Long-Term Evolocumab in Patients With Established Atherosclerotic Cardiovascular Disease

Author:

O’Donoghue Michelle L.1ORCID,Giugliano Robert P.1ORCID,Wiviott Stephen D.1ORCID,Atar Dan23,Keech Anthony1,Kuder Julia F.1,Im KyungAh1,Murphy Sabina A.1,Flores-Arredondo Jose H.4,López J. Antonio G.4ORCID,Elliott-Davey Mary5,Wang Bei4,Monsalvo Maria Laura4,Abbasi Siddique4,Sabatine Marc S.1ORCID

Affiliation:

1. TIMI 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.).

2. Department of Cardiology, Oslo University Hospital Ulleval, Norway (D.A.).

3. Institute of Clinical Medicine, University of Oslo, Norway (D.A.).

4. Global Development, Amgen, Thousand Oaks, CA (J.H.F.-A., J.A.G.L., B.W., M.L.M., S.A.).

5. Amgen Ltd, Cambridge, United Kingdom (M.E.-D.).

Abstract

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.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Physiology (medical),Cardiology and Cardiovascular Medicine

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