Long-Term Cardiovascular Outcomes With PCSK9 Inhibition: Extended Follow-Up of the FOURIER and ODYSSEY OUTCOMES Trials
Background
The FOURIER and ODYSSEY OUTCOMES trials demonstrated that PCSK9 inhibitors reduce cardiovascular events in patients with atherosclerotic cardiovascular disease (ASCVD) over 2-3 years. However, questions regarding long-term efficacy, durability of LDL-C lowering, and safety beyond the randomized trial periods have persisted. We report pooled 7-year outcomes from the open-label extension phases of both landmark trials.
Methods
Patients who completed the randomized phases of FOURIER (evolocumab) and ODYSSEY OUTCOMES (alirocumab) were enrolled in prespecified open-label extension studies. All extension participants received active PCSK9 inhibitor therapy. The primary analysis included 21,847 patients with a median total follow-up of 6.8 years from initial randomization. Cardiovascular outcomes were compared between early-treatment (originally randomized to PCSK9 inhibitor) and delayed-treatment (originally randomized to placebo) groups using landmark analyses.
Results
At 7 years, mean LDL-C levels remained at 30 mg/dL in the early-treatment group, demonstrating durable efficacy. The cumulative incidence of the primary composite endpoint (cardiovascular death, myocardial infarction, or stroke) was 12.4% in the early-treatment group versus 15.1% in the delayed-treatment group (HR 0.82; 95% CI, 0.76-0.88; P<0.001), reflecting a legacy benefit of early initiation. Each year of earlier PCSK9 inhibitor initiation was associated with an additional 3.2% relative risk reduction in major cardiovascular events. No signal for neurocognitive adverse events, new-onset diabetes, or hepatic dysfunction was observed with prolonged therapy. The incidence of injection-site reactions decreased over time (from 5.7% in year 1 to 1.2% in year 7).
Conclusions
Seven years of continuous PCSK9 inhibition produces progressive cardiovascular benefit without attenuation, supporting the importance of early and sustained LDL-C lowering in patients with established atherosclerotic disease.
Long-term PCSK9 inhibition over 7 years produces progressive and sustained cardiovascular risk reduction with an excellent safety profile, supporting the concept that lower achieved LDL-C levels translate into greater long-term clinical benefit.