Long-Term Administration of Tolvaptan in Autosomal Dominant Polycystic Kidney Disease

Abstract

Background and objectives: In the 3-year Tolvaptan Efficacy and Safety in Management of ADPKD and Its Outcomes (TEMPO) 3:4 and 1-year Replicating Evidence of Preserved Renal Function: an Investigation of Tolvaptan Safety and Efficacy in ADPKD (REPRISE) trials, tolvaptan slowed the decline of eGFR in patients with autosomal dominant polycystic kidney disease at early and later stages of CKD, respectively. Our objective was to ascertain whether the reduction associated with the administration of tolvaptan is sustained, cumulative, and likely to delay the need for kidney replacement therapy.

Design, setting, participants, & measurements: One hundred and twenty-eight patients with autosomal dominant polycystic kidney disease participated in clinical trials of tolvaptan at the Mayo Clinic. All had the opportunity to enroll into open-label extension studies. Twenty participated in short-term studies or received placebo only. The remaining 108 were analyzed for safety. Ninety seven patients treated with tolvaptan for ≥1 year (mean±SD, 4.6±2.8; range, 1.1-11.2) were analyzed for efficacy using three approaches: (1) comparison of eGFR slopes and outcome (33% reduction from baseline eGFR) to controls matched by sex, age, and baseline eGFR; (2) Stability of eGFR slopes with duration of follow-up; and (3) comparison of observed and predicted eGFRs at last follow-up.

Results: Patients treated with tolvaptan had lower eGFR slopes from baseline (mean±SD, -2.20±2.18 ml/min per 1.73 m² per year) and from month 1 (mean±SD, -1.97±2.44 ml/min per 1.73 m² per year) compared with controls (mean±SD, -3.50±2.09 ml/min per 1.73 m² per year; P<0.001), and lower risk of a 33% reduction in eGFR (risk ratio, 0.63; 95% confidence interval, 0.38 to 0.98 from baseline; risk ratio, 0.53; 95% confidence interval, 0.31 to 0.85 from month 1). Annualized eGFR slopes of patients treated with tolvaptan did not change during follow-up and differences between observed and predicted eGFRs at last follow-up increased with duration of treatment.

Conclusions: Follow-up for up to 11.2 years (average 4.6 years) showed a sustained reduction in the annual rate of eGFR decline in patients treated with tolvaptan compared with controls and an increasing separation of eGFR values over time between the two groups.

Keywords: ADPKD; Benzazepines; EGFR protein, human; Follow-Up Studies; Humans; Polycystic Kidney, Autosomal Dominant; Receptor, Epidermal Growth Factor; Renal Insufficiency, Chronic; Renal Replacement Therapy; TEMPO; Tolvaptan; Vasopressin Receptor Antagonist; chronic kidney disease; glomerular filtration rate; polycystic kidney disease; vasopressin.

Graphical abstract

Figure 1.

The flow chart of the study population describes the study sources, enrollment into an open label extension, overall duration of follow-up, and approaches used to evaluate the long-term efficacy of treatment with tolvaptan.

Figure 2.

Tolvaptan slows the rate of eGFR decline and its effect is sustained and cumulative over time. (A and B) Kaplan–Meier analysis showed that the risks of a 33% reduction of eGFR from baseline (BL) or month 1 (Mo1) value were significantly less in the patients treated with tolvaptan than in the controls, with risk ratios of 0.63 (95% CI, 0.38 to 0.98) and 0.53 (95% CI, 0.31 to 0.85), respectively. (C) The annualized eGFR slopes of tolvaptan-treated patients plotted against duration of follow-up were consistent between year 1 and year 11; the slope of regression line was −0.11 ml/min per 1.73 m² per year (95% CI, −0.32 to 0.09). (D) Observed–predicted eGFR at the last follow-up plotted against duration of follow-up; as the duration of follow-up increases, the observed eGFRs became increasingly higher than the predicted eGFRs. The slope of the regression line with a zero y-intercept is 0.96 ml/min per 1.73 m² per year (95% CI, 0.47 to 1.45).