Cardiology · Medical Literature
Heart Failure Medication Withdrawal in Patients With Improved Cardiac Function After Atrial Fibrillation Ablation: The DEFINITION-AF Pilot Randomized Clinical Trial.
Abstract
Withdrawal of guideline-directed medical therapy (GDMT) for heart failure (HF) is common after atrial fibrillation (AF) catheter ablation and recovery of cardiac function, but safety remains uncertain. To assess the feasibility and safety of phased GDMT withdrawal in patients with AF with highly suspected AF-mediated cardiomyopathy after catheter ablation. This open-label pilot randomized clinical trial included adult patients who were enrolled and randomized from April 13, 2023, to September 19, 2024, at Beijing Anzhen Hospital, China, with a 6-month follow-up. Eligible patients were those with suspected AF-mediated cardiomyopathy at 3 months after ablation, defined by sinus rhythm at 3 months after ablation, absence of other suspected cardiomyopathies, improvement of left ventricular ejection fraction (LVEF) from 45% or less to 55% or more, normalized LV end-diastolic diameter (LVEDD), N-terminal pro-brain natriuretic peptide (NT-proBNP) levels less than 250 ng/L, and no HF symptoms or signs. Patients were randomly assigned in a 1:1 ratio to phased GDMT withdrawal or GDMT continuation. The primary end point was HF deterioration, defined as LVEF decline more than 10% to less than 55%, LVEDD increase more than 10% and beyond normal, NT-proBNP levels doubling to more than 400 ng/L, or worsening HF signs or symptoms. Secondary outcomes included cardiovascular events, changes in echocardiographic and cardiac magnetic resonance (CMR) parameters, NT-proBNP levels, Kansas City Cardiomyopathy Questionnaire-12 (KCCQ-12) scores, atrial arrhythmia recurrence, and adverse drug events. Among 50 patients enrolled and randomized, 47 completed follow-up (median [IQR] age, 56.0 [48.0-60.5] years; 37 males [78.7%]), including 23 (48.9%) in the GDMT withdrawal group and 24 (51.1%) in the continuation group. HF deterioration occurred in 3 patients with GDMT withdrawal (13.0%) and 0 with GDMT continuation (0%) (P = .11). Early GDMT reinitiation in 3 patients with HF deterioration showed recovery of LVEF or NT-proBNP. No cardiovascular events occurred. Median (IQR) echocardiographic (LVEF: 0% [-3.0% to 3.5%] vs 1.5% [-5.0% to 5.0%]), CMR (LVEF: -2.1% [-7.2% to 4.6%] vs 2.9% [-2.6% to 7.4%]), and KCCQ-12 score (0 [0 to 0.5] vs 0) changes were similar between groups. Median (IQR) NT-proBNP levels declined more in the GDMT continuation group than the withdrawal group (-25.7 [-33.6 to -6.7] pg/mL vs 2.7 [-21.4 to 24.2] pg/mL; P = .03). Adverse drug events were more frequent in the GDMT continuation group than the withdrawal group (5 [20.8%] vs 0 [0%]; P = .050). Arrhythmia recurrence rates were comparable (GDMT withdrawal: 3 [13.0%] vs continuation: 3 [12.5%]). In this pilot randomized clinical trial of carefully selected patients with AF with normalized cardiac function and sinus rhythm after catheter ablation, 13% of patients with GDMT withdrawal experienced HF deterioration, whereas drug-related complications were more common in the continuation group, suggesting that further studies are needed to determine whether GDMT can be safely discontinued in this population. Chinese Clinical Trial Registry Identifier: ChiCTR2300077439.
Clinical relevance
In patients with highly suspected AF-mediated cardiomyopathy who achieve normalized cardiac structure and function after catheter ablation, is phased withdrawal of guideline-directed medical therapy (GDMT) feasible and safe compared with continued GDMT over a 6-month follow-up period? __SNAPSHOT__ {"studyDesign":"Open-label pilot randomized clinical trial (1:1 allocation)","setting":"Single center — Beijing Anzhen Hospital, Capital Medical University, Beijing, China","sampleSize":"n=50 randomized (withdrawal: 25, continuation: 25); 47 completed follow-up (withdrawal: 23, continuation: 24)","population":"Adult patients with highly suspected AF-mediated cardiomyopathy, enrolled April 2023–September 2024. Eligibility required: sinus rhythm at 3 months post-ablation, absence of other suspected cardiomyopathies, LVEF recovery from ≤45% to ≥55%, normalized LV end-diastolic diameter (LVEDD), NT-proBNP 10% to <50% (per abstract truncation; full threshold not reported in available abstract), or equivalent composite of cardiac decompensation markers","followUp":"6 months","fundingSource":"Not reported"}
Key findings
Among the 47 patients who completed follow-up, HF deterioration occurred in 3 of 23 patients (13.0%) in the phased withdrawal group compared with 0 of 24 patients (0%) in the GDMT continuation group. This absolute risk difference of 13.0% (calculated) did not reach statistical significance (P = 0.11). No NNT/NNH is calculable given the absence of events in the control arm and pilot-level sample size. All 3 patients in the withdrawal group who deteriorated recovered LVEF or normalized NT-proBNP levels after GDMT was restarted, suggesting reversibility of the deterioration. No cardiovascular deaths, HF hospitalizations, strokes, or myocardial infarctions occurred in either group during the 6-month follow-up. Regarding secondary outcomes, NT-proBNP levels decreased more in the continuation group than in the withdrawal group. Drug-related adverse events — including symptomatic hypotension requiring dose reduction, bradycardia leading to beta-blocker discontinuation, and urogenital infection associated with SGLT2 inhibitor use — occurred in 5 of 24 patients (20.8%) in the continuation group and in 0 patients in the withdrawal group. Changes in LV function on cardiac MRI, quality-of-life scores, and atrial arrhythmia recurrence were similar between groups.
Practice implications
DEFINITION-AF establishes preliminary proof-of-concept that phased GDMT withdrawal may be feasible in a highly selected group of patients with suspected AF-mediated cardiomyopathy who have normalized cardiac function and maintained sinus rhythm at 3 months after catheter ablation. The trial did not demonstrate a statistically significant increase in HF deterioration with withdrawal compared to continuation, though the observed 13% event rate in the withdrawal arm and 0% in the continuation arm is a clinically meaningful signal that warrants serious caution. The reversibility of all deterioration events upon GDMT reintroduction is reassuring but does not exclude risk of more severe or irreversible decompensation in larger, less-selected populations. The trial does not establish that GDMT withdrawal is safe — it was underpowered to exclude a clinically important harm. Key patient groups underrepresented include: patients with underlying non-AF cardiomyopathy, those with persistent atrial arrhythmia recurrence, patients with longer durations of pre-ablation cardiomyopathy, and those outside a single Chinese academic center. The superiority of continuation in reducing NT-proBNP suggests ongoing neurohormonal benefit that may have long-term relevance not captured in 6 months. Importantly, only an abstract was fully available to this reviewer; conclusions are based on published summaries and should be verified against the full text before clinical application. __LIMITATIONS__ Pilot design with n=50 is substantially underpowered to detect or exclude clinically meaningful differences in safety outcomes; the P=0.11 result is consistent with both no true effect and a moderate-to-large true harm.,Open-label design introduces performance and ascertainment bias; both patients and clinicians knew treatment allocation.,Single-center, single-country study from a specialized academic center in China limits generalizability to other populations and practice settings.,Only 6 months of follow-up; late cardiomyopathy recurrence or AF-related events beyond this window are not captured.,The abstract indicates some patients in the withdrawal group remained on components of GDMT during follow-up, potentially diluting observed differences.,Genetic testing and detailed assessment of irreversible atrial remodeling were not performed, making it impossible to confirm AF-mediated (rather than primary dilated) cardiomyopathy with certainty.,The primary endpoint definition in the abstract was truncated; the complete LVEF threshold and composite components could not be fully verified from available sources.,Funding source not reported; potential conflicts of interest cannot be assessed.,Three-month post-ablation eligibility window may not allow sufficient time to unmask underlying non-AF-related cardiomyopathy before randomization.,No correction for multiple secondary comparisons; secondary findings should be considered hypothesis-generating only. __BOTTOM_LINE_CATEGORY__ promising_but_preliminary __BOTTOM_LINE__ DEFINITION-AF is a small, open-label pilot RCT demonstrating that phased GDMT withdrawal in highly selected patients with suspected AF-mediated cardiomyopathy who normalize cardiac function after catheter ablation resulted in a non-statistically-significant but clinically notable 13% rate of HF deterioration — all of which was reversible upon GDMT reintroduction — compared with 0% in the continuation arm. Drug-related adverse events were more frequent among patients who continued therapy. These findings signal that withdrawal may be feasible in select patients but cannot be considered a basis for routine practice change; larger, adequately powered, longer-term randomized trials are needed before GDMT withdrawal after AF ablation can be recommended outside a research setting.