Long-Term Evolocumab in Patients With Established Atherosclerotic Cardiovascular Disease

• Published in: Circulation (New York, N.Y.) Vol. 146; no. 15; pp. 1109 - 1119
• Main Authors: O'Donoghue, Michelle L., Giugliano, Robert P., Wiviott, Stephen D., Atar, Dan, Keech, Anthony, Kuder, Julia F., Im, KyungAh, Murphy, Sabina A., Flores-Arredondo, Jose H., López, J. Antonio G., Elliott-Davey, Mary, Wang, Bei, Monsalvo, Maria Laura, Abbasi, Siddique, Sabatine, Marc S.
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 11.10.2022
• Subjects: Antibodies, Monoclonal - adverse effects; Antibodies, Monoclonal, Humanized; Anticholesteremic Agents - adverse effects; Atherosclerosis - chemically induced; Atherosclerosis - drug therapy; Cardiovascular Diseases - chemically induced; Cardiovascular Diseases - drug therapy; Cholesterol, LDL; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors - therapeutic use; Myocardial Infarction - epidemiology; PCSK9 Inhibitors; Proprotein Convertase 9; Stroke - epidemiology; Subtilisins - therapeutic use; Treatment Outcome; PCSK9 inhibitors; cardiovascular diseases; cholesterol, LDL; evolocumab
• ISSN: 0009-7322; 1524-4539; 1524-4539
• DOI: 10.1161/CIRCULATIONAHA.122.061620

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.