Tolvaptan and Kidney Function Decline in Older Individuals With Autosomal Dominant Polycystic Kidney Disease: A Pooled Analysis of Randomized Clinical Trials and Observational Studies

Rationale & Objective: Tolvaptan is indicated for treatment of patients with autosomal dominant polycystic kidney disease (ADPKD) at risk of rapid progression. Participants aged 56-65 years constituted a small proportion of the Replicating Evidence of Preserved Renal Function: an Investigation of Tolvaptan Safety and Efficacy in ADPKD (REPRISE) trial population. We assessed effects of tolvaptan on estimated glomerular filtration rate (eGFR) decline in participants aged >55 years. Study Design: This was a pooled data analysis from 8 studies of tolvaptan or non-tolvaptan standard of care (SOC). Setting & Participants: Participants aged >55 years with ADPKD were included. Data on participants in >1 study were linked longitudinally for maximum follow-up duration, with matching for age, sex, eGFR, and chronic kidney disease (CKD) stage to minimize confounding. Interventions: Tolvaptan or non-tolvaptan SOC. Outcomes: Treatment effects on annualized eGFR decline were compared using mixed models with fixed effects for treatment, time, treatment-by-time interaction, and baseline eGFR. Results: In the pooled studies, 230 tolvaptan-treated and 907 SOC participants were aged >55 years at baseline. Ninety-five participant pairs from each treatment group were matched, all in CKD G3 or G4, ranging from 56.0 to 65.0 years (tolvaptan) or from 55.1 to 67.0 years (SOC). The eGFR annual decline rate was significantly reduced by 1.66 mL/min/1.73 m² (95% CI, 0.43-2.90; P = 0.009) in the tolvaptan group compared with SOC (−2.33 versus −3.99 mL/min/1.73 m²) over 3 years. Limitations: Limitations include potential bias because of study population differences (bias risk was reduced through matching and multiple regression adjustment); vascular disease history data was not uniformly collected, and therefore not adjusted; and natural history of ADPKD precludes evaluating certain clinical endpoints within the study time frame. Conclusions: In individuals aged 56-65 years with CKD G3 or G4, compared to a SOC group with mean GFR rate of decline ≥3 mL/min/1.73 m²/year, tolvaptan was associated with efficacy similar to that observed in the overall indication. Funding: Otsuka Pharmaceutical Development & Commercialization, Inc (Rockville, MD). Trial Registration: TEMPO 2:4 (NCT00413777); phase 1 tolvaptan trial (no NCT number; trial number 156-06-260); phase 2 tolvaptan trial (NCT01336972); TEMPO 4:4 (NCT01214421); REPRISE (NCT02160145); long-term tolvaptan safety extension trial (NCT02251275); OVERTURE (NCT01430494); HALT Progression of Polycystic Kidney Disease (HALT-PKD) study B (NCT01885559).