Biomarker-Guided Versus Clinically Guided Fluid Management in Heart Failure: A Protocol for a Systematic Review and Meta-Analysis (Preprint)

BACKGROUND Fluid overload in heart failure (HF) remains a critical driver of morbidity and mortality. Current guideline-directed fluid management strategies based on clinical signs and symptoms lack sensitivity for the early detection of congestion. This limitation often leads to delayed interventions or suboptimal fluid removal, contributing to high rates of rehospitalization and poor patient outcomes. Biomarker-guided strategies, particularly using B-type natriuretic peptide (BNP) or N-terminal pro-BNP (NT-proBNP), offer a potential solution by providing objective, real-time feedback on hemodynamic stress. OBJECTIVE This study aims to conduct a systematic review and meta-analysis to evaluate the efficacy and safety of biomarker-guided fluid management compared to standard, clinically guided strategies in patients with HF. The primary objectives are to determine whether a biomarker-guided approach reduces all-cause mortality and HF-related hospitalizations. Secondary objectives include assessing the impact on renal function, quality of life, and changes in biomarker levels. METHODS We will conduct a systematic search of PubMed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and Web of Science from their inception to May 2025. We will include randomized controlled trials and prospective cohort studies that compare fluid management guided by BNP or NT-proBNP to clinically guided standard care in adult patients with HF. Two investigators will independently perform study selection, data extraction, and risk of bias assessment using the Cochrane Risk of Bias 2.0 (RoB 2) and the Risk Of Bias In Non-randomized Studies of Interventions (ROBINS-I) tools. The primary outcomes are all-cause mortality and HF-related hospitalizations. Secondary outcomes include worsening renal function, quality of life measured by validated questionnaires, and biomarker trajectory. Statistical analysis will be performed using RevMan 5.4. We will use a random-effects model for meta-analysis and conduct subgroup analyses based on HF phenotype (eg, reduced vs preserved ejection fraction) and biomarker type. RESULTS This study will synthesize the available evidence on the efficacy and safety of biomarker-guided fluid management in HF. The findings, based on outcomes such as mortality, hospitalization rates, renal function, and quality of life, will be submitted for publication in a peer-reviewed journal. CONCLUSIONS This systematic review will consolidate the current evidence for biomarker-guided fluid management in HF. The findings are expected to inform clinical guidelines and decision-making by providing a comprehensive assessment of the benefits and risks of this approach. Furthermore, this review will identify existing research gaps and suggest directions for future investigations to optimize fluid management strategies in this vulnerable patient population. CLINICALTRIAL PROSPERO CRD420250652134; https://www.crd.york.ac.uk/PROSPERO/view/CRD420250652134