stage between the trial populations, namely, earlier-stage CKD in TEMPO 3:4 and later-stage CKD in REPRISE. Deterioration in kidney function accelerates over the course of ADPKD, enabling the easier detection of inhibitory effects on eGFR decline in patients with later-stage disease.20,21 The importance of CKD stage at baseline is supported by the observation that when differences in subject baseline characteristics were accounted for via Figure 3. (a) Eligible ages for trial enrollment and mean age of subjects matched by propensity score. (b) Eligible eGFR for trial enrollment and mean eGFR of subjects matched by propensity score. eGFR, estimated glomerular filtration rate; PBO, placebo; TOL, tolvaptan. CLINICAL RESEARCH AJ Mallett et al.: Adherence and Tolvaptan Effect Size in ADPKD 1036 Kidney International Reports (2021) 6, 1032–1040 propensity matching, the treatment effect was not significantly different between TEMPO 3:4 and REPRISE. The lack of a significant treatment difference observed between tolvaptan and placebo within the matched REPRISE population may be due to the small size of the propensity matched subgroup relative to the total REPRISE cohort, which represents a limitation of the analysis. An analysis of changes in TKV in TEMPO 3:4 completers versus the total trial population showed similar results to the eGFR analyses, with little evident effect of completion on outcomes. Tolvaptan was consistently associated with a slowing of eGFR decline by approximately 1 ml/min per 1.73 m2 /year relative to placebo in TEMPO 3:4 and REPRISE across completers and the overall trial populations. Although evaluating the efficacy of treatment for ADPKD remains an underresearched topic and there are no generally agreed-on standards for the clinic,22 a slowing of eGFR loss of 1 ml/min per 1.73 m2 /year is clinically meaningful and can be expected to substantially slow progression to ESKD.23 Similarly, tolvaptan slowed the annual increase in TKV by approximately half, which can be expected to make an impact on patient outcomes and quality of life over the long-term. We found associations between baseline characteristics and treatment completion in TEMPO 3:4. Subjects who were older or took blood pressure medication were more likely to be completers, possibly because they were already accustomed to daily pharmacotherapy. Mean baseline blood pressure itself did not significantly differ by completer/noncompleter status. A history of hematuria or kidney pain was negatively associated with treatment completion. Previous research on predictors of medication utilization supports a positive association between older age and better adherence, whereas data on the impact of comorbidity or the use of multiple medications on adherence are equivocal.24–26 Lower body mass index was also positively associated with treatment completion in TEMPO 3:4. The finding of correlations between subject characteristics and completer/noncompleter status in TEMPO 3:4 but not REPRISE may be due to the longer treatment period in TEMPO 3:4 (3 years vs. 1 year). Differences in trial design and trial populations between TEMPO 3:4 and REPRISE must also be borne in mind. The double-blind treatment phase of REPRISE included only subjects who tolerated tolvaptan during a preceding single-blind phase. Subjects enrolled in REPRISE may also have been aware of the earlier TEMPO 3:4 findings demonstrating efficacy of tolvaptan in ADPKD and thus have been more willing to tolerate aquaretic adverse events. Given the established association of decreased drug compliance with negative health outcomes in chronic conditions, more research on predictors of medication persistence is needed in the context of treatment for ADPKD.27,28 Limitations of the analysis are the post hoc nature of the analyses and the relatively small proportion of Figure 4. Tolvaptan effect on eGFR slope (ml/min per 1.73 m2 /year) in TEMPO 3:4 and REPRISE in subjects matched by propensity score (a). Comparison of tolvaptan effect on eGFR slope (ml/min per 1.73 m2 /year) between TEMPO 3:4 and REPRISE in subjects matched by propensity score (b). a Comparison of TOL versus PBO in the subset of propensity-matched subjects within TEMPO 3:4 and REPRISE. b Comparison of TOL effect between TEMPO 3:4 and REPRISE. eGFR data are standard error. eGFR, estimated glomerular filtration rate; PBO, placebo; TOL, tolvaptan. AJ Mallett et al.: Adherence and Tolvaptan Effect Size in ADPKD CLINICAL RESEARCH Kidney International Reports (2021) 6, 1032–1040 1037 noncompleters in each trial arm (ranging from 7.7% to 23.0%). The small number of noncompleters may have decreased the power to detect differential effects of completer versus noncompleter status. When REPRISE was conducted, more was understood about the shortterm hemodynamic effects of tolvaptan, with the timing of eGFR assessments designed to take these effects into account in evaluating long-term efficacy. The assessment of treatment effect was therefore not identical between TEMPO 3:4 and REPRISE. In addition, outcomes after drug discontinuation were monitored differently in each trial. In REPRISE, eGFR data after discontinuation were included in the dataset for the overall population only for subjects who underwent the Month 12 visit and at least 1 follow-up serum creatinine