Effect of Frailty on Cardiovascular Clinical Trials: A Systematic Review and Meta-Analysis

Haowen Jiang; Jie Jun Wong; Ru-San Tan; Fei Gao; Louis Ly Teo; Jordan B Strom; Chim C Lang; Angela S Koh

doi:10.1016/j.jacadv.2025.101889

Effect of Frailty on Cardiovascular Clinical Trials: A Systematic Review and Meta-Analysis

JACC Adv. 2025 Jun 23;4(7):101889. doi: 10.1016/j.jacadv.2025.101889. Online ahead of print.

Authors

Haowen Jiang¹, Jie Jun Wong¹, Ru-San Tan², Fei Gao², Louis Ly Teo², Jordan B Strom³, Chim C Lang⁴, Angela S Koh⁵

Affiliations

¹ National Heart Centre Singapore, Singapore.
² National Heart Centre Singapore, Singapore; Duke-National University of Singapore Medical School, Singapore.
³ Richard A. and Susan F. Smith Center for Outcomes Research in Cardiology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
⁴ Division of Molecular and Clinical Medicine, School of Medicine, University of Dundee Ninewells Hospital and Medical School, Dundee, United Kingdom; National University of Malaysia, Bangi, Malaysia.
⁵ National Heart Centre Singapore, Singapore; Duke-National University of Singapore Medical School, Singapore. Electronic address: angela.koh.s.m@singhealth.com.sg.

PMID: 40555009
DOI: 10.1016/j.jacadv.2025.101889

Abstract

Background: Patients with cardiovascular (CV) diseases are increasingly frail but rarely represented in trials. Understanding effect modification by frailty on CV trials is critical as it could help define treatment strategies in frail patients.

Objectives: This meta-analysis aims to assess the implications of frailty on CV outcomes in clinical trials.

Methods: Randomized controlled trials examining the effects of frailty in the context of CV trials were included (CRD42024528279). Outcomes included a composite of major adverse cardiac events (MACE), all-cause mortality, CV mortality, hospitalizations, and frailty-specific outcomes (physical, quality of life, and frailty scores). HRs and 95% CIs were pooled for clinical endpoints, and standardized mean differences (SMDs) were calculated for frailty-specific outcomes.

Results: Thirty unique randomized controlled trials were included with a pooled total of 87,711 participants. Frail patients had a significantly increased risk of MACE (HR: 2.33 [95% CI: 1.87-2.91], P < 0.001, I² = 83%), all-cause mortality (HR: 2.34 [95% CI: 1.80-3.05], P < 0.01, I² = 75%), CV mortality (HR: 1.76 [95% CI: 1.60-1.93], P < 0.001, I² = 0%), and hospitalizations (HR: 2.38 [95% CI: 1.65-3.43], P < 0.001, I² = 92%) compared to nonfrail patients. In the frailest group, trial interventions decreased MACE (HR: 0.81 [95% CI: 0.74-0.88], P < 0.001, I² = 0%) and hospitalization (HR: 0.81 [95% CI: 0.72-0.90], P < 0.001, I² = 0%) risks with no significant difference in mortality risk (P > 0.05) compared with the control group. Trial interventions significantly improved physical (SMD: 0.15, 0.04-0.26) and quality of life (SMD: 0.15, 0.09-0.21) but not frailty scores (P > 0.05).

Conclusions: While frailty prognosticated a higher risk of CV events and mortality, frailty did not reduce treatment efficacy. CV trial interventions appear beneficial even in the frailest group.

Keywords: cardiovascular disease; clinical trials; frailty.