HF Drug Withdrawal After AF Ablation Shows Mixed Safety Signals

Atrial fibrillation (AF) and heart failure (HF) frequently coexist, and each condition can worsen the other through mechanisms such as tachycardia, atrioventricular dyssynchrony, and impaired atrial contraction.¹ When AF is the primary driver of cardiomyopathy—so-called AF-mediated cardiomyopathy—catheter ablation can restore sinus rhythm and normalize left ventricular ejection fraction (LVEF) in many patients. Once cardiac function recovers, however, clinicians and patients have little prospective evidence to guide decisions about whether HF medications can be safely reduced or discontinued.

A new pilot randomized clinical trial, DEFINITION-AF, published in JAMA Network Open, provides early prospective evidence on this question, although its findings suggest that the decision is far from straightforward.

“Prolonged GDMT [guideline-directed medical therapy] may cause adverse effects and increase costs. In clinical practice, HF medication discontinuation is common in patients with AF with improved cardiac function following ablation, yet its safety has not been well evaluated,” wrote the researchers of the study. “Therefore, we conducted a pilot randomized clinical trial to assess the feasibility and safety of phased GDMT withdrawal in patients with HF with improved ejection fraction (HFimpEF) following successful AF catheter ablation.”

Investigators at Beijing Anzhen Hospital in China enrolled 50 adults with suspected AMC who, 3 months after catheter ablation, had normalized LVEF (> 55%, up from < 45% before ablation), normal left ventricular end-diastolic diameter, low N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, sinus rhythm, and no HF symptoms. In this single-center, open-label pilot trial, participants were randomized 1:1 to phased GDMT withdrawal—medications tapered or discontinued stepwise every 2 weeks—or to continued therapy and were followed for 6 months. The primary end point was HF deterioration, defined using thresholds consistent with the earlier TRED-HF pilot trial (NCT02859311) in recovered dilated cardiomyopathy.

Among the 47 patients who completed follow-up, HF deterioration occurred in 3 of 23 patients (13.0%) in the withdrawal group compared with none of 24 patients in the continuation group, a difference that did not reach statistical significance (P = .11). All 3 patients who deteriorated experienced recovery of LVEF or NT-proBNP levels after GDMT was restarted. No cardiovascular deaths, HF hospitalizations, strokes, or myocardial infarctions occurred in either group.

Secondary outcomes provided additional signals regarding potential trade-offs between continuation and withdrawal. NT-proBNP levels improved more in the continuation group than in the withdrawal group, and blood pressure rose more modestly among patients who stopped medications. At the same time, adverse drug events—including symptomatic hypotension, bradycardia, and a urogenital infection associated with a sodium-glucose cotransporter 2 (SGLT2) inhibitor—occurred in 5 of 24 patients (20.8%) who continued therapy compared with none of those who withdrew treatment (P = .050). Arrhythmia recurrence rates were similar between groups, at approximately 13%.

Context From Prior Research

DEFINITION-AF's design deliberately mirrors TRED-HF, a UK pilot trial that tested phased HF medication withdrawal in patients with recovered dilated cardiomyopathy rather than AF-mediated disease.² In TRED-HF, approximately 44% of patients who withdrew treatment relapsed within 6 months, considerably higher than the 13% observed in DEFINITION-AF. The contrast suggests that the underlying cause of cardiac recovery—reversible, arrhythmia-driven dysfunction vs primary dilated cardiomyopathy—may influence the risk of relapse after GDMT withdrawal, although cross-trial comparisons should be interpreted cautiously because of differences in patient populations and study designs.

Managed Care Implications

For managed care organizations, the trial highlights a familiar tension between reducing polypharmacy-related costs and adverse events and maintaining protection against disease relapse. GDMT for HF—including angiotensin receptor-neprilysin inhibitors, β-blockers, mineralocorticoid receptor antagonists, and SGLT2 inhibitors—carries meaningful direct costs and demonstrated measurable adverse drug events in this small cohort, particularly hypotension.¹ A strategy that could safely reduce medication burden in appropriately selected patients may help alleviate both cost and tolerability concerns.

However, with only 50 patients and a nonsignificant primary end point, DEFINITION-AF alone is insufficient to support changes in coverage or utilization management decisions. Any consideration of GDMT withdrawal should likely be limited to highly selected patients resembling those enrolled in the trial—those with normalized imaging, low natriuretic peptide levels, and sustained sinus rhythm—and should involve close clinical monitoring, since early detection and rapid GDMT reinitiation appeared to reverse HF deterioration in this cohort. Larger, adequately powered trials will be needed before withdrawal protocols could reasonably inform formulary policy or quality metrics.

The investigators also noted that the study's small sample size, single-center design, and relatively short follow-up limit the generalizability of the findings and preclude definitive conclusions regarding the safety of GDMT withdrawal.

“In this pilot randomized clinical trial of selected patients with AF with normalized cardiac function and sinus rhythm after catheter ablation, 3 of 23 patients (13%) with phased GDMT withdrawal had HF deterioration compared with 0% among those who continued GDMT,” wrote the researchers. “Drug-related complications were more likely in those who continued GDMT. Further larger studies with longer follow-up are needed to determine whether GDMT can be safely discontinued in this population.”

References

1. Li S, Sun Y, Lai Y, et al. Heart failure medication withdrawal in patients with improved cardiac function after atrial fibrillation ablation: the DEFINITION-AF pilot randomized clinical trial. JAMA Netw Open. 2026;9(6):e2620145. doi:10.1001/jamanetworkopen.2026.20145
2. Halliday BP, Wassall R, Lota AS, et al. Withdrawal of pharmacological treatment for heart failure in patients with recovered dilated cardiomyopathy (TRED-HF): an open-label, pilot, randomized trial. Lancet. 2019;393(10166):61-73