Beyond the map—the challenges and considerations in designing studies exploring uncharted territory

This commentary refers to ‘Withdrawal of heart failure therapy after atrial fibrillation rhythm control with ejection fraction normalization: the WITHDRAW-AF trial’, by L. Segan et al., https://doi.org/10.1093/eurheartj/ehaf563 and the discussion piece ‘Withdrawal of HF therapy in recovered AF-mediated cardiomyopathy: clarifying trial designs’, by L. Fauchier and T. Lenormand, https://doi.org/10.1093/eurheartj/ehag285. We thank the authors for their thoughtful commentary1 on the WITHDRAW-AF trial2 and the methodological aspects of the study design. We agree that the study findings provide preliminary insights into the feasibility and short-term safety of structured withdrawal of guideline-directed medical therapy (GDMT) for heart failure in a carefully selected population with presumed AF-mediated cardiomyopathy. While we recognize the authors’ use of the term ‘superiority-to-detect-harm’ as a conceptual description focusing on clinically important deterioration, we would emphasize that this terminology does not reflect the intended trial design. WITHDRAW-AF was not framed within a comparative efficacy paradigm, but rather as a feasibility study prioritizing patient safety and early detection of relapse under intensive monitoring conditions. Accordingly, the absence of excess relapse should be interpreted as supportive of feasibility under strict conditions, rather than as evidence of comparative effectiveness between continuation and withdrawal strategies.