Agents with vasodilator properties in acute heart failure: how to design successful trials

Agents with vasodilator properties in acute heart failure: how to design successful trials

Alexandre Mebazaa1,2,3*, Dan Longrois4, Marco Metra5, Christian Mueller6, Arthur Mark Richards7,8, Lothar Roessig9, Marie France Seronde10, Naoki Sato11, Norman Stockbridge12,Wendy Gattis Stough13, Angeles Alonso14, Robert J. Cody15, Nancy Cook Bruns9, Mihai Gheorghiade16, Johannes Holzmeister17, Said Laribi18†, and Faiez Zannad19†. European Journal of Heart Failure (2015) 17, 652–664

Source: 1University Paris Diderot, Sorbonne Paris Cité, Paris, France; 2U942 INSERM, AP-HP, Paris, France; 3APHP, Department of Anesthesia and Critical Care, Hôpitaux Universitaires Saint Louis-Lariboisière, Paris, France; 4Département d’Anesthésie-Réanimation, Hôpital Bichat-Claude Bernard, University Paris Diderot, Sorbonne Paris Cité, Paris, U1148 INSERM, Paris, France; 5Cardiology, University of Brescia, Brescia, Italy; 6Department of Cardiology, University Hospital Basel, Basel, Switzerland; 7Cardiovascular Research Institute, National University of Singapore, Singapore; 8Yong Loo Lin School of Medicine, National University of Singapore, Singapore; 9Global Clinical Development, Bayer Pharma AG, Berlin, Germany; 10Department of Cardiology, University Hospital of Besançon, U942 INSERM, Besançon, France; 11Internal Medicine, Cardiology, and Intensive Care Medicine, Nippon Medical School Musashi-Kosugi Hospital, Kanagawa, Japan; 12Division of Cardiovascular and Renal Products, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA; 13Campbell University College of Pharmacy and Health Sciences, NC, USA; 14Scientific Advice Working Party European Medicines Agency, Madrid, Spain; 15Janssen Research and Development, Raritan, NJ, USA; 16Department of Medicine, Center for Cardiovascular Innovation, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; 17Cardiorentis AG, Zug, Switzerland; 18APHP, Department of Emergency Medicine, Hôpitaux Universitaires Saint Louis-Lariboisière, INSERM U942, Paris, France; and 19INSERM, Centre d’Investigation Clinique 9501 and Unité 961, Centre Hospitalier Universitaire, and the Department of Cardiology, Nancy University, Université de Lorraine, Nancy, France

Abstract: Agents with vasodilator properties (AVDs) are frequently used in the treatment of acute heart failure (AHF). AVDs rapidly reduce preload and afterload, improve left ventricle to aorta and right ventricle to pulmonary artery coupling, and may improve symptoms. Early biomarker changes after AVD administration have suggested potentially beneficial effects on cardiac stretch, vascular tone, and renal function. AVDs that reduce haemodynamic congestion without causing hypoperfusion might be effective in preventing worsening organ dysfunction. Existing AVDs have been associated with different results on outcomes in randomized clinical trials, and observational studies have suggested that AVDs may be associated with a clinical outcome benefit. Lessons have been learned from past AVD trials in AHF regarding preventing hypotension, selecting the optimal endpoint, refining dyspnoea measurements, and achieving early randomization and treatment initiation. These lessons have been applied to the design of ongoing pivotal clinical trials, which aim to ascertain if AVDs improve clinical outcomes. The developing body of evidence suggests that AVDs may be a clinically effective therapy to reduce symptoms, but more importantly to prevent end-organ damage and improve clinical outcomes for specific patients with AHF. The results of ongoing trials will provide more clarity on the role of AVDs in the treatment of AHF.