Tolvaptan in Acute Heart Failure and Volume Overload
Does the addition of tolvaptan to background diuretic therapy, improve shortness of breath in acute heart failure accompanied by hyponatremia, renal dysfunction, or inadequate initial diuretic response?
The SECRET of CHF was a double-blind trial, where patients were randomized to tolvaptan 30 mg daily or placebo. Enrollment in the trial required hospitalization within the prior 36 hours, active shortness of breath, and any of the following: 1) estimated glomerular filtration rate <60 ml/min/1.73 m2; 2) hyponatremia (serum sodium ≤134 mEq/L); or 3) diuretic resistance (urine output ≤125 ml/h following intravenous furosemide ≥40 mg). The primary endpoint was change in self-assessed dyspnea score, assessed at 8 and 16 hours, by a 7-point Likert scale using a repeated-measures, generalized estimating equations model applied to patients with available data, with Type I error (alpha) of 0.05.
The study investigators randomized 250 patients. They found no difference in the primary endpoint of day 1 reduction in shortness of breath, despite significantly greater weight reduction with tolvaptan (-2.4 ± 2.1 vs. -0.9 ± 1.8 kg; p < 0.001). At day 3, dyspnea reduction was greater with tolvaptan (p = 0.01) and percent improved (tolvaptan vs. placebo: 81.2% vs. 66.3%; p = 0.02). There were two significant treatment-by-subgroup interactions: patients without elevated jugular venous pressure (p < 0.001) and those without ascites (p = 0.009) showed directional favorability of tolvaptan over placebo for the primary endpoint, compared to patients with these findings.
The study authors concluded that despite rapid and persistent weight loss with tolvaptan therapy, in acute heart failure patients selected for greater potential benefit from vasopressin receptor inhibition, tolvaptan was not associated with greater early improvement in shortness of breath.
Acute heart failure is a very heterogeneous condition, with varying degrees of renal and cardiac involvement, making standardization of therapy a challenge and in this study tolvaptan did not significantly improve early shortness of breath. More research is required in patients with cardiorenal syndrome.
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