Renoprotection by long‐term low‐dose tolvaptan in patients with heart failure and hyponatremia

AIMS: In previous randomized controlled trials, the use of tolvaptan (TLV) at a fixed dose of 30 mg/day for 1 year did not provide renal benefits in patients with heart failure (HF). This retrospective, cohort study examined the renoprotective effects of long‐term, flexible‐dose, and lower‐dose TLV use. METHODS AND RESULTS: Tolvaptan users were defined as patients receiving TLV for at least 180 consecutive days or those who continued it until death, any cardiac events, or renal replacement therapy even if it was taken for <180 days. Of a total of 584 HF patients, 78 TLV users were identified. The median age, baseline B‐type natriuretic peptide, and estimated glomerular filtration rate (eGFR) were 71 years, 243 pg/mL, and 54 mL/min/1.73 m(2), respectively. During follow‐up (median, 461 days), TLV use (median average dose, 7.5 mg/day) was associated with frequent dose reductions of loop diuretics (incidence rate ratio [IRR], 1.5; 95% confidence interval [CI], 1.1–2.2), particularly in patients with serum sodium ≤135 mEq/L (IRR, 2.9; 95% CI, 1.5–5.7) (P (interaction) = 0.04). In a mixed effects model, propensity score (PS)‐matched TLV users had higher eGFRs over time than PS‐matched never‐users (P < 0.01). The entire cohort analyses (N = 584) yielded similar results. The renal benefit of TLV in terms of annualized eGFR slope was more pronounced in patients with lower sodium levels (P (interaction) = 0.03). This effect modification was extinguished when patients who underwent a loop diuretic dose reduction during the follow‐up period were excluded from the analysis. CONCLUSIONS: Long‐term, flexible‐dose, and low‐dose TLV use was associated with better renal function, particularly in hyponatremic HF, possibly due to its loop diuretic dose‐sparing effect in the long term.