Introduction: Tolvaptan, a vasopressin type 2 receptor antagonist, is indicated for the treatment of severe hyponatremia in US, but the broader indication is applied in Japan, i.e. diuretic-resistant congestive heart failure regardless of serum sodium level. Due to its aquaretic nature, hypernatremia is the most serious and potentially life-threatening adverse event of tolvaptan. Our previous study showed that hypernatremia almost exclusively occurred within the first week after starting tolvaptan.
Hypothesis: The adverse event of hypernatremia is attributable to the patient characteristics before tolvaptan treatment, and is avoidable by an appropriate risk stratification.
Methods: This is the Post-Marketing Surveillance to investigate the effectiveness and safety of tolvaptan in Japan since 2011 to 2016, and was conducted as a prospective, multicenter, observational study.
Results: We collected 3,350 patients' data from 492 investigational sites in Japan. The mean age was 77.3±12.4 (3-106 years), and the mean daily dose of tolvaptan was 9.4±3.8 mg/day. The incidence rate of hypernatremia defined as ≥150 mEq/L was 3.65%. A multivariate analysis revealed that serum sodium level, serum potassium level, and BUN/creatinine ratio were independent risk factors for hypernatremic event. A hypernatremia risk score was developed using the odds ratios of these factors. Among those who had risk scores ≥17.80, the incidence rate of hypernatremia was rising in proportion to the initial dose of tolvaptan, ~3% in 3.75 mg, ~10% in 7.5 mg, and ~20% in 15 mg. On the other hand, hypernatremic event was rare no matter which dose of tolvaptan was chosen in patients with risk scores <17.8.
Conclusions: This largest registry of tolvaptan treatment led us to develop a novel risk scoring system for predicting hypernatremia. Starting with a lower dose of tolvaptan is highly recommended to avoid hypernatremia, especially in patients stratified into the high risk group.