By Michael H. Crawford, MD, Editor
Synopsis: A small trial of withdrawing guideline-directed medical therapy (GDMT) for reduced ejection fraction (EF) heart failure in patients with atrial fibrillation in whom EF recovered after restoration of normal sinus rhythm has shown that withdrawal of GDMT was not associated with a decline in EF over 12 months in most patients.
Source: Segan L, Kistler PM, Nanayakkara S, et al. Withdrawal of heart failure therapy after atrial fibrillation rhythm control with ejection fraction normalization: The WITHDRAW-AF trial. Eur Heart J. 2025; Aug 12. doi.org/10.1093/eurheartj/ehaf563. [Online ahead of print].
In atrial fibrillation (AF)-induced cardiomyopathy (AFCM), left ventricular ejection fraction (EF) usually normalizes after restoration of normal sinus rhythm (NSR), yet guidelines recommend the continuation of guideline-directed medical therapy (GDMT) for heart failure irrespective of the etiology. However, in the case of AFCM with the return of normal EF in NSR, is this really necessary?
To answer this question, a multicenter, open-label, cross-sectional, randomized trial with blinded endpoint determination was conducted at four centers in Australia. The aim of the WITHDRAW-AF trial was to determine the effect of short-term withdrawal of GDMT in patients with AFCM whose EF returned to normal with restoration of NSR predominantly by ablation (97%). Enrollment criteria were EF < 40% during AF for six or more months; taking at least two GDMT agents, including loop diuretics; EF had normalized (50% or more) with restoration of NSR; being asymptomatic; being euvolemic; having no late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR) imaging; and having a N-terminal pro-B-type natriuretic peptide (NT-proBNP) < 250 ng/L. Excluded were patients who needed beta-blockers or renin-angiotensin-aldosterone system blockers for other reasons, had significant renal dysfunction, or had moderate or more valve disease.
Enrolled patients were randomized to immediate withdrawal of GDMT or withdrawal delayed for six months. GDMT medications were sequentially weaned over 12 weeks and then the patients were observed for six months. Following repeat EF determination by echocardiography, the two groups were crossed over to the other arm so that each subject served as their own control. Any hypertension was managed with amlodipine. The primary outcome was maintenance of EF ≥ 50% at six months post-GDMT withdrawal. Various secondary outcomes were assessed, including recurrent AF, which was assessed by a single lead electrocardiogram recording twice a week or loop recorders where applicable. Analysis was by intention-to-treat.
Between 2021 and 2024, 60 patients were enrolled (30 in each group; mean age 60 years, 18% women). In the initial randomized comparison, EF remained ≥ 50% in 90% of the patients with GDMT withdrawn and in 100% of those in whom GDMT was maintained (odds ratio [OR], 1.18; 95% confidence interval [CI], 0.27-2.82; P = 0.47). After crossover, 93% of the patients with GDMT withdrawn maintained an EF ≥ 50%. Among the secondary outcomes, heart rate and blood pressure increased after withdrawal, but there were no significant changes in NT-proBNP, symptoms, or quality of life. Over 12 months of follow-up, EF remained ≥ 50% in 91% of the patients and AF recurred in 43% of the patients. Those whose EF decreased to < 50% had no symptoms and did not experience any adverse clinical events over 12 months. The authors concluded that in most patients with AFCM in whom NSR is restored, withdrawing GDMT was not associated with a decline in EF or the development of heart failure symptoms.
Commentary
GDMT has risks, such as bradycardia, hypotension, reduced renal function, adverse drug effects, and the risk of falls. Also, GDMT is costly, especially if it is continued indefinitely. Previous studies, such as TRED-HF, have shown that more than one-third of patients with dilated cardiomyopathy and normalized EF on GDMT will relapse if it is withdrawn, but few patients in these studies had AF. Thus, the WITHDRAW-AF study is of interest and suggests that withdrawing GDMT in AFCM patients with EF normalization after restoration of NSR is safe and potentially desirable. However, we must take into consideration that this was a highly selective patient population.
Patients with alternative causes of reduced EF were excluded by CMR. All the patients had a normal EF for six months and were not in clinical heart failure before GDMT was withdrawn. Interestingly, if the patients were subgrouped into those with and without an EF < 30% in AF, this did not predict who was going to relapse when taken off GDMT. A predictor of relapses was a WITHDRAW-AF average enrollment EF of 52% in those who relapsed vs. 58% in those who did not (P < 0.001). This is not surprising, since 50% to 55% EF is a gray zone and is more sensitive to errors in measurement. Thus, perhaps an EF of > 55% would be a better determinant of who could be taken off GDMT.
There were significant limitations to the WITHDRAW-AF study. The total number of patients was small and highly selective. Consequently, a larger study with extended follow-up is warranted. Also, they did not assess the effect of withdrawing SGLT2 inhibitors, since they were not in wide use at the time of the study. In addition, the use of short ECG samples twice per week may have underestimated AF recurrence. Finally, the absence of LGE on CMR may not exclude all potential causes of cardiomyopathy.
Michael H. Crawford, MD, is Professor Emeritus of Medicine and Consulting Cardiologist, UCSF Health, San Francisco.
