Tolvaptan in Patients with Autosomal Dominant Polycystic Kidney Disease

作者：Torres, Vicente E.^*; Chapman, Arlene B.; Devuyst, Olivier; Gansevoort, Ron T.; Grantham, Jared J.; Higashihara, Eiji; Perrone, Ronald D.; Krasa, Holly B.; Ouyang, John; Czerwiec, Frank S.

来源：New England Journal of Medicine, 2012, 367(25): 2407-2418.

DOI：10.1056/NEJMoa1205511

• VASOPRESSIN V-2-RECEPTOR ANTAGONIST
• LONG-ACTING SOMATOSTATIN
• VOLUME PROGRESSION
• ORAL TOLVAPTAN
• RENAL-FUNCTION
• CYST GROWTH
• SIROLIMUS
• OPC-41061
• MODEL

BACKGROUND @@@ The 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. @@@ METHODS @@@ In 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. @@@ RESULTS @@@ Over 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 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 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). @@@ CONCLUSIONS @@@ Tolvaptan, 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.)

• 出版日期2012-12-20