Evolution of natriuretic peptide biomarkers in heart failure: Implications for clinical care and clinical trials

Abstract

Natriuretic peptides (NPs) are recommended by international guidelines to exclude non-heart failure causes of acute dyspnea and to assess prognosis. NPs are commonly used as an entry criterion for clinical trials, to minimize enrollment of misdiagnosed patients, or to ensure enrollment of a sufficiently at-risk population. NP values used to select trial populations to date have been inconsistent across studies. Future trials should consider using standardized thresholds for NP levels, with protocol-specified adaptations appropriate for the specific study and patient population to account for factors that can influence the NP level. NPs have been used as an endpoint for proof-of-concept or phase 2 clinical trials, although it is important to remember that positive results in early phase studies may be unstable due to small numbers and the play of chance, and they are not always reproducible in phase 3 trials. Likewise, failure to reduce NP in phase 2 may not necessarily indicate that a drug will be ineffective on clinical outcomes in phase 3. NP guided therapy has been intensively studied, but the clinical outcome benefits of this approach remain uncertain. Neprilysin inhibitors have stimulated further exploration of the NP system and how it influences, and is potentially influenced by, heart failure therapies. This paper discusses the utility of NPs in the current clinical research and practice environment and addresses areas in need of further research from the perspectives of academic clinical trialists, clinicians, biostatisticians, regulators, and pharmaceutical industry scientists who participated in the 13th Global Cardiovascular Clinical Trialists Forum.