Tolvaptan in Patients with ADPKD: Post Hoc Analysis of the TEMPO 3:4 Trial

The principal function of vasopressin is decreasing urinary output. The effects of vasopressin are facilitated by the V1a, V1b, and V2 receptors. The V2 receptor is responsible for the antidiuretic effect and is activated by a minimal change in vasopressin signal. The V1a receptor is responsible for vasoconstriction and requires higher vasopressin levels.

Activation of the V2 receptor is crucial for water hemostasis, but can also be harmful in various kidney disorders, including autosomal dominant polycystic kidney disease (ADPKD). Patients with ADPKD are treated with tolvaptan, a selective V2 receptor antagonist, which has been shown to slow the rate of disease progression in patients at risk of rapid decline in kidney function.

According to Judith E. Heida, MD, and colleagues, tolvaptan could theoretically have effects on blood pressure, including an increase in vascular resistance via increase V1a receptor activation and a resulting increase in blood pressure. Conversely, preventing vasopressin binding to the V2 receptor could result in a decrease in blood pressure. In the long-term, tolvaptan ameliorates the rate of disease progression, and may reduce the development of secondary symptoms of kidney disease, including hypertension.

The researchers conducted a post hoc analysis of data from the TEMPO 3:4 trial to examine the magnitude and time course of the effect of tolvaptan on blood pressure expressed as a continuous variable, taking into account measured values as well as use of blood pressure-lowering medication. Results of the analysis were reported in the Journal of the American Society of Nephrology [2021;32(7):1801-1812].

The TEMPO 3:4 trial was a prospective, multicenter, double-blind, randomized, controlled trial assessing the efficacy of tolvaptan in patients with early-stage ADPKD. The trial included 1445 patients with ADPKD who were randomized 2:1 to tolvaptan or placebo for 3 years. The post hoc analysis included evaluations of systolic and diastolic blood pressure, mean arterial pressure, hypertension status, and use and dosing of antihypertensive drugs over the course of the trial.

Of the 1445 patients, 916 were randomized to tolvaptan and 484 to placebo. The two groups were similar in baseline characteristics. Baseline blood pressures were comparable in the two study arms: 129 mm Hg systolic and 82.5 mm Hg diastolic blood pressure in the tolvaptan arm; 128 mm Hg systolic blood pressure and 82.4 mm Hg diastolic blood pressure in the placebo arm. In the tolvaptan arm, 81% of patients had hypertension compared with 84% in the placebo arm. In both study arms, 77% of patients were taking antihypertensive medications at baseline; the majority of medications were renin-angiotensin-aldosterone system (RAAS) inhibitors. The two arms were similar in dosages of the antihypertensives.

In patients with normotension at baseline, there was no difference between the two arms in baseline blood pressure, although body mass index in patients in the tolvaptan arm (n=179) was significantly higher than in patients in that subgroup of the control arm (n=79). Patients in the tolvaptan arm also used a cholesterol-lowering drug more often and had a higher height-adjusted total kidney volume than those in the control arm. Among patients with hypertension at baseline, there were no significant differences in blood pressure or other baseline characteristics between the tolvaptan arm (n=782) and the control arm (n=405).

Following 3 weeks of study treatment, copeptin was significantly higher in the tolvaptan arm than in the control arm. There were no significant differences between the two arms in patient characteristics related to blood pressure, including systolic and diastolic blood pressure or number and dose of antihypertensive drugs. Tolvaptan use resulted in a decrease in mean body weight from 79.7 kg to 78.8 kg and an increase in mean plasma sodium from 140.4 mmol/L to 142.6 mmol/L, suggesting a decrease in circulating volume. There were significant associations between changes in copeptin levels and the changes in body weight (R=0.08; P=.02) and plasma sodium (R=0.16; P<.001), but  not with blood pressure. In the placebo arm, there was a significant increase in weight (P=.007) and plasma sodium remained stable (P=.85).

Over time, a small difference in blood pressure between the two arms occurred: a significant decrease in systolic blood pressure after 28 months and in diastolic blood pressure after 32 months. At the end of the study period, both systolic and diastolic blood pressure were lower in the tolvaptan arm than in the control arm (systolic blood pressure, 126 vs 129 mm Hg, respectively, P=.002 and diastolic blood pressure, 81.2 vs 82.6 mm Hg, respectively, P=.01). Average number of antihypertensive drugs was given at a similar dose in the two arms. After 28 months of treatment, average mean arterial pressure was also significantly lower in the tolvaptan arm than in the control arm (99.7 vs 100.9 mm Hg, respectively; P=.04).

After long-term use of tolvaptan, approximately 3 weeks after withdrawal of study medication, data were available for 734 patients in the tolvaptan arm and 407 patients in the control arm. Differences that were observed at month 36 had leveled off between the two study arms. In the tolvaptan arm, there was a significant increase in systolic blood pressure from 125 to 127 mm Hg (P<.001) as well as in diastolic blood pressure (from 80.4 to 81.0 mm Hg; P=.04). The number and dose of antihypertensive medications used in the two arms remained similar.  There was no change in the placebo arm in systolic blood pressure or diastolic blood pressure.

The authors acknowledged some limitations to the study including the post hoc design, the possibility of variability in outcomes due to differences in choice of blood pressure therapy, blood pressure being measured during outpatient clinic visits rather than at home, and not measuring vasopressin directly.

In conclusion, the researchers said, “This study demonstrates that start of tolvaptan treatment in patients with ADPKD does not have a clinically significant long-term effect on blood pressure, perhaps due to simultaneously occurring blood pressure-increasing and blood pressure-lowering effects that cancel out. During prolonged use, however, gradually blood pressure becomes lower in patients on tolvaptan compared with patients on placebo. This observation can likely be attributed to a sustained natriuretic effect, possibly in combination with the beneficial effect of tolvaptan on disease progression. When after 3 years of treatment, tolvaptan is stopped, there is an increase in blood pressure in tolvaptan-treated patients up to a level that is again similar to that of the placebo-treated subjects. This increase is likely caused by the sudden recovery of the V2-mediated antidiureris and sodium reabsorption, resulting in an excess of circulating volume. This acute effect of stopping tolvaptan is expected to disappear in the long term.”

The TEMPO 3:4 trial was funded by Otsuka Pharmaceutical and Otsuka Pharmaceutical Development and Commercialization, Inc. (Rockville, Maryland).

Takeaway Points

1. Researchers reported results of a post hoc analysis of data from the TEMPO 3:4 trial to examine the magnitude and time course of the effect of tolvaptan use on blood pressure in patients with autosomal dominant polycystic kidney disease.
2. TEMPO 3:4 included two arms: patients receiving tolvaptan (n=916) and patients receiving a placebo (control, n=484). Baseline blood pressure was similar in the two arms.
3. After 3 years of treatment, mean systolic and diastolic blood pressure were significantly lower in the tolvaptan arm than in the control arm; at 3 weeks after discontinuation of the study medication, the differences leveled off.