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Long-Term Evolocumab in Patients With Established Atherosclerotic Cardiovascular Disease
Michelle L O'Donoghue1, Robert P Giugliano1, Stephen D Wiviott1
1TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (M.L.O., R.P.G., S.D.W., J.F.K., K.I., S.A.M., M.S.S.).
Insights
Long-term use of evolocumab significantly reduced cardiovascular events and deaths in high-risk patients. This PCSK9 inhibitor demonstrated sustained safety and efficacy over 8 years, showing no increased adverse events compared to placebo.
Area of Science:
- Cardiovascular Medicine
- Pharmacology
- Clinical Trials
Background:
- The FOURIER trial showed evolocumab reduced LDL-C and cardiovascular events.
- Long-term data on evolocumab's safety and efficacy were limited.
Purpose of the Study:
- To evaluate the long-term safety and efficacy of evolocumab in patients with atherosclerotic cardiovascular disease.
- To assess cardiovascular outcomes and adverse events over an extended period.
Main Methods:
- Patients from the FOURIER trial were enrolled in open-label extension studies (FOURIER-OLE).
- Data were pooled from US and European extension studies, with primary analyses focusing on adverse event incidence.
- Lipid values and major adverse cardiovascular events were prospectively collected over a median of 5.0 years of follow-up.
Main Results:
- Evolocumab treatment led to a median LDL-C of 30 mg/dL, with 63.2% achieving LDL-C <40 mg/dL.
- Long-term adverse event rates (serious AEs, muscle events, new diabetes, stroke, neurocognitive events) did not exceed placebo and showed no increase over time.
- Patients on evolocumab had a 15% lower risk of major adverse cardiovascular events and a 23% lower risk of cardiovascular death compared to placebo.
Conclusions:
- Long-term LDL-C lowering with evolocumab is safe and well-tolerated for over 8 years.
- Evolocumab demonstrated sustained cardiovascular risk reduction compared to delayed treatment initiation.
- The study supports the long-term benefit of evolocumab in high-risk cardiovascular patients.
Background:
In FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk), the proprotein convertase subtilisin-kexin type 9 inhibitor evolocumab reduced low-density lipoprotein cholesterol (LDL-C) and risk of cardiovascular events and was safe and well tolerated over a median of 2.2 years of follow-up. However, large-scale, long-term data are lacking.
Methods:
The parent FOURIER trial randomized 27 564 patients with atherosclerotic cardiovascular disease and LDL-C ≥70 mg/dL on statin to evolocumab versus placebo. Patients completing FOURIER at participating sites were eligible to receive evolocumab in 2 open-label extension studies (FOURIER-OLE [FOURIER Open-Label Extension]) in the United States and Europe; primary analyses were pooled across studies. The primary end point was the incidence of adverse events. Lipid values and major adverse cardiovascular events were prospectively collected.
Results:
A total of 6635 patients were enrolled in FOURIER-OLE (3355 randomized to evolocumab and 3280 to placebo in the parent study). Median follow-up in FOURIER-OLE was 5.0 years; maximum exposure to evolocumab in parent plus FOURIER-OLE was 8.4 years. At 12 weeks in FOURIER-OLE, median LDL-C was 30 mg/dL, and 63.2% of patients achieved LDL-C <40 mg/dL on evolocumab. Incidences of serious adverse events, muscle-related events, new-onset diabetes, hemorrhagic stroke, and neurocognitive events with evolocumab long term did not exceed those for placebo-treated patients during the parent study and did not increase over time. During the FOURIER-OLE follow-up period, patients originally randomized in the parent trial to evolocumab versus placebo had a 15% lower risk of cardiovascular death, myocardial infarction, stroke, or hospitalization for unstable angina or coronary revascularization (hazard ratio, 0.85 [95% CI, 0.75-0.96]; P=0.008); a 20% lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80 [95% CI, 0.68-0.93]; P=0.003); and a 23% lower risk of cardiovascular death (hazard ratio, 0.77 [95% CI, 0.60-0.99]; P=0.04).
Conclusions:
Long-term LDL-C lowering with evolocumab was associated with persistently low rates of adverse events for >8 years that did not exceed those observed in the original placebo arm during the parent study and led to further reductions in cardiovascular events compared with delayed treatment initiation.
Registration:
URL: https://www.
Clinicaltrials:
gov; Unique identifiers: NCT02867813 and NCT03080935.
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