Dataset Information

A Post Hoc Analysis of Statin Use in Tolvaptan Autosomal Dominant Polycystic Kidney Disease Pivotal Trials.

ABSTRACT:

Background and objectives

Tolvaptan is approved to slow kidney function decline in adults with autosomal dominant polycystic kidney disease (ADPKD) at risk of rapid progression. Because in vitro studies indicated that the tolvaptan oxobutyric acid metabolite inhibits organic anion-transporting polypeptide (OATP)1B1 and OATP1B3, United States prescribing information advises avoiding concurrent use with OATP1B1/1B3 substrates, including hepatic hydroxymethyl glutaryl-CoA reductase inhibitors (statins). This post hoc analysis of the pivotal phase 3 tolvaptan trials (Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes [TEMPO] 3:4 trial [NCT00428948] and Replicating Evidence of Preserved Renal Function: an Investigation of Tolvaptan Safety and Efficacy in ADPKD [REPRISE] trial [NCT02160145]) examined the safety of concurrent tolvaptan/statin use.

Design, setting, participants, & measurements

The trials randomized a combined total of 2815 subjects with early- to late-stage ADPKD to tolvaptan (n=1644) or placebo (n=1171) for 3 years (TEMPO 3:4) and 1 year (REPRISE). Statin use was unrestricted, and 597 subjects (21.2% overall; 332 [20.2%] tolvaptan, 265 [22.6%] placebo) received statins. Statin use (duration, dose change, statin change, permanent discontinuation), incidences of statin-related adverse events, and hepatic transaminase elevations were determined for subjects who received tolvaptan+statin, placebo+statin, tolvaptan alone, and placebo alone.

Results

No differences in statin use parameters between tolvaptan- and placebo-treated subjects were observed. No statistically significant increases in commonly reported statin-related adverse events (e.g., musculoskeletal disorders, gastrointestinal symptoms) were seen between subjects receiving tolvaptan+statin and placebo+statin. For example, in TEMPO 3:4, frequencies were 5.4% and 7.8%, respectively, for myalgia (difference -2.4%; 95% confidence interval, -11.2% to 6.4%) and 9.3% and 7.8%, respectively, for abdominal pain (difference 1.5%; -7.9% to 10.9%). In an analysis that excluded participants concurrently using allopurinol, the frequency of alanine transaminase or aspartate transaminase >3× upper limit of normal in the pooled study populations was 3.6% for the tolvaptan+statin group and 2.3% for the placebo+statin group (difference 1.4%; -2.0% to 4.7%).

Conclusions

Tolvaptan has been used safely in combination with statins in clinical trials.

Podcast

This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2020_04_06_CJN.08170719.mp3.

SUBMITTER: Shoaf SE

PROVIDER: S-EPMC7269222 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:BackgroundTolvaptan slows kidney function decline in patients with autosomal dominant polycystic kidney disease (ADPKD) who are at risk of rapid progression. Given that treatment requires commitment to long-term use, we evaluated the effects of tolvaptan discontinuation on the trajectory of ADPKD progression.MethodsThis was a post hoc analysis of pooled data from two clinical trials of tolvaptan (TEMPO 2:4 [NCT00413777] and TEMPO 3:4 [NCT00428948]), an extension trial (TEMPO 4:4 [NCT01214421]), and an observational study (OVERTURE [NCT01430494]) that enrolled patients from the other trials. Individual subject data were linked longitudinally across trials to construct analysis cohorts of subjects with a tolvaptan treatment duration > 180 days followed by an off-treatment observation period of > 180 days. For inclusion in Cohort 1, subjects were required have ≥ 2 outcome assessments during the tolvaptan treatment period and ≥ 2 assessments during the follow-up period. For Cohort 2, subjects were required to have ≥ 1 assessment during the tolvaptan treatment period and ≥ 1 assessment during the follow-up period. Outcomes were rates of change in estimated glomerular filtration rate (eGFR) and total kidney volume (TKV). Piecewise-mixed models compared changes in eGFR or TKV in the on-treatment and post-treatment periods.ResultsIn the Cohort 1 eGFR population (n = 20), the annual rate of eGFR change (in mL/min/1.73 m2) was -3.18 on treatment and -4.33 post-treatment, a difference that was not significant (P = 0.16), whereas in Cohort 2 (n = 82), the difference between on treatment (-1.89) and post-treatment (-4.94) was significant (P < 0.001). In the Cohort 1 TKV population (n = 11), TKV increased annually by 5.18% on treatment and 11.69% post-treatment (P = 0.06). In Cohort 2 (n = 88), the annual TKV growth rates were 5.15% on treatment and 8.16% post-treatment (P = 0.001).ConclusionsAlthough limited by small sample sizes, these analyses showed directionally consistent acceleration in measures of ADPKD progression following the discontinuation of tolvaptan.

Project description:BackgroundThe course of autosomal dominant polycystic kidney disease (ADPKD) is often associated with pain, hypertension, and kidney failure. Preclinical studies indicated that vasopressin V(2)-receptor antagonists inhibit cyst growth and slow the decline of kidney function.MethodsIn this phase 3, multicenter, double-blind, placebo-controlled, 3-year trial, we randomly assigned 1445 patients, 18 to 50 years of age, who had ADPKD with a total kidney volume of 750 ml or more and an estimated creatinine clearance of 60 ml per minute or more, in a 2:1 ratio to receive tolvaptan, a V(2)-receptor antagonist, at the highest of three twice-daily dose regimens that the patient found tolerable, or placebo. The primary outcome was the annual rate of change in the total kidney volume. Sequential secondary end points included a composite of time to clinical progression (defined as worsening kidney function, kidney pain, hypertension, and albuminuria) and rate of kidney-function decline.ResultsOver a 3-year period, the increase in total kidney volume in the tolvaptan group was 2.8% per year (95% confidence interval [CI], 2.5 to 3.1), versus 5.5% per year in the placebo group (95% CI, 5.1 to 6.0; P<0.001). The composite end point favored tolvaptan over placebo (44 vs. 50 events per 100 follow-up-years, P=0.01), with lower rates of worsening kidney function (2 vs. 5 events per 100 person-years of follow-up, P<0.001) and kidney pain (5 vs. 7 events per 100 person-years of follow-up, P=0.007). Tolvaptan was associated with a slower decline in kidney function (reciprocal of the serum creatinine level, -2.61 [mg per milliliter](-1) per year vs. -3.81 [mg per milliliter](-1) per year; P<0.001). There were fewer ADPKD-related adverse events in the tolvaptan group but more events related to aquaresis (excretion of electrolyte-free water) and hepatic adverse events unrelated to ADPKD, contributing to a higher discontinuation rate (23%, vs. 14% in the placebo group).ConclusionsTolvaptan, as compared with placebo, slowed the increase in total kidney volume and the decline in kidney function over a 3-year period in patients with ADPKD but was associated with a higher discontinuation rate, owing to adverse events. (Funded by Otsuka Pharmaceuticals and Otsuka Pharmaceutical Development and Commercialization; TEMPO 3:4 ClinicalTrials.gov number, NCT00428948.).

Project description:BackgroundPrevious clinical studies of autosomal dominant polycystic kidney disease (ADPKD) reported that loss of kidney function usually follows a steep and relentless course. A detailed examination of individual patterns of decline in estimated glomerular filtration rate (eGFR) has not been performed.Study designLongitudinal post hoc analysis of data collected during the Halt Progression of Polycystic Kidney Disease (HALT-PKD) trials.Setting & participants494 HALT-PKD Study A participants (younger; preserved eGFR) and 435 Study B participants (older; reduced eGFR) who had more than 3 years of follow-up and 7 or more eGFR assessments.MeasurementsLongitudinal eGFR assessments using the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) creatinine equation.PredictorsDemographic, clinical, laboratory, and imaging features of participants.OutcomesProbability of linear and nonlinear decline patterns or of stable eGFR calculated for each participant from a Bayesian model of individual eGFR trajectories.ResultsMost (62.5% in Study A and 81% in Study B) participants had a linear decline in eGFR during up to 8 years of follow-up. A proportion (22% in Study A and 13% in Study B) of progressors had a nonlinear pattern. 15.5% of participants in Study A and 6% in Study B had a prolonged (≥4.5 years) period of stable eGFRs. These individuals (Study A) had significantly smaller total kidney volumes, higher renal blood flows, lower urinary albumin excretion, and lower body mass index at baseline and study end. In Study B, participants with reduced but stable eGFRs were older than the progressors. Two-thirds of nonprogressors in both studies had PKD1 mutations, with enrichment for weak nontruncating mutations.LimitationsRelatively short follow-up of a clinical trial population.ConclusionsAlthough many individuals with ADPKD have a linear decline in eGFR, prolonged intervals of stable GFRs occur in a substantial fraction. Lower body mass index was associated with more stable kidney function in early ADPKD.

Project description: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.