Introduction: The Paradigm of Atrial Fibrillation-Mediated Cardiomyopathy
Atrial fibrillation-mediated cardiomyopathy (AFCM) represents a critical and often reversible subset of heart failure (HF) with reduced ejection fraction (HFrEF). In these patients, the arrhythmia itself—either through rapid ventricular rates, loss of atrial kick, or irregular rhythm—is the primary driver of ventricular dysfunction. Historically, once the rhythm is controlled and the left ventricular ejection fraction (LVEF) normalizes, clinicians have been faced with a therapeutic dilemma: should HF pharmacotherapy be continued indefinitely, or can it be safely withdrawn?
Current guidelines largely extrapolate from studies like TRED-HF, which examined dilated cardiomyopathy (DCM) and found high rates of relapse after medication withdrawal. However, AFCM is pathophysiologically distinct, as the inciting trigger (atrial fibrillation) can often be definitively addressed via catheter ablation. The WITHDRAW-AF trial was designed to provide evidence-based clarity on whether de-prescribing is a viable path for these patients.
Highlights of the WITHDRAW-AF Trial
The trial brings forward several pivotal findings for the management of AFCM:
1. Maintenance of Function: 90% of patients who withdrew HF therapy maintained an LVEF ≥50% at six months, compared to 100% in the continued therapy group.
2. Methodological Rigor: The use of Cardiac Magnetic Resonance (CMR) as the primary assessment tool ensures high precision in measuring ventricular volumes and function.
3. Clinical Stability: There were no significant differences in NT-proBNP levels, functional capacity, or quality of life between those on and off HF medications.
4. Successful Rhythm Control: With 97% of participants having undergone catheter ablation, the study underscores the importance of a durable rhythm control strategy as a prerequisite for medication withdrawal.
Study Design and Methodology
The WITHDRAW-AF trial was a multi-center, randomized, crossover trial conducted between 2021 and 2024. It enrolled 60 patients with a history of persistent AF (duration <1 year) and documented AFCM who had achieved LVEF normalization (LVEF ≥50%) and maintained sinus rhythm for at least six months following rhythm control interventions.
Participants were randomized 1:1 into two groups:
– Group A (Early Withdrawal): Staged withdrawal of HF therapy (beta-blockers, ACE inhibitors/ARBs/ARNIs, and MRAs) over a short period, followed by 6 months of observation.
– Group B (Delayed Withdrawal): Continued HF therapy for 6 months, followed by a crossover to staged withdrawal for the subsequent 6 months.
The primary endpoint was the maintenance of CMR-derived LVEF ≥50% at the 6-month mark. Secondary endpoints included changes in left ventricular end-diastolic volume index (LVEDVi), global longitudinal strain (GLS), NT-proBNP levels, 6-minute walk distance, and Minnesota Living with Heart Failure Questionnaire (MLHFQ) scores.
Key Findings and Statistical Analysis
The trial results provide a reassuring signal for clinicians considering medication de-escalation in this specific cohort. At the end of the initial 6-month randomized phase, LVEF was maintained at ≥50% in 90% of the withdrawal group versus 100% of the continued therapy group. The odds ratio (OR) was 1.18 (95% CI 0.27-2.82, P = .47), indicating no statistically significant difference in the risk of LVEF decline.
Cardiac Imaging and Remodeling
CMR data showed that mean LVEF remained stable across both groups. At 6 months, Group A (off therapy) had a mean LVEF of 58%, while Group B (on therapy) had a mean LVEF of 59% (P = .236). Furthermore, there were no adverse signals in terms of cardiac remodeling; left ventricular volumes and mass remained within normal limits regardless of medication status. Transthoracic echocardiography (TTE) performed at various intervals corroborated these findings, showing no significant variation in diastolic function or strain parameters.
Biomarkers and Functional Outcomes
NT-proBNP, a sensitive marker for ventricular wall stress and HF status, remained low and stable throughout the study. Similarly, patients reported no decline in quality of life or functional capacity. The 6-minute walk distance and MLHFQ scores were comparable between the groups, suggesting that the symptomatic benefits of LVEF recovery are maintained even without the support of traditional HF pharmacotherapy, provided sinus rhythm is preserved.
Arrhythmia Recurrence and Safety
A critical component of the study was the monitoring of AF burden. Since the cardiomyopathy is rhythm-mediated, recurrence of AF would theoretically pose a risk of LVEF decline. However, the trial reported that AF burden remained extremely low across the population, likely due to the high efficacy of catheter ablation (utilized in 97% of cases). This highlights that the safety of medication withdrawal is inextricably linked to the success of the rhythm control strategy.
Clinical Discussion and Expert Commentary
The WITHDRAW-AF trial addresses a significant gap in the management of recovered HFrEF. While the TRED-HF trial previously cautioned against medication withdrawal in non-ischemic DCM, the WITHDRAW-AF findings suggest that AFCM may be a ‘curable’ form of heart failure where the hemodynamic trigger is the primary driver. If the trigger is removed and rhythm stability is ensured, the neurohormonal blockade provided by HF medications may no longer be mandatory.
However, several nuances must be considered. First, the study population was relatively young (median age 60) and had a relatively short duration of persistent AF (<1 year) before intervention. This suggests that the 'window of reversibility' is key. Patients with decades of AF and significant atrial or ventricular fibrosis may not exhibit the same resilience upon medication withdrawal.
Furthermore, while the primary endpoint was met, the trial was not powered to detect rare adverse events or long-term outcomes beyond 12 months. Clinicians should exercise caution in patients with significant co-morbidities, such as hypertension or coronary artery disease, where beta-blockers or ACE inhibitors may be indicated for reasons other than LVEF support.
Conclusion
The WITHDRAW-AF trial provides evidence that for patients with AF-mediated cardiomyopathy who achieve sinus rhythm and LVEF normalization, staged withdrawal of heart failure therapy is generally safe and does not lead to a significant decline in cardiac function within 6 to 12 months. This shifts the clinical focus toward aggressive rhythm control—primarily through catheter ablation—as a means to not only improve symptoms but potentially liberate patients from lifelong polypharmacy. Future research should focus on longer-term follow-up and identifying specific biomarkers that can predict which patients are at highest risk for relapse upon withdrawal.
Funding and Clinical Trials
This trial was supported by various academic and clinical research grants. ClinicalTrials.gov Identifier: NCT04825626.
References
1. 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. 2026;47(2):250-262.
2. Halliday BP, Tan RS, Adeyemi JS, et al. Withdrawal of pharmacological treatment for HF with recovered LVEF (TRED-HF): an open-label, pilot, randomised trial. Lancet. 2019;393(10166):61-73.
3. Prabhu S, Taylor AJ, Costello BT, et al. Catheter Ablation Versus Medical Rate Control in Atrial Fibrillation and Systolic Dysfunction: The CAMERA-MRI Study. J Am Coll Cardiol. 2017;70(16):1949-1961.
4. Packer M. Arrhythmia-induced cardiomyopathy: JACC State-of-the-Art Review. J Am Coll Cardiol. 2020;75(23):2927-2935.
