Effects of tolvaptan on physician-assessed symptoms and signs in patients hospitalized with acute heart failure syndromes: Analysis from the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) Trials Peter S. Pang, MD, a,b Mihai Gheorghiade, MD, b Jamil Dihu, MD, c Karl Swedberg, MD, d Sadiya Khan, MD, e Aldo P. Maggioni, MD, f Liliana Grinfeld, MD, g Faiez Zannad, MD, h John C. Burnett, Jr, MD, i John Ouyang, PhD, j James E. Udelson, MD, k and Marvin A. Konstam, MD k Chicago, IL; Gothenburg, Sweden; Florence, Italy; Buenos Aires, Argentina; Nancy, France; Rochester, MN; Rockville, MD; and Boston, MA Background A rapid and sustained relief of heart failure (HF) symptoms and signs is an important goal of management in patients hospitalized for acute HF syndromes (AHFS). To date, no novel therapy in AHFS have been shown to improve signs and symptoms throughout hospitalization. This study explores the clinical effects of tolvaptan, a vasopressin-2-receptor antagonist, in addition to standard medical therapies on physician-assessed signs and symptoms in hospitalized AHFS patients. Methods The EVEREST trial randomized 4,133 patients admitted with worsening HF and reduced ejection fraction (≤40%) within 48 hours after hospital admission. On each inpatient day, investigators assessed dyspnea, orthopnea, fatigue, jugular venous distension (JVD), rales, and pedal edema by predefined ordinal scales. Responder analyses were performed for each sign and symptom, with significant clinical response defined as a change in one point on the measurement scale. Results Post hoc analysis demonstrated greater likelihood of clinical improvement in physician-assessed dyspnea, edema, orthopnea, and JVD among tolvaptan-treated subjects (P b .05) as early as inpatient day 1. This difference was observed throughout hospitalization only for JVD and orthopnea through day 3. Conclusion The addition of tolvaptan to standard therapy for AHFS improves physician-assessed signs and symptoms during hospitalization without serious adverse short- or long-term effects. (Am Heart J 2011;161:1067-72.) Acute heart failure (HF) syndromes (AHFS) patients are characterized by elevated left ventricular filling pressures and/or low cardiac output resulting in pulmo- nary and systemic congestion. 1 This volume-overload state manifests clinically by worsening symptoms and signs of HF, including dyspnea, jugular venous distension (JVD), rales, and edema. 1 These signs and symptoms are the primary reasons why patients present to the hospital for AHFS. In the United States, N1 million admissions for AHFS occur each year, accounting for N20 billion dollars per year and a high postdischarge rehospitalization and mortality rates, approaching 30% within 90 days. 2-4 A similar health care burden is seen throughout Europe in countries represented by the European Society of Cardiology. 5 The onset of symptoms, such as dyspnea and orthopnea, and signs, such as edema, may begin days if not weeks before admission. 4 Relief from these signs and symptoms is a major goal of in-hospital therapy and is currently accomplished primarily through use of intravenous loop From the a Department of Emergency Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, b Section of Experimental Therapeutics, Center for Cardiovascular Innovation, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, c Division of Cardiology, Advocate Lutheran General Hospital, University of Illinois at Chicago, Chicago, IL, d Department of Emergency and Cardiovascular Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden, e Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, f Associazione Nazionale Medici Cardiologi Ospedalieri Research Center, Florence, Italy, g Departmento de Diagnostico y Tratamiento, Servicio de Hemodinamia, Hospital Italiano, Buenos Aires, Argentina, h Centre d'Investigations Cliniques, Nancy, France, i Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, j Department of Biometrics, Otsuka Maryland Research Institute, Rockville, MD, and k Division of Cardiology, Tufts-New England Medical Center, Boston, MA. Submitted January 25, 2011; accepted February 16, 2011. Reprint requests: Mihai Gheorghiade, MD, FACC, Director of Experimental Therapeutics, Center for Cardiovascular Innovation, Professor of Medicine and Surgery, Northwestern University Feinberg School of Medicine, Co-director, Cardiovascular Center for Drug Development, Duke University, 645 N. Michigan Avenue, Suite 1006, Chicago, IL 60611. E-mail: m-gheorghiade@northwestern.edu 0002-8703/$ - see front matter © 2011, Mosby, Inc. All rights reserved. doi:10.1016/j.ahj.2011.02.027