The Effect of Tolvaptan on BP in Polycystic Kidney Disease: A Post Hoc Analysis of the TEMPO 3:4 Trial

Abstract

Background: The V2 receptor antagonist tolvaptan is prescribed to patients with autosomal dominant polycystic kidney disease to slow disease progression. Tolvaptan may alter BP via various acute and chronic effects.

Methods: To investigate the magnitude and time course of the effect of tolvaptan use on BP, we conducted a post hoc study of the TEMPO 3:4 trial, which included 1445 patients with autosomal dominant polycystic kidney disease randomized 2:1 to tolvaptan or placebo for 3 years. We evaluated systolic and diastolic BP, mean arterial pressure, hypertension status, and use and dosing of antihypertensive drugs over the course of the trial.

Results: At baseline, BP did not differ between study arms. After 3 weeks of tolvaptan use, mean body weight had decreased from 79.7 to 78.8 kg, and mean plasma sodium increased from 140.4 to 142.6 mmol/L (both P<0.001), suggesting a decrease in circulating volume. We observed none of these changes in the placebo arm. Nonetheless, BP remained similar in the study arms. After 3 years of treatment, however, mean systolic BP was significantly lower in participants receiving tolvaptan versus placebo (126 versus 129 mm Hg, respectively; P=0.002), as was mean diastolic BP (81.2 versus 82.6 mm Hg, respectively; P=0.01). These differences leveled off at follow-up 3 weeks after discontinuation of the study medication. Use of antihypertensive drugs remained similar in both study arms during the entire study.

Conclusions: Long-term treatment with tolvaptan gradually lowered BP compared with placebo, which may be attributed to a beneficial effect on disease progression, a continued natriuretic effect, or both.

Clinical trial registry name and registration number: TEMPO 3:4, NCT00428948.

Keywords: ADPKD; V2 receptor antagonist; blood pressure; vasopressin.

Copyright © 2021 by the American Society of Nephrology.

Figures

Graphical abstract

Figure 1.

BP and BP-lowering medication of participants during the TEMPO 3:4 trial. The tolvaptan study arm (n=961) is represented by solid circles, and placebo (n=484) is represented by open circles. Systolic and diastolic BP are presented in millimeters of mercury, and average dosage of antihypertensive drugs in defined daily dosages (DDDs). Error bars represent 95% confidence intervals of the mean. Treatment duration is expressed in months with the exception of w3, which indicates week 3, and FU, which indicates follow-up. *P=0.05 calculated with a mixed model repeated measures analysis.

Figure 2.

BP and BP-lowering medication during the TEMPO 3:4 trial in subgroups of participants according to baseline hypertension status. (A) includes patients with normotension at baseline (n=258), and (B) includes patients with hypertension at baseline (n=1187). The tolvaptan study arm is represented by solid circles, and placebo is represented by open circles. Systolic and diastolic BP are presented in millimeters of mercury, and average dosage of antihypertensive drugs in defined daily dosages (DDDs). Error bars represent 95% confidence intervals of the mean. Treatment duration is expressed in months with the exception of w3, which indicates week 3, and FU, which indicates follow-up. *P=0.05.

Figure 3.

Effect of tolvaptan onchange in mean arterial pressure in the overall study population and in various subgroups during the TEMPO 3:4 trial. Change in mean arterial pressure between baseline and last visit on study medication (either year 3 or early end of treatment) was studied. Bars represent mean difference in change of mean arterial pressure between tolvaptan and placebo arms (“treatment effect”) and 95% confidence interval. Mean arterial pressure was calculated as diastolic BP +0.412×(systolic BP – diastolic BP).