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Updated: Jan 24, 2026
In Silico Clinical Trials for Cardiovascular Disease
Published on: May 27, 2022
Effect of the PCSK9 Inhibitor Evolocumab on Total Cardiovascular Events in Patients With Cardiovascular Disease: A
Sabina A Murphy1, Terje R Pedersen2, Zbigniew A Gaciong3
1TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, Masschusetts.
Insights
Evolocumab significantly reduced total cardiovascular events, including recurrent myocardial infarctions and strokes, in patients with atherosclerotic disease. This PCSK9 inhibitor therapy offers substantial benefits beyond preventing first events.
Area of Science:
- Cardiovascular Medicine
- Pharmacology
- Clinical Trials
Background:
- Patients with atherosclerotic disease on statin therapy remain at high risk for recurrent cardiovascular events.
- The PCSK9 inhibitor evolocumab has demonstrated efficacy in reducing low-density lipoprotein cholesterol and first cardiovascular events.
- Understanding the impact of evolocumab on total cardiovascular events is crucial for patient management and health economics.
Purpose of the Study:
- To evaluate the effect of evolocumab on the total number of cardiovascular events in patients with stable atherosclerotic disease.
- To assess the comprehensive benefit of evolocumab in preventing both first and subsequent cardiovascular events.
Main Methods:
- Secondary analysis of the randomized, double-blind FOURIER trial involving 27,564 patients on statin therapy.
- Patients were followed for a median of 2.2 years, comparing evolocumab to placebo.
- Total cardiovascular events, including myocardial infarction, stroke, and revascularization, were analyzed between treatment arms.
Main Results:
- Evolocumab reduced total primary end point (PEP) events by 18% (incidence rate ratio [RR], 0.82; P < .001), encompassing both first and subsequent events.
- For every 1000 patients treated for 3 years, evolocumab prevented 52 total PEP events compared to placebo.
- Significant reductions in total myocardial infarctions (RR, 0.74), strokes (RR, 0.77), and coronary revascularizations (RR, 0.78) were observed with evolocumab.
Conclusions:
- Adding evolocumab to statin therapy significantly reduces total cardiovascular events, including myocardial infarction and stroke.
- The benefit of evolocumab extends to preventing subsequent events, more than doubling the number of prevented events compared to analyses of first events only.
- These findings support the continued use of aggressive lipid-lowering therapy with PCSK9 inhibitors to mitigate recurrent cardiovascular risk.
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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