Abstract and Introduction
Abstract
The last decade of acute heart failure (HF) research is characterized by disappointments in large phase 2 and 3 pharmacologic studies of therapeutics including calcium-sensitizing agents and antagonists of endothelin, vasopressin, and adenosine. As a result, pharmacologic management for acute HF has changed little in recent years, and adverse event rates remain higher than in chronic HF. Despite neutral results in many acute HF trials, recent studies including RELAX-AHF, ASTRONAUT, and PRONTO have highlighted the role of appropriate timing of patient enrollment, targeting the "right" patients, and selecting appropriate end points and sites. We describe lessons learned from recent trials in acute HF and outline strategies to improve the potential for success in future trials. This review is based on discussions between scientists, clinical trialists, and regulatory representatives at the 9th Global Cardio Vascular Clinical Trialists Forum in Paris, France, from November 30 to December 1, 2012.
Introduction
The last decade of acute heart failure (HF) research is characterized by disappointments in large phase 2 and 3 pharmacologic studies of therapeutics including B-type natriuretic peptide (BNP) agonists and antagonists of endothelin, vasopressin, and adenosine. As a result, management for acute HF has changed little in the recent years, and most guidelines are based on consensus rather than evidence. Hospitalization for HF represents a critical juncture for patients because their event rates are more than twice those of individuals without recent hospitalization. Greater than one-third of patients hospitalized with HF will be rehospitalized or dead within 90 days after discharge. Although recent progress in characterizing patients with acute HF has occurred, evidence for strategies to reduce their postdischarge event rate is sparse. However, several recent studies have highlighted the importance of appropriate timing of patient enrollment, targeting the "right" patients, and selecting appropriate end points and sites. We describe lessons learned from recent acute HF trials and outline strategies to improve the chance for success in future trials. We discuss the large-scale randomized trials of RELAXin in Acute HF (RELAX-AHF) and the Aliskiren Trial on Acute Heart Failure Outcomes (ASTRONAUT) and the pilot study of clevidipine (PRONTO). These trials were selected based on recent publication or presentation status and their use in illustrating issues related to the design of acute HF trials. We included the PRONTO trial to discuss emergency department enrollment rather than specifics related to the investigational therapy. These discussions can be placed in the context of other reviews of neutral acute HF trials including studies of nesiritide, rolofylline, and ultrafiltration. This review is based on discussions between scientists, clinical trialists, and regulatory representatives at the 9th Global Cardio Vascular Clinical Trialists Forum in Paris, France, from November 30 to December 1, 2012.