Short-term clinical effects of tolvaptan, an oral vasopressin antagonist, in patients hospitalized for heart failure

The EVEREST clinical status trials

The Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST) Investigators

Research output: Contribution to journalArticle

606 Citations (Scopus)

Abstract

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, doubleblind, 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.

Original languageEnglish (US)
Pages (from-to)1332-1343
Number of pages12
JournalJournal of the American Medical Association
Volume297
Issue number12
DOIs
StatePublished - Mar 28 2007

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Heart Failure
Clinical Trials
Placebos
Body Weight
Dyspnea
Edema
Outcome Assessment (Health Care)
Antidiuretic Hormone Receptor Antagonists
tolvaptan
Vasopressin Receptors
South America
North America
Vasopressins
Visual Analog Scale
Diuretics
Hypotension
Signs and Symptoms
Renal Insufficiency
Weight Loss
Inpatients

All Science Journal Classification (ASJC) codes

  • Medicine(all)

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Short-term clinical effects of tolvaptan, an oral vasopressin antagonist, in patients hospitalized for heart failure : The EVEREST clinical status trials. / The Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST) Investigators.

In: Journal of the American Medical Association, Vol. 297, No. 12, 28.03.2007, p. 1332-1343.

Research output: Contribution to journalArticle

The Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST) Investigators. / Short-term clinical effects of tolvaptan, an oral vasopressin antagonist, in patients hospitalized for heart failure : The EVEREST clinical status trials. In: Journal of the American Medical Association. 2007 ; Vol. 297, No. 12. pp. 1332-1343.
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title = "Short-term clinical effects of tolvaptan, an oral vasopressin antagonist, in patients hospitalized for heart failure: The EVEREST clinical status trials",
abstract = "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, doubleblind, 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.",
author = "{The Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST) Investigators} and Mihai Gheorghiade and Konstam, {Marvin A.} and Burnett, {John C.} and Liliana Grinfeld and Maggioni, {Aldo P.} and Karl Swedberg and Udelson, {James E.} and Faiez Zannad and Thomas Cook and John Ouyang and Christopher Zimmer and Cesare Orlandi and M. Konstam and J. Burnett and A. Maggioni and A. Miller and C. O’connor and Bahit, {M. C.} and P. Carson and M. Haass and R. Patten and Paul Hauptman and I. Pena and M. Metra and R. Oren and S. Roth and J. Sackner-Bernstein and S. Goldstein and H. Dargie and D. Demets and K. Dickstein and B. Greenberg and J. Lerman and B. Massie and B. Pitt and R. Bechhofer and S. Anderson and J. C.burnett and J. Udelson and Dieterich, {H. A.} and Z. Capkova and F. Gadaleta and M. Mule and Principato, {M. B.} and R. Benza and K. Vijay and M. Goldberg and R. Siegel and Y. Aude and U. Elkayam",
year = "2007",
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doi = "10.1001/jama.297.12.1332",
language = "English (US)",
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TY - JOUR

T1 - Short-term clinical effects of tolvaptan, an oral vasopressin antagonist, in patients hospitalized for heart failure

T2 - The EVEREST clinical status trials

AU - The Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST) Investigators

AU - Gheorghiade, Mihai

AU - Konstam, Marvin A.

AU - Burnett, John C.

AU - Grinfeld, Liliana

AU - Maggioni, Aldo P.

AU - Swedberg, Karl

AU - Udelson, James E.

AU - Zannad, Faiez

AU - Cook, Thomas

AU - Ouyang, John

AU - Zimmer, Christopher

AU - Orlandi, Cesare

AU - Konstam, M.

AU - Burnett, J.

AU - Maggioni, A.

AU - Miller, A.

AU - O’connor, C.

AU - Bahit, M. C.

AU - Carson, P.

AU - Haass, M.

AU - Patten, R.

AU - Hauptman, Paul

AU - Pena, I.

AU - Metra, M.

AU - Oren, R.

AU - Roth, S.

AU - Sackner-Bernstein, J.

AU - Goldstein, S.

AU - Dargie, H.

AU - Demets, D.

AU - Dickstein, K.

AU - Greenberg, B.

AU - Lerman, J.

AU - Massie, B.

AU - Pitt, B.

AU - Bechhofer, R.

AU - Anderson, S.

AU - C.burnett, J.

AU - Udelson, J.

AU - Dieterich, H. A.

AU - Capkova, Z.

AU - Gadaleta, F.

AU - Mule, M.

AU - Principato, M. B.

AU - Benza, R.

AU - Vijay, K.

AU - Goldberg, M.

AU - Siegel, R.

AU - Aude, Y.

AU - Elkayam, U.

PY - 2007/3/28

Y1 - 2007/3/28

N2 - 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, doubleblind, 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.

AB - 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, doubleblind, 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.

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U2 - 10.1001/jama.297.12.1332

DO - 10.1001/jama.297.12.1332

M3 - Article

VL - 297

SP - 1332

EP - 1343

JO - JAMA - Journal of the American Medical Association

JF - JAMA - Journal of the American Medical Association

SN - 0002-9955

IS - 12

ER -