European Heart Journal Advance Access published online on June 27, 2009
European Heart Journal, doi:10.1093/eurheartj/ehp253
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Effects of tolvaptan on dyspnoea relief from the EVEREST trials
1 Department of Emergency Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
2 The Cardiovascular Center, Tufts Medical Center, Boston, MA, USA
3 Department of Clinical Development, Otsuka Maryland Research Institute, Rockville, MD, USA
4 Department of Emergency and Cardiovascular Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
5 Centre d'Investigations Cliniques, Nancy, France
6 Division of Cardiology, Department of Medicine, Northwestern University Feinberg School of Medicine, 201 East Huron Street, Galter 10-240, Chicago, IL 60611, USA
7 Section of Cardiology, San Francisco Veterans Affairs Medical Center and School of Medicine, University of California-San Francisco, San Francisco, CA, USA
8 Associazione Nazionale Medici Cardiologi Ospedalieri Research Center, Florence, Italy
9 Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, USA
10 Departmento de Diagnostico y Tratamiento, Servicio de Hemodinamia, Hospital Italiano, Buenos Aires, Argentina
11 Department of Biometrics, Otsuka Maryland Research Institute, Rockville, MD, USA
Received 24 October 2008; revised 28 April 2009; accepted 27 May 2009 * Corresponding author. Tel: +1 312 695 0051, Fax: +1 312 695 1434, Email: m-gheorghiade{at}northwestern.edu
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.
Key Words: Acute heart failure syndromes • Heart failure • Dyspnoea • Vasopressin antagonists • Clinical trials