Simple Score to Predict Treatment Response to Low-Dose Tolvaptan in Patients with Heart Failure

Abstract

The recommended starting dose of Tolvaptan for heart failure (HF) is 7.5 mg/day in Japan; the recommended dose is 3.75 mg/day for older patients to avoid excessive diuresis and hypernatremia. However, lowdose Tolvaptan may delay the release of congestion in some patients. We aimed to develop a score to predict treatment responders to 3.75 mg tolvaptan.We retrospectively analyzed 106 patients with HF who initially received 3.75 mg/day of Tolvaptan in the derivation cohort (April 2013-December 2017) and 63 patients receiving 3.75 mg/day of Tolvaptan in the validation cohort (January 2018-April 2021). Treatment responders to 3.75 mg tolvaptan did not require dose escalation of Tolvaptan for congestion relief. In multivariate analysis, blood urea nitrogen (BUN) < 39 mg/dL and hematocrit > 35% were selected as variables to predict treatment responders. These were assigned 1 point each, and patients were stratified into groups with 2 points (n = 32), 1 point (n = 39), and 0 points (n = 35). The frequency of treatment responders was 82.9% in the 2-point group, 61.5% in the 1-point group, and 34.4% in the 0-point group (P < 0.05). The predictive ability of the score was acceptable with an area under the receiving operator characteristic curve (AUC) 0.726 (P < 0.05); its performance was maintained in the validation cohort (AUC 0.733, P < 0.05).A simple score using BUN and hematocrit could identify treatment responders to 3.75 mg tolvaptan, which may help determine the appropriate starting dose of Tolvaptan, balancing efficiency with safety for older patients with HF.

Letter by Nakagawa, <i>et al</i>. Regarding Article, "Simple Score to Predict Treatment Response to Low-Dose Tolvaptan in Patients with Heart Failure"

“…Takami and colleagues demonstrated that a simple score consisting of blood urea nitrogen < 39 mg/dL and hematocrit > 35% could identify "treatment responders" to 3.75 mg/day of tolvaptan, who did not require up-titration of tolvaptan. 1) They suggested initiating tolvaptan at 7.5 mg/day, instead of 3.75 mg/day, for the non-responders to avoid the delay of appropriate treatment. Several concerns have been raised.…”

“…The initial concern is a definition of "response" to tolvaptan, which was a primary outcome of their study. 1) There were no specific criteria for selecting the dose and up-titration of tolvaptan, and a critical bias might have affected their findings. Some of the patients with a fixeddose might have experienced a favorable urine response by 3.75 mg/day of tolvaptan, whereas the dose of tolvaptan might have been fixed at 3.75 mg/day to avoid hemodynamic deterioration or hypernatremia in others with high risk.…”

“…They recommend utilizing their novel score and in-itiating 7.5 mg/day of tolvaptan for those who were estimated to require dose escalation to avoid delay of appropriate treatment. 1) However, "clinical non-responders" might be refractory also to 7.5 mg/day of tolvaptan. Could they enjoy the improvement in urine volume following the dose escalation of tolvaptan?…”

“…The authors stated, "older patients with heart failure often have difficulty feeling thirsty: therefore, excessive diuresis increases their risk of dehydration and hypernatremia". 1) In their study, some patients who were initiated on tolvaptan at 7.5 mg/day encountered hypernatremia. Taken all together, it might be safer to initiate 3.75 mg/day for all patients irrespective of the calculated score to avoid drug-related adverse events.…”

Reply to Letter Regarding Article, "Simple Score to Predict Treatment Response to Low-Dose Tolvaptan in Patients with Heart Failure"

“…In our study, not urine volume, but required dose-escalation of tolvaptan was used to define a non-responder of tolvaptan. 2) The decision regarding dose-escalation was made by each attending physician; therefore, the current results may be affected by the decision bias of the attending physician as described in the paragraph of the limitations of our article. However, as shown in the excluded criteria, cases in which dose escalation was withheld due to elevated sodium levels despite inadequate urine output were excluded from the analysis.…”