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Randomized Controlled Trial
. 2025 Feb 11;85(5):504-512.
doi: 10.1016/j.jacc.2024.11.019.

Long-Term Lipid Lowering With Evolocumab in Older Individuals

Samer Al Said  1 , Michelle L O'Donoghue  1 , Xinhui Ran  1 , Sabina A Murphy  1 , Dan Atar  2 , Anthony Keech  3 , Jose H Flores-Arredondo  4 , Bei Wang  4 , Marc S Sabatine  1 , Robert P Giugliano  5
Affiliations
Randomized Controlled Trial

Long-Term Lipid Lowering With Evolocumab in Older Individuals

Samer Al Said et al. J Am Coll Cardiol. .

Abstract

Background: Concerns about the efficacy and safety of intensive low-density lipoprotein cholesterol lowering in older patients have led to weaker recommendations in the U.S. guidelines for patients ≥75 years of age compared to younger patients. Data are sparse on long-term benefits of proprotein convertase subtilisin/kexin type 9 inhibition in older patients.

Objectives: This study aims to assess the long-term benefit of evolocumab among patients aged ≥75 years.

Methods: The FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) trial randomized 27,564 patients who were 18 to 85 years of age with atherosclerotic cardiovascular disease to evolocumab vs placebo with 2.2 years of median follow-up. In the open-label extension (FOURIER-OLE), 6,635 participants were transitioned to open-label evolocumab for an additional 5-year median follow-up. The primary endpoint (cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization) was compared based on the original allocation to evolocumab vs placebo stratified by age (<75 vs ≥75 years). Analyses were underpowered for individual components of the composite endpoint. The annualized incidence rates for adverse events of interest were calculated for the OLE population across age groups during the parent FOURIER trial by randomized treatment arm and during the combined parent and FOURIER-OLE studies for patients originally allocated to evolocumab.

Results: Of 27,564 patients, 2,526 (9%) were ≥75 years of age at entry into FOURIER (median age: 77 years [Q1-Q3: 76-79 years]). The median follow-up in FOURIER and FOURIER-OLE was 7.1 years (Q1-Q3: 6.7-7.6 years), with a maximum of 8.7 years. Earlier initiation of evolocumab reduced the rate of the primary endpoint at least as well in older (HR: 0.79; 95% CI: 0.64-0.97) as in younger patients (HR: 0.86; 95% CI: 0.80-0.92; P interaction = 0.43). The absolute risk reductions were 5.4% (95% CI: -2.0% to 12.8%) in older and 2.3% (95% CI: 0.1%-4.5%) in younger patients, leading to numbers needed to treat of 19 and 44, respectively. The annualized incidence rates of safety events generally appeared similar across treatment arms in both age groups.

Conclusions: Early initiation of long-term evolocumab provides older patients with atherosclerotic cardiovascular disease cardiovascular benefits at least as good as those observed in younger patients, with a more favorable number needed to treat in older patients for reducing a composite endpoint and no significant safety concerns. These findings may be helpful in guiding future recommendations.

Keywords: elderly; evolocumab; lipid lowering therapy; older individuals; proprotein convertase subtilisin/kexin type 9 inhibitors.

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Conflict of interest statement

Funding Support and Author Disclosures The FOURIER and FOURIER OLE trials were funded by Amgen. Dr Al Said has received a postdoctoral grant from the German Research Foundation (GZ: SA 4598/2-1). Dr O’Donoghue has received grants from Amgen, Novartis, and AstraZeneca; and has received honoraria and/or Data and Safety Monitoring Board fees from Amgen, Novartis, AstraZeneca, Janssen, and Novo Nordisk. Ms Ran and Ms Murphy are members of the TIMI Study Group, which has received institutional research grant support through Brigham and Women’s Hospital from Abbott, Abiomed Inc, Amgen, Anthos Therapeutics, ARCA Biopharma Inc, AstraZeneca, Boehringer Ingelheim, Daiichi-Sankyo, Ionis Pharmaceuticals Inc, Janssen Research and Development LLC, MedImmune, Merck, Novartis, Pfizer, Regeneron Pharmaceuticals Inc, Roche, Saghmos Therapeutics Inc, Softcell Medical Limited, The Medicines Company, Verve Therapeutics Inc, and Zora Biosciences. Dr Atar has received speaker fees from Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, GlaxoSmithKline, Merck Sharp and Dohme, Novartis, Novo Nordisk, Pfizer, Pharmacosmos, Philips, Roche-Diagnostics, Sanofi, Takeda, and Vifor; and has received grant support (to the institution) from Bristol Myers Squibb/Pfizer, Medtronic, Bayer, and Roche-Diagnostics. Dr Keech has received grants and personal fees from Abbott and Mylan; and has received personal fees from Amgen, AstraZeneca, Pfizer, Sanofi, and Novartis. Drs Flores-Arredondo and Wang are employed by Amgen. Dr Sabatine has received research grants through Brigham and Women's Hospital from Abbott, Amgen, Anthos Therapeutics Inc, AstraZeneca, Boehringer Ingelheim, Daiichi-Sankyo, Ionis, Marea, Merck, Novartis, Pfizer, Saghmos Therapeutics, and Verve Therapeutics; and has received consulting fees from Amgen, AMPEL BioSolutions, Anthos Therapeutics Inc, AstraZeneca, Beren Therapeutics, Boehringer Ingelheim, Dr Reddy's Laboratories, Fibrogen, Merck, Moderna, Novo Nordisk, Precision BioSciences, and Silence Therapeutics. Dr Giugliano has received research support from Amgen, Daiichi-Sankyo, and Ionis; has received honoraria for lectures from Amgen, Big Sky Cardiology, Daiichi-Sankyo, Dr Reddy’s Laboratories, Medical Education Resources, Pfizer, SUMMEET, and Vox Media; and has received consulting fees from Amgen, AstraZeneca, Daiichi-Sankyo, Inventiva, and Sanofi.

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