Pharmacological reasons that may explain why randomized clinical trials have failed in acute heart failure syndromes

Acute heart failure (AHF) represents a clinical challenge as it encloses a heterogeneous group of syndromes (AHFS) with different pathophysiology, clinical presentations, prognosis and response to therapy. In the last 25 years multiple therapeutic targets have been identified and numerous new drugs were evaluated but, up to now, all failed to demonstrate a consistent benefit on clinical outcomes. Moreover, a repeated finding has been the poor correlation between the encouraging results of preclinical and early clinical trials and the lack of effect on outcomes observed in phase III trials. We review several possible pharmacological reasons that may explain the lack of success to develop new drugs and the pharmacological challenges to overcome in the future to develop new more effective and safer drugs for the treatment of AHFS.