Methodological Issues in Outpatient Worsening Heart Failure Research

We read with great interest the prospective analysis by McCambridge et al. on the management and outcomes of worsening heart failure (WHF) in the outpatient setting (ESC Heart Fail. 2025; doi: 10.1002/ehf2.15400). The authors should be commended for addressing an important and timely topic. However, I would like to highlight several issues that may limit the interpretation and generalizability of the findings. First, the study applied two different definitions of WHF: (a) a prespecified, objective definition requiring symptoms of worsening together with clinical signs of congestion and/or supportive biomarker or imaging evidence, and (b) a broader, subjective definition based solely on senior physician judgment when the objective criteria were not met. Notably, about 16% of patients were included under this discretionary pathway. Such heterogeneity increases the risk of misclassification and makes it difficult to compare results with other registries and trials. Recent international consensus statements have underlined the need for a single, standardized definition of WHF to ensure comparability and external validity across studies.1, 2 Second, the investigation was monocentric and included 234 patients over 19 months. While the prospective design is a strength, the limited sample size and the setting in a specialized heart failure clinic restrict broader applicability, particularly in health systems without comparable ambulatory infrastructure. Moreover, patients managed in emergency departments without hospitalization were excluded, potentially omitting a clinically relevant subset. Third, the finding that fewer than half of patients with reduced ejection fraction were on optimal guideline-directed medical therapy (GDMT) at baseline is striking. Underuse of foundational therapies—angiotensin receptor–neprilysin inhibitors, beta-blockers, mineralocorticoid receptor antagonists, and sodium-glucose cotransporter-2 inhibitors—likely contributed to the high recurrence rate (24.5% at 3 months). Contemporary data demonstrate that full implementation of GDMT significantly reduces adverse outcomes in HFrEF, underscoring the need for rigorous therapeutic optimization.3 Another point concerns the definition of ‘clinical stability’, which relied largely on symptom resolution and physical examination. Despite treatment, natriuretic peptide values remained markedly elevated at ‘stability’, suggesting persistent subclinical congestion. This highlights the limitations of purely clinical assessment and supports the integration of objective tools such as natriuretic peptide–guided strategies, echocardiographic congestion indices, or novel remote haemodynamic monitoring technologies to more accurately define stability and prevent early relapse.4, 5 In conclusion, while this prospective study contributes valuable insight into the management of outpatient WHF, its methodological constraints—variable definitions, limited sample size, exclusion of non-clinic patients, and suboptimal GDMT—should temper interpretation. Future multicentre investigations incorporating standardized diagnostic criteria, comprehensive GDMT implementation, and objective markers of stability are needed to guide practice and improve outcomes in this high-risk population. This letter was prepared with the assistance of GPT-5 (OpenAI) solely for English language editing, as I am a native French speaker. The intellectual content is entirely my own.