Frailty, Guideline-Directed Medical Therapy, and Outcomes in HFrEF: From the GUIDE-IT Trial

Muhammad Shahzeb Khan, Matthew W. Segar, Muhammad Shariq Usman, Sumitabh Singh, Stephen J. Greene, Gregg C. Fonarow, Stefan D. Anker, G. Michael Felker, James L. Januzzi, Javed Butler, Ambarish Pandey

Research output: Contribution to journalArticlepeer-review

7 Scopus citations


Objectives: In this study, we sought to evaluate the association of frailty with the use of optimal guideline-directed medical therapy (GDMT) and outcomes in heart failure with reduced ejection fraction (HFrEF). Background: The burden of frailty in HFrEF is high, and the patterns of GDMT use according to frailty status have not been studied previously. Methods: A post hoc analysis of patients with HFrEF enrolled in the GUIDE-IT (Guiding Evidence-Based Therapy Using Biomarker Intensified Treatment in Heart Failure) trial was conducted. Frailty was assessed with the use of a frailty index (FI) using a 38-variable deficit model, and participants were categorized into 3 groups: class 1: nonfrail, FI <0.21); class 2: intermediate frailty, FI 0.21-0.31), and class 3: high frailty, FI >0.31). Multivariate-adjusted Cox models were used to study the association of frailty status with clinical outcomes. Use of optimal GDMT over time (beta-blockers, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, and mineralocorticoid receptor antagonists) across frailty strata was assessed with the use of adjusted linear and logistic mixed-effect models. Results: The study included 879 participants, of which 56.3% had high frailty burden (class 3 FI). A higher frailty burden was associated with a significantly higher risk of HF hospitalization or death in adjusted Cox models: high frailty vs nonfrail HR: 1.76, 95% CI: 1.20-2.58. On follow-up, participants with high frailty burden also had a significantly lower likelihood of achieving optimal GDMT: high frailty vs non-frail GDMT triple therapy use at study end: 17.7% vs 28.4%; P interaction, frailty class × time <0.001. Conclusions: Patients with HFrEF with a high burden of frailty have a significantly higher risk for adverse clinical outcomes and are less likely to be initiated and up-titrated on an optimal GDMT regimen.

Original languageEnglish (US)
Pages (from-to)266-275
Number of pages10
JournalJACC: Heart Failure
Issue number4
StatePublished - Apr 2022


  • frailty
  • guideline-directed medical therapy
  • heart failure with reduced ejection fraction
  • mortality

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine


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