • 10Amgen, Thousand Oaks, California
  • 11Sydney Medical School, National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney, Australia
  • 12Imperial College London, London, England
JAMA Cardiol. Published online May 22, 2019. doi:10.1001/jamacardio.2019.0886
Key Points

Question  Does the PCSK9 inhibitor evolocumab affect the total number of cardiovascular events among patients with stable atherosclerotic disease receiving statin therapy?

Findings  In a prespecified secondary analysis of the Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) trial, evolocumab improved clinical outcomes with significant reductions in total primary end point events, driven by decreases in myocardial infarction, stroke, and coronary revascularization, which revealed more than double the number of events prevented compared with an analysis of only first events.

Meaning  The addition of evolocumab to statin therapy provides further support for the benefit of continuing aggressive lipid-lowering therapy to prevent recurrent cardiovascular events.

Abstract

Importance  The PCSK9 inhibitor evolocumab reduced low-density lipoprotein cholesterol and first cardiovascular events in the Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) trial, but patients remain at high risk of recurrent cardiovascular events.

Objective  To evaluate the effect of evolocumab on total cardiovascular events, given the importance of total number of cardiovascular events to patients, clinicians, and health economists.

Design, Setting, and Participants  Secondary analysis of a randomized, double-blind clinical trial. The FOURIER trial compared evolocumab or matching placebo and followed up patients for a median of 2.2 years. The study included 27 564 patients with stable atherosclerotic disease receiving statin therapy. Data were analyzed between May 2017 and February 2019.

Main Outcomes and Measures  The primary end point (PEP) was time to first cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization; the key secondary end point was time to first cardiovascular death, myocardial infarction, or stroke. In a prespecified analysis, total cardiovascular events were evaluated between treatment arms.

Results  The mean age of patients was 63 years, 69% of patients were taking high-intensity statin therapy, and the median LDL-C at baseline was 92 mg/dL (to convert to millimoles per liter, multiply by 0.0259). There were 2907 first PEP events and 4906 total PEP events during the trial. Evolocumab reduced total PEP events by 18% (incidence rate ratio [RR], 0.82; 95% CI, 0.75-0.90; P < .001) including both first events (hazard ratio, 0.85; 95% CI, 0.79-0.92; P < .001) and subsequent events (RR, 0.74; 95% CI, 0.65-0.85). There were 2192 total primary events in the evolocumab group and 2714 total events in the placebo group. For every 1000 patients treated for 3 years, evolocumab prevented 22 first PEP events and 52 total PEP events. Reductions in total events were driven by fewer total myocardial infarctions (RR, 0.74; 95% CI, 0.65-0.84; P < .001), strokes (RR, 0.77; 95% CI, 0.64-0.93; P = .007), and coronary revascularizations (RR, 0.78; 95% CI, 0.71-0.87; P < .001).

Conclusions and Relevance  The addition of the PCSK9 inhibitor evolocumab to statin therapy improved clinical outcomes, with significant reductions in total PEP events, driven by decreases in myocardial infarction, stroke, and coronary revascularization. More than double the number of events were prevented with evolocumab vs placebo as compared with the analysis of only first events. These data provide further support for the benefit of continuing aggressive lipid-lowering therapy to prevent recurrent cardiovascular events.

Trial Registration  ClinicalTrials.gov identifier: NCT01764633

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