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Randomized Controlled Trial
. 2026 Jan 7;47(2):250-262.
doi: 10.1093/eurheartj/ehaf563.

Withdrawal of heart failure therapy after atrial fibrillation rhythm control with ejection fraction normalization: the WITHDRAW-AF trial

Louise Segan  1   2   3   4   5 , Peter M Kistler  1   2   3   4   5   6 , Shane Nanayakkara  1   2   4   5 , Andrew Taylor  1   2   3   7 , James Hare  1   2 , Benedict Costello  1   8 , David Chieng  1   2   3   4   5 , Rose Crowley  1   2   3   4   5 , Jeremy William  1   2   3   4   5 , Hariharan Sugumar  1   2   3   4   5 , Kenneth Cho  1   2   3 , Aleksandr Voskoboinik  1   2   3   4   5 , Liang-Han Ling  1   2   3   9 , Ziporah Nderitu  1   2 , Sonia Azzopardi  1   2 , Annie Curtin  1   2 , Manuja Premaratne  4 , Alex J McLellan  3   6   7   9 , Justin Mariani  1   2   9 , Joseph B Morton  3   6   7 , Geoffrey Lee  3   6   7   10 , Stephen Joseph  5   8 , Christopher Reid  11 , David M Kaye  1   2   4 , Jonathan M Kalman  3   6   7 , Sandeep Prabhu  1   2   3   4   10   12
Affiliations
Randomized Controlled Trial

Withdrawal of heart failure therapy after atrial fibrillation rhythm control with ejection fraction normalization: the WITHDRAW-AF trial

Louise Segan et al. Eur Heart J. .

Abstract

Background and aims: Atrial fibrillation-mediated cardiomyopathy (AFCM) represents an important reversible cause of left ventricular systolic dysfunction. Current clinical practice is indefinite heart failure (HF) pharmacotherapy despite left ventricular ejection fraction (LVEF) normalization. However, whether this is necessary to maintain normal LVEF, in addition to rhythm control, is uncertain.

Methods: This multi-centre, randomized trial conducted between 2021 and 2024 examined the impact of staged withdrawal of HF therapy following AF rhythm control and LVEF normalization in AFCM. Participants were randomized (1:1) to early withdrawal (Group A) or continued therapy for 6 months followed by delayed withdrawal (Group B), in a crossover design. The primary endpoint was the randomized comparison of cardiac magnetic resonance (CMR) LVEF maintenance ≥50% at 6 months, during which time Group A had withdrawn therapy and Group B remained on treatment. Secondary outcomes included cardiac remodelling, functional status, biomarkers, quality of life, and arrhythmia recurrence on vs off HF therapy. The total follow-up duration was 12 months.

Results: Between July 2021 and May 2024, 60 patients were enrolled (age 60 [55-65] years, previous persistent AF <1 year and maintaining sinus rhythm for minimum 6 months following AF rhythm control [catheter ablation in 97%]). All participants completed treatment withdrawal and 12-month follow-up. In the initial randomized comparison, LVEF was maintained ≥50% at 6 months in 90% of participants undergoing HF therapy withdrawal (Group A), compared with 100% who continued medical therapy (Group B) (odds ratio [OR] 1.18, 95% confidence interval [CI] 0.27-2.82, P = .47). CMR LVEF was similar between randomization groups at the end of the randomization phase (Group A: LVEF 58% [95% CI 54-60] vs Group B: LVEF 59% [95% CI 55-64], P = .236) and across study time points (mixed effects P = .37). Transthoracic echocardiography characteristics, N-terminal pro-B-type natriuretic peptide, functional status, quality of life and AF burden were similar on vs off HF therapy in the overall population.

Conclusions: Withdrawal of HF therapy following AF rhythm control for prior AFCM and recovered LVEF was not associated with a decline in LVEF for most patients in the following 6 months.

Keywords: AF-mediated cardiomyopathy; Arrhythmia-induced cardiomyopathy; Atrial fibrillation; Catheter ablation; Clinical trial; Heart failure therapy; Normalized left ventricular ejection fraction.

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Figures

Structured Graphical Abstract
Structured Graphical Abstract
In individuals with presumed atrial fibrillation-mediated cardiomyopathy and normalized left ventricular ejection fraction (LVEF) following AF rhythm control, staged withdrawal of heart failure (HF) therapy was feasible, with 90% maintaining LVEF ≥50% and stable left ventricular systolic function at long-term follow-up (f/u). Those who relapsed showed prompt recovery after therapy re-initiation, supporting a cautious, individualized withdrawal approach in selected patients. CMR, cardiac magnetic resonance; LGE, late gadolinium enhancement; LV, left ventricular; OR, odds ratio; TTE, transthoracic echocardiography.
Figure 1
Figure 1
Study protocol. Participants were randomized to either initial medication withdrawal (top) or continued medical therapy (bottom) for 6 months, followed by double crossover to the alternate treatment arm. Participants who demonstrated maintenance of left ventricular ejection fraction (LVEF) ≥50% following medication withdrawal were offered the option to remain off heart failure (HF) therapy for a further 12 months following study completion in a pre-specified long-term follow-up sub-analysis with transthoracic echocardiography performed 12 months following study completion to monitor long-term LVEF off HF pharmacotherapy
Figure 2
Figure 2
Comparison of left ventricular ejection fraction (LVEF) according to randomization and across study time points. Before rhythm control refers to LVEF at left ventricular systolic dysfunction (LVSD) diagnosis. Timing of catheter ablation was not mandated by the study protocol and varied across participants. Study enrolment occurred following sustained sinus rhythm and LVEF normalization, and subsequent time points reflect standardized study assessments. LVEF was then assessed across study time points and included: enrolment (termed ‘baseline’), 6 months, 12 months and long-term LVEF according to allocation. (A) corresponds to Group A with initial medication withdrawal and (B) corresponds to Group B, who underwent medication withdrawal at 6 months. Red symbols correspond to values 6 months post-medication withdrawal
Figure 3
Figure 3
Median left ventricular ejection fraction (LVEF) at left ventricular systolic dysfunction (LVSD) diagnosis, at study enrolment and at long-term follow-up. LVEF before rhythm, at study enrolment and at long-term follow-up in the overall study sample. This combined LVEF measures from Group A and Group B across these time points
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