Effects of tolvaptan on dyspnoea relief from the EVEREST trials

Abstract

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.

Figures

Figure 1

Patient-assessed dyspnoea status at inpatient Day 1 in the combined EVEREST trial population. Note. Patients with continuous or frequent dyspnoea at baseline; Patients were asked ‘Compared to how much difficulty you were having with your breathing just before trial drug was started, how is your breathing now?’; Worsened includes minimally worse, moderately worse, and markedly worse. Reproduced with permission from Gheorghiade et al. Copyright © (2007), American Medical Association. All Rights reserved.

Figure 2

Timing of patient-assessed dyspnoea measurement relative to first dose or hospital admission. (A) Timing of patient assessment of dyspnoea relative to dosing by treatment group. (B) Timing of patient assessment of dyspnoea relative to time of hospital admission by treatment group.

Figure 3

Patient-assessed dyspnoea as a function of time from first dose of study drug. *P < 0.05 van Elteren test.

Figure 4

Patient-assessed dyspnoea as a function of time from hospital admission. *P < 0.05 van Elteren test.

Figure 5

Association between patient-assessed dyspnoea status and body weight change at inpatient Day 1. Note: worse includes minimally worse, moderately worse, and markedly worse. For association between weight change and treatment: P < 0.0001 for dyspnoea status adjusted for treatment; P < 0.0001 adjusted for dyspnoea status; and P = 0.3008 for dyspnoea–treatment interaction.

Figure 6

Patient-assessed dyspnoea response by baseline subgroup represented as treatment effect (>0.5 favours tolvaptan) and 95% confidence interval.