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Original Contribution
March 28, 2007

Short-term Clinical Effects of Tolvaptan, an Oral Vasopressin Antagonist, in Patients Hospitalized for Heart Failure: The EVEREST Clinical Status Trials

Author Affiliations

Author Affiliations: Division of Cardiology, Northwestern University, Feinberg School of Medicine, Chicago, Ill (Dr Gheorghiade); Division of Cardiology, Tufts-New England Medical Center, Boston, Mass (Drs Konstam and Udelson); Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minn (Dr Burnett); Departments of Biometrics (Dr Ouyang) and Clinical Development (Drs Zimmer and Orlandi), Otsuka Maryland Research Institute, Rockville; Department of Biostatistics and Medical Informatics, University of Wisconsin, Madison (Dr Cook); Departmento de Diagnostico y Tratamiento, Servicio de Hemodinamia, Hospital Italiano, Buenos Aires, Argentina (Dr Grinfeld); Associazione Nazionale Medici Cardiologi Ospedalieri Research Center, Florence, Italy (Dr Maggioni); Sahlgrenska University Hospital/Östra, Gothenburg, Sweden (Dr Swedberg); and Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d’Investigations Cliniques, Nancy, France (Dr Zannad).

JAMA. 2007;297(12):1332-1343. doi:10.1001/jama.297.12.1332

Context Heart failure causes more than 1 million US hospitalizations yearly, mostly related to congestion. Tolvaptan, an oral, nonpeptide, selective vasopressin V2-receptor antagonist, shows promise in this condition.

Objective To evaluate short-term effects of tolvaptan when added to standard therapy in patients hospitalized with heart failure.

Design, Setting, and Patients Two identical prospective, randomized, double-blind, placebo-controlled trials at 359 sites in North America, South America, and Europe were conducted during the inpatient period of the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST) between October 7, 2003, and February 3, 2006. A total of 2048 (trial A) and 2085 (trial B) patients hospitalized with heart failure and congestion were studied.

Intervention Patients were randomized to receive either tolvaptan (30 mg/d) or matching placebo, within 48 hours of admission.

Main Outcome Measures Primary end point was a composite of changes in global clinical status based on a visual analog scale and body weight at day 7 or discharge if earlier. Secondary end points included dyspnea (day 1), global clinical status (day 7 or discharge), body weight (days 1 and 7 or discharge), and peripheral edema (day 7 or discharge).

Results Rank sum analysis of the composite primary end point showed greater improvement with tolvaptan vs placebo (trial A, mean [SD], 1.06 [0.43] vs 0.99 [0.44]; and trial B, 1.07 [0.42] vs 0.97 [0.43]; both trials P<.001). Mean (SD) body weight reduction was greater with tolvaptan on day 1 (trial A, 1.71 [1.80] vs 0.99 [1.83] kg; P<.001; and trial B, 1.82 [2.01] vs 0.95 [1.85] kg; P<.001) and day 7 or discharge (trial A, 3.35 [3.27] vs 2.73 [3.34] kg; P<.001; and trial B, 3.77 [3.59] vs 2.79 [3.46] kg; P<.001), whereas improvements in global clinical status were not different between groups. More patients receiving tolvaptan (684 [76.7%] and 678 [72.1%] for trial A and trial B, respectively) vs patients receiving placebo (646 [70.6%] and 597 [65.3%], respectively) reported improvement in dyspnea at day 1 (both trials P<.001). Edema at day 7 or discharge improved significantly with tolvaptan in trial B (P = .02) but did not reach significance in trial A (P = .07). Serious adverse event frequencies were similar between groups, without excess renal failure or hypotension.

Conclusion In patients hospitalized with heart failure, oral tolvaptan in addition to standard therapy including diuretics improved many, though not all, heart failure signs and symptoms, without serious adverse events.

Trial Registration clinicaltrials.gov Identifier: NCT00071331

Trial Registration Published online March 25, 2007 (doi:10.1001/jama.297.12.1332).