Effects of tolvaptan on dyspnoea relief from the EVEREST trials.

AIMS To describe the effects of tolvaptan therapy on dyspnoea relief based on timing of delivery, influence of concomitant therapies, and baseline patient and clinical characteristics. Also, the influence of clinical trial design on dyspnoea measurement, from the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) trials. METHODS AND RESULTS Post hoc analysis was performed based on the endpoint of patient-assessed dyspnoea. Changes from baseline at inpatient Day 1 were compared between treatment groups by the van Elteren test. Pre-determined subgroup analyses were also performed. Tolvaptan's effects are greatest within 12 h after first dose with an additional, but modest dyspnoea improvement benefit irrespective of time after admission. Overall, patients continue to report dyspnoea improvement up to 60 h after admission. The window of enrolment, up to 48 h after admission, combined with measurement on 'Day 1' led to a wide range over when dyspnoea was assessed. CONCLUSION Post hoc analysis suggests that tolvaptan modestly improves dyspnoea compared with standard therapy alone, regardless if given early or relatively late after hospitalization, and also across major pre-specified subgroups, despite ongoing background therapy aimed at relieving signs and symptoms. Significant variability around when dyspnoea was assessed, in addition to the persistence of dyspnoea despite ongoing background therapy, may influence how future clinical trials assess dyspnoea in acute heart failure syndromes.

[1]  A. Cohen-Solal,et al.  Levosimendan vs dobutamine for patients with acute decompensated heart failure: the SURVIVE Randomized Trial. , 2007, JAMA.

[2]  C. O'connor,et al.  Rationale and study design for a multicenter, randomized, double-blind, placebo-controlled study of the effects of tolvaptan on the acute and chronic outcomes of patients hospitalized with worsening congestive heart failure. , 2003, American heart journal.

[3]  M. Gheorghiade,et al.  A proposal to standardize dyspnoea measurement in clinical trials of acute heart failure syndromes: the need for a uniform approach. , 2008, European heart journal.

[4]  K. Swedberg,et al.  Short-term clinical effects of tolvaptan, an oral vasopressin antagonist, in patients hospitalized for heart failure: the EVEREST Clinical Status Trials. , 2007, JAMA.

[5]  K. Swedberg,et al.  Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the EVEREST Outcome Trial. , 2007, JAMA.

[6]  J. Ornato,et al.  ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult—Summary Article , 2005 .

[7]  J. Teerlink Dyspnea as an end point in clinical trials of therapies for acute decompensated heart failure. , 2003, American heart journal.

[8]  C. O'connor,et al.  Effects of tezosentan on symptoms and clinical outcomes in patients with acute heart failure: the VERITAS randomized controlled trials. , 2007, JAMA.

[9]  J. Cleland,et al.  Clinical trials update: highlights of the scientific sessions of the XXIII Congress of the European Society of Cardiology — WARIS II, ESCAMI, PAFAC, RITZ‐1 and TIME , 2001, European journal of heart failure.

[10]  P. Poole‐Wilson Intravenous nesiritide vs nitroglycerin for treatment of decompensated congestive heart failure: a randomized controlled trial. , 2002 .

[11]  M. Packer Revive Ii: Multicenter Placebo-controlled Trial of Levosimendan on Clinical Status in Acutely Decompensated Heart Failure , 2005 .

[12]  James B. Young Intravenous nesiritide vs nitroglycerin for treatment of decompensated congestive heart failure: A randomized controlled trial , 2002 .

[13]  R. Califf,et al.  Short-term intravenous milrinone for acute exacerbation of chronic heart failure: a randomized controlled trial. , 2002, JAMA.

[14]  Gerhard Nahler,et al.  Committee for Proprietary Medicinal Products (CPMP) , 2009 .

[15]  K. Adams,et al.  Characteristics and outcomes of patients hospitalized for heart failure in the United States: rationale, design, and preliminary observations from the first 100,000 cases in the Acute Decompensated Heart Failure National Registry (ADHERE). , 2005, American heart journal.

[16]  C. Yancy Climbing the mountain of acute decompensated heart failure: the EVEREST Trials. , 2007, JAMA.

[17]  J. Cleland,et al.  Clinical trials update from Heart Rhythm 2008 and Heart Failure 2008: ATHENA, URGENT, INH study, HEART and CK‐1827452 , 2008, European journal of heart failure.