Novel Risk Score Efficiently Prevents Tolvaptan-Induced Hypernatremic Events in Patients With Heart Failure

Abstract

tions were reported to occur following tolvaptan treatment in a dose-dependent manner, with rates of 6%, 11%, and 13% for 30, 45, and 60 mg tolvaptan, respectively. 7 Although the risk of hypernatremia was not clear in the pivotal Phase 3 QUEST study, 8 we reported 3 risk factors for hypernatremic events using the interim results of the Samsca Post-Marketing Surveillance In the Heart faiLurE (SMILE) study conducted in 2014. 9 These factors were higher baseline sodium concentration, lower baseline potassium concentration, and a 15-mg starting dose of tolvaptan. Moreover, based on subanalysis of the SMILE study in 2015, 10 we recommended a lower dose of tolvaptan for older patients (i.e., those >80 years of age) to prevent hypernatremic events. Herein, we report on the development of a risk score to predict the prevalence of hypernatremia using the final dataset of the SMILE study. MethodsThe present prospective multicenter observational study was conducted in compliance with Good Post-Marketing Study Practice, an ordinance issued by the Ministry of Health, Labor and Welfare for the implementation of post-marketing surveillance of new drugs approved in Japan. The study period was from 2011 to 2016, and the D iuretic resistance was common in the Acute Decompensated Heart Failure Registry (ADHERE), 1 being observed in 30% of patients with heart failure. Until the approval of tolvaptan, a vasopressin V2 receptor antagonist, there were limited therapeutic options for patients with heart failure and fluid retention who did not respond sufficiently to conventional diuretics.Tolvaptan has been approved in the US since 2009, with current indications for tolvaptan being the treatment of clinically significant hypervolemic and euvolemic hyponatremia, as well as Syndrome of Inappropriate Antidiuretic Hormone (SIADH). 2 However, in Japan, tolvaptan was approved in 2010 for the following expanded indication, which is quite different from indications in the US: "volume overload in heart failure patients when adequate response was not obtained with other diuretics (e.g., loop diuretics)". 3,4 Tolvaptan significantly increases urine volume with water excretion into the urine 5 and sometimes results in marked increases in serum sodium concentrations. Therefore, tolvaptan treatment must be started in an inpatient setting to avoid the adverse event of hypernatremia caused by its pharmacological action of aquaresis. In the EVEREST study, in which patients were treated with 30 mg tolvaptan, the incidence of hypernatremia was 1.7%. 6 In another study, abnormally high serum sodium concentra- Sugitani, Toyama 930-0914, Japan. E-mail: kinugawa0422@gmail.com ISSN-1346-9843 All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: cj@j-circ.or.jp Novel Risk Score Efficiently Prevents Tolvaptan-Induced Hypernatremic Events in Patients With Heart FailureKoichiro Kinugawa, MD, PhD; Naoki Sato, MD, PhD; Takayuki Inomata, MD, PhD; Moriyoshi Yasuda, PhD; Yoshiyuki Shibasaki, BSc; Toshiyuki Shimakawa, BScBackgrou...

Real-World Effectiveness and Tolerability of Tolvaptan in Patients With Heart Failure ― Final Results of the Samsca Post-Marketing Surveillance in Heart Failure (SMILE) Study ―

“…An interim analysis of the SMILE study in 1,053 evaluable patients reported significant improvement or absence of lower limb edema, pulmonary congestion, dyspnea, jugular venous distention, and hepatomegaly at Days 7 and 14 (P<0.0001 for all symptoms). 16 This final analysis confirms the interim results and indicates clinically meaningful symptom-free rates also for 3rd sound and rales.…”

“…Risk factors for tolvaptan-induced hypernatremic events have previously been analyzed and reported in detail. 16 A risk score nomogram based on the final SMILE dataset has been developed to identify at-risk patients who should begin tolvaptan treatment at a dosage of 3.75 mg/day. Although cases of elevated liver enzymes related to tolvaptan were reported in clinical trials of patients with autosomal dominant polycystic kidney disease, 17 the tolvaptan dosage was much higher (60-120 mg/ day) than that indicated for use in patients with HF.…”

Update of acute and long-term tolvaptan therapy

“…We recently proposed a scoring system to predict the occurrence of hypernatremic events, and age is a strong risk factor for hypernatremia, particularly when tolvaptan was administered at a high dose (i.e. 15 mg/day) [24]. A low starting dose (i.e.…”

Tolvaptan-Induced Hypernatremia Related to Low Serum Potassium Level Accompanying High Blood Pressure in Patients with Acute Decompensated Heart Failure

“…Sometimes, hypernatremia results in central nervous system disturbance. There is a population that is a risk to the development of hypernatremia [14], and risk factors for hypernatremia in tolvaptan treatment were previously reported [9][10][11]. This study aimed to elucidate clinical factors associated with hypernatremia in patients with ADHF treated with full medications and tolvaptan in real-world practice.…”

“…The serum sodium level increases as a result of aquaresis in almost all cases, and hypernatremia can be lethal in some patients [7,8] and was identi ed as a signi cant adverse event to be prevented [9]. Therefore, a lower dose of tolvaptan to prevent hypernatremia has been recommended in the initial phase [10,11], because tolvaptan treatment can dose dependently lead to abnormal hypernatremia [12,13]. Sometimes, hypernatremia results in central nervous system disturbance.…”