Key result
GDMT withdrawal in complete recovery resulted in 27/140 (19.3%) adverse events vs 2/76 (2.6%) with continuation, while rhythm control reduced CV death (RR 0.65, 95% CI 0.50-0.84).
Why the study?
Heart failure with improved ejection fraction (HFimpEF) represents a heterogeneous state of remission rather than a cure, and the safety of withdrawing guideline-directed medical therapy (GDMT) after LVEF recovery remains uncertain.
Does withdrawing or de-escalating guideline-directed medical therapy after LVEF recovery increase relapse and adverse events compared to continuation in patients with heart failure with improved ejection fraction?
Meta-Analysis (n=24,520)
Does withdrawing or de-escalating guideline-directed medical therapy after LVEF recovery increase relapse and adverse events compared to continuation in patients with heart failure with improved ejection fraction?
Current evidence is insufficient to establish the long-term safety of withdrawing guideline-directed medical therapy in patients with heart failure with improved ejection fraction, highlighting the need for adequately powered, phenotype-stratified randomized withdrawal trials.
Answers are grounded in this paper and cite their sources.
Supports continued GDMT after LVEF recovery in HFimpEF; extends remission concept and cautions against routine withdrawal.
(1) Background: Heart failure with improved ejection fraction (HFimpEF) is a heterogeneous state of remission rather than a cure; the safety of withdrawing guideline-directed medical therapy (GDMT) after left ventricular ejection fraction (LVEF) recovery remains uncertain. (2) Methods: PubMed/MEDLINE, Cochrane CENTRAL and the Cochrane Database of Systematic Reviews were searched to 9 November 2025, with citation searching. Forty-four studies were retained: 38 contributing extractable outcome data (approximately 6665 patients) and six unselected cohorts (17,855 patients) used descriptively. (3) Results: In an exploratory pooling of two rhythm control trials, cardiovascular death was less frequent (RR 0.65, 95% CI 0.50–0.84), whereas the estimate for worsening heart failure hospitalization (RR 0.75, 95% CI 0.63–0.90) was sensitive to the pooling model. An indirect cross-study comparison suggested differences in relapse after withdrawal but cannot establish causality. In the complete recovery subgroup, study-defined adverse events occurred in 27/140 patients after withdrawal versus 2/76 with continuation; differing designs and definitions limit interpretation. The withdrawal-specific predictive performance of biomarkers remains unvalidated. (4) Conclusions: Current evidence is insufficient to establish the long-term safety of GDMT withdrawal in any etiological phenotype. Recovery evidence must be distinguished from direct withdrawal evidence, and adequately powered, phenotype-stratified randomized withdrawal trials are needed.
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Fronea et al. (2026) conducted a meta-analysis in Heart failure with improved ejection fraction (HFimpEF) (n=24,520). Guideline-directed and targeted therapy de-escalation/withdrawal (and rhythm control in exploratory pooling) vs. Therapy continuation was evaluated on Study-defined adverse events in the complete recovery subgroup (and cardiovascular death in rhythm control trials) (RR 0.65, 95% CI 0.50-0.84). GDMT withdrawal in complete recovery resulted in 27/140 (19.3%) adverse events vs 2/76 (2.6%) with continuation, while rhythm control reduced CV death (RR 0.65, 95% CI 0.50-0.84).
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