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

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

Judith E. Heida ,1 Ron T. Gansevoort,1 Vicente E. Torres,2 Olivier Devuyst ,3,4 Ronald D. Perrone ,5 Jennifer Lee,6 Hui Li,6 John Ouyang,6 and Arlene B. Chapman7

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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; P50.002), as was mean diastolic BP (81.2 versus 82.6 mm Hg, respectively; P50.01). 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

JASN 32: 1801–1812, 2021. doi: https://doi.org/10.1681/ASN.2020101512

Vasopressin and antidiuretic hormone are names V2 receptor, although indispensable for water that refer to the pleiotropic effects of this peptide. homeostasis, can also be damaging in a variety of Although the former name is most often used, the kidney disorders, including autosomal dominant latter may be more appropriate because decreasing polycystic kidney disease (ADPKD).7 The V2 urinary output is the principal function of vaso- receptor regulates water permeability of the tubular pressin. Effects of vasopressin are facilitated by cell membrane via an intracellular second three types of receptors, the V1a, V1b, and V2 1 receptors, present on various cell types. The V2 Received October 27, 2020. Accepted March 01, 2021. receptor, responsible for the antidiuretic effect, is Published online ahead of print. Publication date available at activated by a minimal change in vasopressin sig- www.jasn.org. nal.2,3 In contrast, activation of the V1a receptor, 4–6 Correspondence: Dr. Ron T. Gansevoort, Department of responsible for vasoconstriction, requires con- Nephrology, University Medical Center Groningen, Hanzeplein siderably higher vasopressin levels.3 1, PO Box 30.001, 9700 RB Groningen, The Netherlands. Not all of the effects of vasopressin are beneﬁ- Email: [email protected] cial. It has been recognized that activation of the Copyright ß 2021 by the American Society of Nephrology

JASN 32: 1801–1812, 2021 ISSN : 1046-6673/3207-1801 1801 CLINICAL RESEARCH www.jasn.org messenger, cAMP.8 In patients with ADPKD, growth of kid- Significance Statement ney cysts is stimulated by an increase in intracellular cAMP, leading to loss of kidney function and ultimately, resulting Patients with autosomal dominant polycystic kidney disease are in ESKD.9 Patients with ADPKD are therefore treated with treated with tolvaptan, a V2 receptor antagonist, to slow progres- tolvaptan, a selective V2 receptor antagonist, which has been sion toward ESKD. In theory, tolvaptan could have both BP-increasing and BP-decreasing effects. To investigate the mag- shown to slow the rate of disease progression in patients at nitude and time course of the effect of tolvaptan use on BP, the 10,11 risk of rapid kidney function decline. By preventing bind- authors conducted a post hoc analysis of data from the TEMPO ing of vasopressin to the V2 receptor, tolvaptan induces neph- 3:4 trial, which randomized 1445 patients with autosomal domi- rogenic diabetes insipidus, which causes a compensatory rise nant polycystic kidney disease to tolvaptan or placebo. Their anal- in plasma vasopressin.12 It is important to note that tolvaptan ysis shows that directly after start of tolvaptan therapy, BP does not change, but in the long term, BP gradually becomes lower has a high selectivity for the V2 receptor and does not block the in patients with tolvaptan compared with placebo. This observa- 13 effect of vasopressin on the V1a receptor. Consequently, tion might be attributed to the beneficial effect of tolvaptan on given the higher levels of vasopressin induced by treatment, disease progression, a sustained natriuretic effect, or both. the V1a receptor is activated more than usual. This could have undesired off-target effects, of which a change in BP summary, 1445 patients were enrolled for 2:1 randomization could be one. to either treatment with tolvaptan or placebo between 2007 Tolvaptan could theoretically have several effects on BP. In and 2009. Inclusion criteria were age between 18 and 50 years, the short term, via increased V1a receptor activation, one total kidney volume (TKV) measured by magnetic resonance could expect an increase in vascular resistance and thus, an imaging .750 ml, and Cockcroft–Gault-calculated creatinine 14,15 increase in BP. However, as mentioned above, V1a recep- clearance of 60 ml/min or greater. Exclusion criteria included tor activation has a variety of effects. It also increases sodium but were not limited to concomitant diseases that were likely 16 excretion, thereby potentially decreasing BP. In addition, to confound study end points, such as poorly controlled diabe- preventing vasopressin binding to the V2 receptor could result tes mellitus. Participants allocated to the treatment arm were – in a reduction of BP because of loss of V2 receptor mediated started on a dosage regimen of 45 mg in the morning and 15 ENaC channel activation and therefore, sodium reabsorption, mg in the late afternoon, which was increased to 60/30 mg loss of renin angiotensin aldosterone system (RAAS) activa- after 1 week and thereafter, to 90/30 mg in the third week if tol- – tion due to a decrease of V2 receptor dependent renin pro- erated. Participants remained on the highest tolerated dose for 17,18 duction, and loss of circulating volume due to aquaresis. 36 months. Primary outcome was the annual rate of change in Finally, in the long term, tolvaptan ameliorates the rate of TKV, and secondary outcomes included annual rate of change disease progression, possibly also reducing the develop- in eGFR. Tolvaptan efficacy was studied on top of standard ment of secondary symptoms of kidney disease, such as clinical care, which included optimal BP control. Study rec- hypertension. ommendations defined in 2007, at the start of the trial, consid- The original publication of the TEMPO 3:4 trial disclosed 10 ered optimal control to start antihypertensive treatment at a only limited information on the effect of tolvaptan on BP. systolic BP of 130 mm Hg or a diastolic BP of 85 mm Hg. Change in BP was expressed as worsening hypertension, Adjustments in antihypertensive therapy could be made dur- defined as a change in BP category, or as worsening of hyper- ing the entire study period in case BP exceeded the limits on tension requiring an increase in hypertensive treatment. No two consecutive visits. RAAS inhibitors were recommended effect was found. However, the use of a categorical variable as first-line antihypertensive drug. The choice for second- as outcome measure may have resulted in a loss of power to line therapy was left to the discretion of the treating physician. find differences between the two study groups. Therefore, Long-term use of diuretics was discouraged for safety reasons. this study investigates the magnitude and time course of the This study was approved by all local ethics committees of effect of tolvaptan on BP expressed as a continuous variable, the participating sites and was conducted according to the not only taking into account measured values but also, use International Conference of Harmonization Good Clinical of BP-lowering medication. Practice Guidelines. Written informed consent was obtained from all participants. METHODS Data Collection Study Population and Design Data were collected at baseline, during treatment at week 3, at This study is a post hoc analysis of the TEMPO 3:4 trial, a pro- month 3, and thereafter, after every 4 months for 36 months. A spective, multicenter, double-blinded, randomized, con- follow-up visit was scheduled between 1 and 3 weeks after the trolled trial to assess the efficacy of tolvaptan in patients last dose of study medication. At every visit, a physical exam- with early-stage ADPKD (ClinicalTrials.gov identifier ination was performed, including BP measurement. Systolic NCT00428948). A detailed study protocol of this randomized, BP and diastolic BP were measured at the brachial artery after controlled trial has been published previously.10,19 In 5 minutes of rest in seated position, either manually or with a

1802 JASN JASN 32: 1801–1812, 2021 www.jasn.org CLINICAL RESEARCH validated oscillometric device. BP was measured twice, and if by baseline disease severity–related characteristics (sex, these values varied by .5 mm Hg, they were repeated two median age, Mayo htTKV class, median eGFR, and median more times. Mean of these two or four values was documented. copeptin value). In all of these analyses, a P value ,0.05 was In addition, review of medication use and laboratory assessment considered to indicate statistical significance. Statistical anal- was performed. Plasma sodium, cholesterol, and glucose were yses were performed using SAS 9.4 and GraphPad Prism 8.4.2. measured using standard methodology. Copeptin was measured as a surrogate marker for vasopressin, with an automatic immu- nofluorescence assay with coefficients of variation of 8.0% and RESULTS 10.0%, respectively (BRAHMS GmbH, Henningsdorf, Ger- many).20 TKV was measured by manual tracing of magnetic res- Population at Baseline onance images taken without use of a contrast agent. TKV was In this study, 1445 patients were included, of which 961 were corrected for height (height-adjusted total kidney volume randomized to tolvaptan and 484 were randomized to placebo. [htTKV]) and age to determine Mayo htTKV class, a classifica- There were no significant differences in baseline characteristics tion system designed to predict future disease progression.21 between both study arms (Table 1). Table 2 shows BP and BP-related patient characteristics. At baseline, pressures were BP-Related Patient Characteristics comparable in both study arms, with systolic and diastolic Mean arterial pressure was calculated as diastolic BP BPs of 129614 over 82.569.9 mm Hg for tolvaptan and 10.4123(systolic BP – diastolic BP).22 Hypertension was 128614 over 82.469.3 mm Hg for placebo. Hypertension defined as either having a systolic BP $140 mm Hg or diastolic was present in 81% of the patients randomized to receive tol- BP $90 mm Hg or use of antihypertensive medication. Anti- vaptan and 84% of the patients randomized to receive placebo. hypertensive drugs were divided into five classes: RAAS inhib- In both study arms, 77% of the patients were at baseline on anti- itors, b-blocking agents, calcium channel blockers, diuretics, hypertensive therapy,mostly RAAS inhibitors.Average dosages and others. To be able to compare dosages between different of these antihypertensives were similar in both study arms, classes of antihypertensives, these were expressed as defined namely 1.4461.38 versus 1.4061.34 defined daily doses, daily dose. Reference values to calculate defined daily doses respectively. Plasma copeptin, as a marker of vasopressin, did were obtained from the World Health Organization Collabo- also not differ between the two study arms at baseline (Table 2). rating Centre for Drug statistics Methodology (https://www. Baseline characteristics of patients stratified for hyperten- whocc.no/atc_ddd_index/; accessed on the 25th of March sion status can also be found in Table 1. In patients with nor- 2020) (Supplemental Table 1). motension at baseline, BP at baseline did not differ between study arms, (Supplemental Table 2), even though patients ran- 5 fi Statistical Analyses domized to receive tolvaptan (n 179) had a signi cantly BP and BP-related patient characteristics were evaluated at higher body mass index, used a cholesterol-lowering drug baseline, after short-term use of tolvaptan (3 weeks), after more often, and had a higher htTKV compared with patients 5 longer-term use (36 months), and at the post-treatment fol- who were to receive placebo (n 79) in this subpopulation low-up visit. Change between the baseline and 36 months vis- (Table 1). In patients diagnosed with hypertension at baseline, fi its was studied as intention to treat analysis, including the last there were no signi cant differences in BP or other baseline 5 study visits of patients who ended their participation in the patient characteristics between tolvaptan- (n 782) and 5 study prematurely. Depending on distribution, data were pre- placebo-treated (n 405) study arms. sented as mean 6 SD, median (interquartile range), or per- centage of total, unless stated otherwise. Comparisons Acute Effect of Tolvaptan between tolvaptan and placebo study arms were made with t After 3 weeks of study treatment, copeptin was significantly test for parametric, Mann–Whitney U test for nonparametric higher in the tolvaptan arm compared with the placebo arm. data and Fishers exact tests for categorical data. For compari- At this time point in the study, there were no significant differ- son of the change of BP over time between the study arms in ences in BP-related patient characteristics, such as systolic and the overall study population presented in figures, mixed model diastolic BP or number and dose of antihypertensives, repeated measures analyses were used. Within-subject com- between the tolvaptan and placebo arms (Table 2). BP had parisons between two study visits were performed with paired decreased significantly from baseline in both arms with con- t test for parametric data, Wilcoxon signed rank test for non- currently a slight increase in dosage of antihypertensives. parametric data, and McNemar test for categorical data. As Use of tolvaptan caused body weight to decrease from secondary analysis, patients were divided into two subgroups 79.7618.3 to 78.8618.2 kg and plasma sodium to increase on the basis of hypertension status at baseline (e.g., hyperten- from 140.462.1 to 142.662.6 mmol/L (both P,0.001). sion, as defined above, or normotension). To test the robust- Changes in copeptin levels were significantly associated with ness of primary findings, effect of use of tolvaptan on mean the acute changes in body weight (R50.08; P50.02) and arterial pressure was assessed in several subgroups defined plasma sodium (R50.16; P,0.001) but not with BP in the

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Table 1. Baseline characteristics of TEMPO 3:4 trial participants for the overall study population and according to hypertension status at baseline Overall Normotensive at Baseline Hypertensive at Baseline Characteristic Tolvaptan Placebo Tolvaptan Placebo Tolvaptan Placebo No. 961 484 179 79 782 405 Men, % 52 52 38 35 55 55 White, % 84 84 78 76 86 86 Age, yr 38.667.1 38.867.1 36.767.5 36.967.6 39.066.9 39.267.0 Height, m 1.7460.10 1.7460.10 1.7160.10 1.7160.09 1.7460.10 1.7460.10 Weight, kg 79.7618.3 78.6618.3 72.5617.3 68.4614.8 81.4618.2 80.6618.3 Body mass index, kg/m2 26.365.1 25.965.0 24.464.6 23.263.5a 26.765.1 26.465.1 Blood glucose, mmol/L 5.060.9 5.060.9 5.060.9 4.960.8 5.060.9 5.060.9 Glucose-lowering drugs, % yes 0.6 0.6 0 0 0.8 0.7 Plasma cholesterol, mmol/L 5.260.8 5.260.8 5.160.7 5.160.8 5.260.9 5.260.8 Cholesterol-lowering drugs, % yes 13 12 8.4 0a 14 14 eGFR, ml/min per 1.73 m2 81621 82623 90619 95622 79621 80622 htTKV, ml/m 9796515 9586483 7806331 6826259a 10246538 10126499 Mayo htTKV class, % 1A —— — — — — 1B 8 8 10 6 7 6 1C 37 40 41 56 34 36 1D 37 33 31 20 36 36 1E 16 16 12 9 20 19 2236922 Differences between study arms are tested with t test for parametric, Mann–Whitney U test for nonparametric, and Fishers exact test for categorical data. eGFR was calculated with the Chronic Kidney Disease Epidemiology Collaboration formula. aP,0.05. tolvaptan arm. In the placebo arm, weight increased signifi- Supplemental Figure 1, it is shown that after 28 months of cantly (P50.007), and plasma sodium remained stable treatment, average mean arterial pressure was also signifi- (P50.85). cantly lower in the tolvaptan arm compared with placebo In the subgroup with normotension at baseline, diastolic BP (99.769.4 versus 100.9610.2 mm Hg, respectively; P50.04). after 3 weeks was slightly but statistically significantly higher in Of note, throughout the study, plasma sodium and copeptin the tolvaptan arm when compared with the placebo arm levels of the tolvaptan-treated patients were higher than those (79.768.9 versus 77.168.2 mm Hg, respectively; P50.03), of the placebo-treated patients (P,0.001). Body weight did despite start of antihypertensive therapy dosed at an average not differ (Table 2). of 0.1260.66 defined daily doses in the tolvaptan arm versus In subjects with normotension at baseline, no difference in 0.0160.06 in the placebo arm (P50.12). No differences in sys- systolic BP, diastolic BP (Figure 2), and mean arterial pressure tolic BP were noted. In the subgroup with hypertension at base- (Supplemental Figure 2) was observed between both study line, no differences were found between the two study arms arms during the trial period, whereas average dose of antihy- after 3 weeks in diastolic BP, in systolic BP, or in number and pertensive drugs was slightly higher in the tolvaptan-treated dose of antihypertensive drugs (Supplemental Table 2). subjects at months 20 and 24 but not at week 3 or at the last visit. After 3 years, 42% and 33% of the patients who did not Long-Term Effects of Tolvaptan have an elevated BP at baseline had developed hypertension Figure 1 shows systolic and diastolic BP and dose of antihyper- in the tolvaptan-treated and placebo-treated study arms, tensive drugs over the course of the trial. Over time, a small respectively (P50.13). In the subgroup of patients diagnosed difference in BP between the two study arms occurred, namely with hypertension at baseline, similar observations as in the a significant decrease in systolic BP after 28 months and dia- overall study population were made, with a lower systolic stolic BP after 32 months. At the end of the treatment period BP after 28 month, a lower diastolic BP after 32 months both systolic and diastolic BP were lower in the tolvaptan arm (Figure 2), and a lower mean arterial pressure after 32 months compared to placebo arm, with a systolic BP of 129 6 14 versus (Supplemental Figure 2). 126 6 13, respectively, P50.002 and diastolic BP of 82.6 6 10 versus 81.2 6 9.5 mmHg, respectively, P50.01. Meanwhile, a Shortly after Ending Long-Term Use of Tolvaptan similar average number of antihypertensive drugs (1.46 6 1.01 Approximately 3 weeks after withdrawal of study medica- in the tolvaptan arm versus 1.48 6 1.07 in the placebo arm, tion, data were available for 734 patients participating in the P50.68) was given at a similar dose (2.07 6 1.77 versus 2.05 tolvaptan arm and 407 patients participating in the placebo 6 1.84 defined daily doses, respectively, P50.83). In arm. Differences in BP that were present at month 36 had

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Table 2. Effect of tolvaptan on BP and BP-related patient characteristics during the TEMPO 3:4 trial Characteristic Tolvaptan Placebo P Value Baseline No. 961 484 Systolic BP, mm Hg 129614 128614 0.68 Diastolic BP, mm Hg 82.569.9 82.469.3 0.95 Mean arterial pressure, mm Hg 101.5610.5 101.4610.2 0.80 Heart rate, beats per minute 69610 69611 0.42 Hypertension, % 81 84 0.31 Use of AHT, % 77 77 0.79 No. of AHT classes per patient 1.2060.94 1.2560.97 0.42 Dosage of AHT per patient, DDD 1.4461.38 1.4061.34 0.53 Body weight, kg 79.7618.3 78.6618.3 0.28 Plasma sodium, mmol/L 140.462.1 140.362.0 0.57 Plasma copeptin, pmol/L 6.3 [3.8–11.5] 6.6 [3.8–10.5] 0.78 Week 3 No. 929 478 Systolic BP, mm Hg 126613 126613 0.90 Diastolic BP, mm Hg 81.669.4 80.669.2 0.07 Mean arterial pressure, mm Hg 99.9610.0 99.369.8 0.29 Heart rate, beats per minute 70611 69611 0.70 Hypertension, % 83 82 0.82 Use of AHT, % 78 78 0.89 No. of AHT classes per patient 1.2260.94 1.2961.01 0.23 Dosage of AHT per patient, DDD 1.7061.64 1.7361.67 0.77 Body weight, kg 78.8618.2 78.5618.0 0.80 Plasma sodium, mmol/L 142.662.6 140.362.2 ,0.001 Plasma copeptin, pmol/L 21.9 [16.3–28.1] 6.0 [3.6–10.2] ,0.001 Year 3 or early end of treatment No. 940 482 Systolic BP, mm Hg 126613 129614 0.002 Diastolic BP, mm Hg 81.269.5 82.6610.0 0.01 Mean arterial pressure, mm Hg 99.7610.0 101.5610.7 0.002 Heart rate, beats per minute 70611 70610 0.75 Hypertension, % 87 87 .0.99 Use of AHT, % 82 83 0.77 No. of AHT classes per patient 1.4061.03 1.4961.09 0.15 Dosage of AHT per patient, DDD 2.0261.81 2.0861.90 0.52 Body weight, kg 80.7618.9 80.0618.4 0.57 Plasma sodium, mmol/L 141.662.6 140.362.3 ,0.001 Plasma copeptin, pmol/L 19.9 [15.0–27.5] 7.2 [4.0–13.4] ,0.001 Follow-up visit post-treatment No. 734 407 Systolic BP, mm Hg 127612 128612 0.42 Diastolic BP, mm Hg 81.068.6 81.768.8 0.22 Mean arterial pressure, mm Hg 99.969.1 100.669.4 0.26 Heart rate, beats per minute 70610 69610 0.47 Hypertension, % 89 87 0.39 Use of AHT, % 86 85 0.60 No. of AHT classes per patient 1.4861.03 1.5461.09 0.40 Dosage of AHT per patient, DDD 2.1461.83 2.1461.88 0.97 Body weight, kg 81.0618.7 79.5617.9 0.18 Plasma sodium, mmol/L 139.862.2 140.462.4 ,0.001 Plasma copeptin, pmol/L 6.4 [4.0–11.6] 6.9 [4.3–13.1] 0.08 Differences between study arms were tested with t test for parametric, Mann–Whitney U test for nonparametric, and Fishers exact test for categorical data. Year 3 or early end of treatment signifies that this is an intention to treat analysis also including data of patients who ended their participation in this trial ahead of the final study visit. Mean arterial pressure was calculated as diastolic BP 10.4123(systolic BP – diastolic BP). Of note, copeptin was measured only in patients who completed the entire study, not in patients with early end of treatment. AHT, antihypertensive therapy; DDD, defined daily dose.

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135

130 * * **

125 Systolic blood pressure (mmHg) 120

85 **

75 Diastolic blood pressure (mmHg) 70

1 Antihypertensives (DDD)

0 0w34812162024283236FU Treatment duration No. of patients Tolvaptan 961 921 862 833 814 790 773 761 756 745 739 734 Placebo 484 477 473 461 454 445 436 430 422 419 416 407

Figure 1. BP and BP-lowering medication of participants during the TEMPO 3:4 trial. The tolvaptan study arm (n5961) is represented by solid circles, and placebo (n5484) 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. *P50.05 calculated with a mixed model repeated measures analysis. evened out between the two study arms during this follow-up the placebo arm, systolic BP and diastolic BP did not change. visit (Table 2). In the tolvaptan arm, systolic BP had increased Notwithstanding that at follow-up, no differences between significantly from 125612 to 127612 mm Hg (P,0.001), and tolvaptan and placebo arms were found, in a within–study diastolic BP had increased from 80.468.9 to 81.068.6 mm Hg arm comparison, systolic BP and diastolic BP measured dur- (P50.04); however, the number and dose of antihypertensive ing the follow-up visit were significantly lower compared medications that were used in both arms remained similar. In with baseline in the tolvaptan arm (P50.007 and P50.001,

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A B 135 135 * *** 130 130

125 125

120 120

Systolic blood pressure (mmHg) 115 Systolic blood pressure (mmHg) 115

85 85 ** *

80 80

75 75

Diastolic blood pressure (mmHg) 70 Diastolic blood pressure (mmHg) 70

3 3

2 2

1 ** 1 Antihypertensives (DDD) Antihypertensives (DDD)

0 0 0 w34 8 12162024283236FU 0 w34 8 12162024283236FU Treatment duration Treatment duration

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 (n5258), and (B) includes patients with hypertension at baseline (n51187). 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. *P50.05. respectively) but not in the placebo arm (P50.27 and P50.10, was below the level in the placebo arm (140.462.4 mmol/L; respectively). Meanwhile, the number and dose of antihyper- P,0.001). tensives had increased equally in both study arms (Table 3). Within subclasses of RAAS inhibitors (e.g., ACE inhibitors, Treatment Effect of Tolvaptan in Subgroups angiotensin II receptor blockers, renin inhibitors, and miner- The placebo-adjusted effect of tolvaptan on mean arterial alocorticoid receptor antagonists) and diuretics (e.g., loop diu- pressure after 36 months of treatment did not differ between retics, thiazide diuretics, and potassium-sparing diuretics), subgroups defined on the basis of baseline age, sex, hyperten- there also were no differences in their use between the study sion status, eGFR, Mayo htTKV class, plasma copeptin, and arms (Supplemental Table 3). use of an RAAS inhibitor (Figure 3). After withdrawal of study medication, weight increased in the subjects previously receiving tolvaptan from 80.4618.6 to 81.0618.7 kg, and plasma sodium decreased from 141.662.6 DISCUSSION to 139.862.2 mmol/L (both P,0.001). In the placebo arm, weight and plasma sodium did not change. Notably, plasma In this post hoc study of the TEMPO 3:4 trial, we investigated sodium of the tolvaptan-treated subjects at this final visit the magnitude and time course of the effect of tolvaptan on BP,

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Table 3. Use of antihypertensive drugs at baseline and after ending long-term use of Tolvaptan Tolvaptan, n5734 Placebo, n5407 Class of Antihypertensives P Value for Differencea Baseline Follow-Up P Value Baseline Follow-Up P Value Calcium channel blocker % of participants 20.4 28.2 ,0.001 23.6 32.4 ,0.001 0.16 Defined daily dose 0.3 0.5 0.002 0.4 0.6 0.09 0.67 RAAS inhibitor % of participants 72.5 82.0 ,0.001 72.5 80.3 ,0.001 0.15 Defined daily dose 1.4 1.3 0.19 1.3 1.3 0.69 0.67 b-blocking agent % of participants 17.8 23.3 ,0.001 19.4 23.8 ,0.001 0.52 Defined daily dose 0.3 0.3 0.23 0.2 0.3 0.24 0.74 Diuretic % of participants 4.8 4.2 0.55 4.7 3.7 0.39 0.26 Defined daily dose 0.1 0.1 0.21 0.0 0.1 0.02 0.25 Other antihypertensive % of participants 4.2 7.2 ,0.001 4.7 8.8 0.001 0.57 Defined daily dose 0.1 0.2 0.13 0.1 0.2 0.51 0.67 Total defined daily dose Defined daily dose 1.5 2.2 ,0.001 1.4 2.3 ,0.001 0.06 In this table, the average defined daily dose is calculated in the subjects for whom data were available at both baseline and follow-up visit. Within–study arm comparisons were made with a paired t test or McNemar test as appropriate. aP value for difference between the change of antihypertensive treatment in the tolvaptan arm versus the placebo arm tested using the t test or chi-squared test as appropriate. not only taking into account measured BP as a continuous a decrease in body weight and increase in plasma sodium after variable but also, use of BP-lowering medication. We did start of study medication in the tolvaptan arm but not in the not find an acute effect but observed a gradually developing placebo arm. This effect on total body water has been studied difference in BP between study arms in favor of tolvaptan previously as a therapeutic modality in patients with heart fail- – that was not explained by a difference in antihypertensive ure or hyponatremia as an alternative for diuretics.23 25 Nota- treatment. This difference leveled off after stopping study bly, in our tolvaptan-treated subjects, change in copeptin was medication. associated with change in sodium concentration and body The acute effect of a V2 receptor antagonism was studied weight but not with change in BP, possibly reflecting the after a 3-week titration period in which the highest tolerated opposing mechanisms that are at play. It might be suggested dose of medication was reached. At this visit, none of the that a decreasing effect on BP is counteracted by activation parameters assessed to monitor changes in BP were signifi- of the RAAS system due to intravascular volume depletion. cantly different between tolvaptan- and placebo-treated sub- However, it has been shown in both experimental as well as jects. In both arms, BP had decreased. This may be explained human studies that tolvaptan, in contrast to other diuretics, – by the higher dosages of antihypertensive drugs that were used does not increase renin or aldosterone levels.13,26 28 Given at week 3, prescribed by physicians aiming to reach adequate that markers of the RAAS were not measured, this could not BP control. Alternatively, it could also be that participants had be further addressed in our study. Three small-scale studies grown more familiar with the study setting, which could have with crossover designs have previously investigated the acute resulted in reduction of stress and consequently, a lower BP. In effects of tolvaptan in patients with ADPKD. These studies, the tolvaptan-treated subjects, two additional opposing mech- which included 18, 20, and 27 patients, also found no acute anisms may have been in action, as set out in the introduction. effect on BP after a single dose or 1–3 weeks of tolvaptan treat- – Use of tolvaptan led to a more than three-fold increase in ment.29 31 Of note, given that in our overall population the BP copeptin, measured as a surrogate marker for vasopressin, as effect of tolvaptan might have been obscured by the use of central compensation for the loss of renal urine concentrating BP-lowering medication, we also studied the normotensive capacity. This hormone has regulatory functions that can subgroup separately that did not use such medication as base- increase as well as decrease BP. Although V1a receptors on line. In this specific subgroup, there was a suggestion of an the vascular wall induce vasoconstriction and thus, increase effect of tolvaptan on vascular tone, given that diastolic BP in BP, V1a receptors present in various segments of the kid- was significantly higher in the treatment arm versus the pla- neys have a counterbalancing effect via natriuresis.16,17 These cebo arm and slightly more patients in the tolvaptan arm effects, in combination with aquaresis mediated by tolvaptan had started antihypertensive therapy. However, after 3 weeks blocking the V2 receptor, can lead to a reduction in total of treatment, no effect on systolic BP was observed in this nor- body water and in circulating volume. Indeed, we observed motensive subgroup, and in the hypertensive subgroup, an

1808 JASN JASN 32: 1801–1812, 2021 www.jasn.org CLINICAL RESEARCH

Subgroup Treatment effect of tolvaptan on mean Treatment effect Change in mean arterial pressure from baseline to year 3 or arterial pressure in mmHg in mmHg early end of treatment in mmHg

p-value Tolvaptan Placebo for heterogeneity Overall -1.77 -1.63 0.15 Sex 0.06 Male -2.92 -1.58 1.34 Female -0.54 -1.68 -1.14 Hypertension 0.50 No -0.93 2.07 3.00 Yes -2.07 -2.48 -0.41 Age 0.86 > 39 year -1.67 -1.95 -0.28 ≤ 39 year -1.89 -1.33 0.57 eGFR 0.37 ≤ 80 ml/min/1.73m2 -2.30 -1.99 0.31 > 80 ml/min/1.73m2 -1.15 -1.22 -0.07 Mayo htTKV class 0.67 1E -3.15 -2.14 1.01 1D -0.98 -1.63 -0.66 1C -2.06 -1.41 0.65 1B + 2 -0.29 -0.98 -0.69 Copeptin 0.48 > 6.41 pmol/L -2.49 -1.88 0.61 ≤ 6.41 pmol/L -1.53 -1.61 -0.08 Use of RAAS inhibitor 0.49 yes -1.50 -1.72 -0.22 no -2.49 -1.41 1.07

-10 -5 0 5

Figure 3. Effect of tolvaptan on change 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 10.4123(systolic BP – diastolic BP). effect on diastolic BP was not confirmed. The importance of decrease in BP could also be a reflection of tolvaptan-induced this isolated finding of increase in diastolic BP in the normo- natriuresis. Given that this study indicates that this natriuretic tensive subgroup can, therefore, be debated. effect is small, it may take a longer period of sustained V2 Next, the effect of long-term use of tolvaptan was studied. antagonism to elicit an effect on BP. The BP-lowering effect During 3 years of treatment, a difference between systolic BP of tolvaptan in this 3-year trial is of course relatively minor. and diastolic BP in the subjects with tolvaptan versus placebo However, it should be noted that in clinical practice, tolvaptan emerged gradually. At the end of 3 years, systolic BP and dia- is meant to be prescribed as a renoprotective agent for a pro- stolic BP were 3 and 1.4 mm Hg lower, respectively, in the tol- longed period of time. Given that the BP-lowering effect of tolvaptan compared with the placebo arm, whereas number and vaptan increases gradually over time, it may be expected that a dose of antihypertensive drugs did not differ between the two clinically meaningful effect on BP will arise over the years. Of study arms. We interpret this slowly occurring BP-lowering course, this is an extrapolation of our findings beyond the effect to be the result of attenuation of the rate of disease pro- duration of this study, and future studies using longer-term gression with tolvaptan. When the rate of kidney function data are needed to prove this hypothesis. decline and the TKV growth are reduced by therapy, develop- After discontinuation of tolvaptan, a withdrawal effect was ment of secondary symptoms of kidney disease, such as an observed. Both systolic and diastolic BP increased to a level increase in BP, will also be reduced. Alternatively, this gradual similar to that in the placebo arm. This was not explained by

JASN 32: 1801–1812, 2021 BP during Tolvaptan Use 1809 CLINICAL RESEARCH www.jasn.org concurrent changes in antihypertensive therapy. Simulta- to a sustained natriuretic effect, possibly in combination with neously, body weight increased, and plasma sodium decreased the beneficial effect of tolvaptan on disease progression. When significantly, indicating that the observed change in BP might after 3 years of treatment, tolvaptan is stopped, there is an be the result of an increase in circulating volume. These increase in BP in tolvaptan-treated patients up to a level that changes in sodium and body weight were anticipated, as is again similar to that of the placebo-treated subjects. This they mirror the changes directly after start of tolvaptan at increase is likely caused by the sudden recovery of the week 3. It should be noted that after cession of medication, V2-mediated antidiureris and sodium reabsorption, resulting plasma sodium in the tolvaptan arm was significantly lower in an excess of circulating volume. This acute effect of stop- compared with the placebo arm, which may indicate that there ping tolvaptan is expected to disappear in the long term. is an overcorrection. Although hypothetical, this might be the result of a change in threshold of the osmolar sensory cells that regulate plasma osmolality, caused by the 3 years of tolvaptan- DISCLOSURES induced aquaresis. Reset of the osmotic threshold for thirst has been observed in other states of water imbalance, such as A.B. Chapman, O. Devuyst, R.T. Gansevoort, R.D. Perrone, and V.E. Tor- SIADH as well as psychogenic polydipsia.32,33 We expect res were members of the Steering Committee of the TEMPO 3:4 Trial and are that over time this set point will return to its prestudy level. consultants for Otsuka Pharmaceutical Development and Commercializa- Follow-up data to corroborate this notion are unfortunately tion, Inc. (Rockville, MD). J. Lee, H. Li, and J. Ouyang are employees of Otsuka. Additionally, A.B. Chapman reports consultancy agreements with not available, but this line of reasoning matches our clinical and/or research funding from and/or honoraria from Otsuka, Janssen, Pfizer experience that after stopping tolvaptan, patients report that Pharmaceuticals, Reata, and Sanofi Pharmaceuticals, National Institutes of they remain drinking abundantly for some time, a habit that Health (NIH), and UpToDate, speakers bureau for Jannsen and Otsuka, fades out over a couple of weeks to months. and membership of the Special Emphasis Panel and Review Panel, NIH/ Some limitations of our study should be acknowledged, National Institute of Diabetes and Digestive and Kidney Diseases, and mostly those inherent to the post hoc design. BP would ideally SBIR. O. Devuyst reports consultancy agreements with Alnylam, Galapagos, and Sanofi and research funding from Otsuka and Roche; and scientific have been studied over time without changing antihyperten- advisor or membership via editorial boards of CJASN, Kidney Interna- sive therapy to answer our study question irrefutably. Such a tional, Nephrology Dialysis Transplantation, OJRD, Peritoneal Dialysis strategy is, however, not possible in clinical practice because International, and Pflugers€ Archiv. R.T. Gansevoort reports consultancy subjecting a patient to suboptimal BP control during a agreements with and/or research funding from and/or honoraria from Astra- fi fi 3-year period would be unethical. Second, the choice of BP Zeneca, Bayer, Galapagos, and Sano -Genzyme, Otsuka, and scienti c advisor or membership of the American Journal of Kidney Disease, CJASN, Journal therapy was dependent on the discretion of the treating phy- of Nephrology, Kidney360, Nephrology Dialysis Transplantation, and Nephron sician, a given that may have introduced variability in our out- Clinical Practice. J. Lee has ownership interest in Pfizer. R.D. Perrone reports comes. Because we did not find differences between the two consultancy agreements with and/or research funding from and/or honoraria study arms in the number or dose of antihypertensives overall from Navitor, Palladiobio, Reata, Sanofi-Genzyme, Kadmon, Otsuka, and sci- nor of specific classes of antihypertensives, this is unlikely to entific advisor and membership of UpToDate. V. Torres reports consultancy have induced bias. Third, BP could have been assessed more agreements with and/or research funding from Acceleron Pharma, Blueprint Medicines, Mironid, Otsuka, Palladio Biosciences, Reata, and Sanofi, hono- accurately with home measurements or even 24-hour meas- raria from Otsuka (to institution); and scientific advisor or membership urements, instead of measurement during an outpatient clinic with Mironid, Otsuka, and Sanofi. The remaining author has nothing to 34 visit. In the clinic, BP was measured after 5 minutes of rest disclose. with either a manual or oscillometric device. Despite the rela- tive insensitivity of our BP measurement method, we still observed changes in BP during long-term tolvaptan use. Given FUNDING that tolvaptan induces a profound polyuria and thirst, thus possibly deblinding the study groups to the researchers, one The TEMPO 3:4 trial was funded by Otsuka Pharmaceutical (Tokyo, Japan) may argue that the decrease in BP is merely produced by an and Otsuka Pharmaceutical Development and Commercialization, Inc. observer bias.35 Then again, all participants were encouraged (Rockville, MD). Measurement of copeptin was sponsored by the manufac- fl turer of the copeptin proAVP KRYPTOR assay (BRAHMS GmbH, Hennings- to increase their uid intake during the trial, thereby obscur- dorf, Germany). ing this potential telltale sign. Finally, vasopressin was not measured directly but by its more easy and reliable to measure surrogate marker copeptin.36 ACKNOWLEDGMENTS To conclude, this study demonstrates that start of tolvaptan treatment in patients with ADPKD does not have a clinically We are grateful to all participants and investigators for their contribution to significant short-term effect on BP, perhaps due to simulta- the TEMPO 3:4 trial. neously occurring BP-increasing and BP-lowering effects This post hoc analysis of the TEMPO 3:4 study was conceptualized by A.B. Chapman and R.T. Gansevoort; statistical analyses were performed that cancel out. During prolonged use, however, gradually by J. Lee, H. Li, and J. Ouyang; data interpretation was done by all authors; BP becomes lower in patients on tolvaptan compared with figures were made by J.E. Heida; the manuscript draft was written by R.T. patients on placebo. This observation can likely be attributed Gansevoort and J.E. Heida; the manuscript was revised by all authors;

1810 JASN JASN 32: 1801–1812, 2021 www.jasn.org CLINICAL RESEARCH and all authors approved the final version of the manuscript and can be held predict disease progression and tolvaptan efficacy in autosomal dom- accountable for all aspects of the work. inant polycystic kidney disease. Kidney Int 96: 159–169, 2019 13. Miyazaki T, Fujiki H, Yamamura Y, Nakamura S, Mori T: Tolvaptan, an orally active vasopressin V(2)-receptor antagonist - pharmacology and SUPPLEMENTAL MATERIAL clinical trials. Cardiovasc Drug Rev 25: 1–13, 2007 14. Feng JJ, Arendshorst WJ: Enhanced renal vasoconstriction induced by vasopressin in SHR is mediated by V1 receptors. Am J Physiol This article contains the following supplemental material online at http:// 271: F304–F313, 1996 jasn.asnjournals.org/lookup/suppl/doi:10.1681/ASN.2020101512/-/ 15. Cowley AW Jr, Skelton MM, Kurth TM: Effects of long-term vasopres- DCSupplemental. sin receptor stimulation on medullary blood flow and arterial pressure. Supplemental Table 1. Conversion table for antihypertensive medication Am J Physiol 275: R1420–R1424, 1998 fi regimens to de ne daily dosages. 16. Perucca J, Bichet DG, Bardoux P, Bouby N, Bankir L: Sodium excretion Supplemental Table 2. Effect of tolvaptan on BP and BP-related patient in response to vasopressin and selective vasopressin receptor antag- characteristics during the TEMPO 3:4 trial in subgroups according to hyper- onists. J Am Soc Nephrol 19: 1721–1731, 2008 tension status at baseline. 17. Bankir L, Bichet DG, Bouby N: Vasopressin V2 receptors, ENaC, and Supplemental Table 3. Distribution of the use of subclasses of RAAS inhib- sodium reabsorption: A risk factor for hypertension? Am J Physiol itors and diuretics in the overall study population. Renal Physiol 299: F917–F928, 2010 Supplemental Figure 1. Mean arterial pressure and average dosage of anti- 18. 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AFFILIATIONS

1Department of Nephrology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands 2Division of Nephrology and Hypertension, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota 3Institute of Physiology, University of Zurich, Zurich, Switzerland 4Division of Nephrology, Universite Catholique de Louvain, Brussels, Belgium 5Division of Nephrology, Department of Medicine, Tufts Medical Center, Tufts University School of Medicine, Boston, Massachusetts 6Otsuka Pharmaceutical Development & Commercialization, Inc., Rockville, Maryland 7Section of Nephrology, University of Chicago, Chicago, Illinois

1812 JASN JASN 32: 1801–1812, 2021 Blood pressure during tolvaptan use

Supplementary materials

Page 2. Supplementary Table 1. Conversion table for antihypertensive medication

regimens to define daily dosages

Page 3. Supplementary Table 2. Effect of tolvaptan on blood pressure (BP) and BP

related patient characteristics during the TEMPO 3:4 trial in subgroups

according to hypertension status at baseline

Page 6. Supplementary Table 3. Distribution of the use of subclasses of RAAS

inhibitors and diuretics in the overall study population

Page 7. Supplementary Figure 1. Mean arterial pressure and average dosage of

antihypertensive drugs (in defined daily dosages, DDD) of participants during

the TEMPO 3:4 trial.

Page 8. Supplementary Figure 2. Mean arterial pressure and average dosage of

antihypertensive drugs (in defined daily dosages, DDD) in subgroups of the

trial participants according to baseline hypertension status

Blood pressure during tolvaptan use

Supplementary Table 1. Conversion table for antihypertensive medication regimens to define daily dosages. As according to the accompanying guidelines all combination tablets were counted as one defined daily dose per tablet.

Defined daily dosage Defined daily dosage Generic name Generic name (mg) (mg) Aliskiren 150 Lacidipine 4 Amiloride 10 Lercanidipine 10 Amlodipine 5 Lisinopril 10 Atenolol 75 Losartan 50 Barnidipine 10 Manidipine 10 Benazepril 7.5 Methyldopa 1000 Bendroflumethiazide 2.5 Metolazone 5 Betaxolol 20 Metoprolol 150 Bisoprolol 10 Minoxidil 20 Bumetanide 1 Moxonidine 0.3 Candesartan 8 Nadolol 160 Captopril 50 Nebivolol 5 Carvedilol 37.5 Nicardipine 90 Celiprolol 200 Nifedipine 30 Chlorothiazide 500 Nitrendipine 20 Chlortalidone 25 Olmesartan 20 Cilazapril 2.5 Perindopril 4 Cilnidipine 10 Pindolol 15 Clonidine 0.45 Prazosin 5 Dihydralazine sulphate 75 Propranolol 160 Diltiazem 240 Quinapril 15 Doxazosin 4 Ramipril 2.5 Enalapril 10 Sotalol 160 Eplerenone 50 Spirapril 6 Eprosartan 600 Telmisartan 40 Esmolol 2500 Temocapril 10 Etacrynic acid 50 Terazosin 5 Felodipine 5 Torasemide 15 Fosinopril 15 Trandolapril 2 Furosemide 40 Triamterene 100 Hydralazine 75 Trichlormethiazide 4 Hydrochlorothiazide 25 Urapidil 120 Imidapril 10 Valsartan 80 Indapamide 2.5 Verapamil 240 Irbesartan 150 Xipamide 20 Isradipine 5 Zofenopril 30 Labetolol 600

Blood pressure during tolvaptan use

Supplementary Table 2. Effect of tolvaptan on blood pressure (BP) and BP related patient characteristics during the TEMPO 3:4 trial in subgroups according to hypertension status at baseline. Normotension Hypertension Tolvaptan treated Placebo treated p-value Tolvaptan treated Placebo treated p-value Baseline Number 179 79 782 405 Systolic BP (mmHg) 122 ± 10 122 ± 9 0.89 130 ± 14 130 ± 14 0.46 Diastolic BP (mmHg) 77.9 ± 7.6 77.5 ± 6.1 0.68 83.5 ± 10.1 83.4 ± 9.5 0.85 Mean arterial pressure (mmHg) 96.1 ± 8.0 95.9 ± 6.5 0.88 102.7 ± 10.6 102.4 ± 10.5 0.61 Heart rate (beats per minute) 69 ± 9 68 ± 11 0.74 69 ± 11 69 ± 11 0.31 Hypertension (%) - - - 100 100 - Use of AHT (%) - - - 94 93 0.25 No. of classes of AHT per patient 0 0 - 1.48 ± 0.83 1.49 ± 0.87 0.84 Dosage of AHT per patient (DDD) 0 0 - 1.77 ± 1.33 1.67 ± 1.30 0.19 Body weight (kg) 72.5 ± 17.3 68.4 ± 14.8 0.07 81.4 ± 18.2 80.6 ± 18.3 0.49 Plasma sodium (mmol/L) 140.5 ± 2.1 140.2 ± 1.7 0.24 140.3 ± 2.1 140.3 ± 2.0 0.94 Plasma copeptin (pmol/L) 5.9 [3.5 – 9.1] 5.2 [3.7 – 8.2] 0.51 6.6 [3.9 – 11.8] 6.8 [3.8 – 10.7] 0.93 Week 3 Number 171 78 750 399 Systolic BP (mmHg) 122 ± 13 122 ± 11 0.65 127 ± 13 127 ± 13 0.92 Diastolic BP (mmHg) 79.7 ± 8.9 77.1 ± 8.2 0.03 82.0 ± 9.4 81.3 ± 9.2 0.22 Mean arterial pressure (mmHg) 97.3 ± 9.7 95.5 ± 8.4 0.16 100.5 ± 10.0 100.1 ± 9.9 0.46 Heart rate (beats per minute) 70 ± 10 70 ± 11 0.99 70 ± 11 69 ± 11 0.67 Hypertension (%) 21 12 0.08 97 96 0.50 Use of AHT (%) 7 1 0.07 94 93 0.62 No. of classes of AHT per patient 0.08 ± 0.31 0.01 ± 0.11 0.06 1.48 ± 0.83 1.54 ± 0.91 0.30 Dosage of AHT per patient (DDD) 0.12 ± 0.66 0.01 ± 0.06 0.12 2.08 ± 1.58 2.07 ± 1.63 0.93 Body weight (kg) 71.0 ± 16.5 68.1 ± 14.5 0.20 80.6 ± 18.1 80.6 ± 18.0 0.99 Plasma sodium (mmol/L) 142.5 ± 2.8 140.2 ± 1.9 <0.001 142.6 ± 2.6 140.3 ± 2.3 <0.001 Plasma copeptin (pmol/L) 19.5 [15.5 – 25.5] 4.3 [3.1 – 8.7] <0.001 22.3 [16.6 – 28.4] 6.3 [3.8 – 10.4] <0.001

Blood pressure during tolvaptan use

Supplementary Table 2 – continued Normotension Hypertension Tolvaptan treated Placebo treated p-value Tolvaptan treated Placebo treated p-value Year 3 or early end of treatment Number 175 78 766 404 Systolic BP (mmHg) 124 ± 13 126 ± 12 0.44 127 ± 13 129 ± 14 0.004 Diastolic BP (mmHg) 79.9 ± 9.0 80.4 ± 8.2 0.66 81.5 ± 9.6 83.0 ± 10.2 0.01 Mean arterial pressure (mmHg) 98.1 ± 9.5 99.0 ± 8.6 0.51 100.1 ± 10.0 102.0 ± 11.0 0.003 Heart rate (beats per minute) 70 ± 11 69 ± 9 0.59 70 ± 11 70 ± 11 0.58 Hypertension (%) 44 33 0.13 97 96 0.73 Use of AHT (%) 27 19 0.21 95 95 0.78 No. of classes of AHT per patient 0.34 ± 0.61 0.22 ± 0.50 0.12 1.65 ± 0.96 1.73 ± 1.01 0.15 Dosage of AHT per patient (DDD) 0.44 ± 1.06 0.20 ± 0.49 0.06 2.39 ± 1.75 2.46 ± 1.85 0.53 Body weight (kg) 72.7 ± 17.6 69.1 ± 14.9 0.12 82.5 ± 18.7 82.2 ± 18.3 0.78 Plasma sodium (mmol/L) 141.5 ± 2.8 140.4 ± 2.2 0.002 141.7 ± 2.6 140.3 ± 2.3 <0.001 Plasma copeptin (pmol/L) 17.5 [13.5 – 21.2] 5.8 [3.6 – 9.6] <0.001 20.9 [15.4 – 28.4] 7.6 [4.3 – 14.5] <0.001 Follow-up Number 126 67 608 340 Systolic BP (mmHg) 125 ± 11 124 ± 11 0.58 127 ± 12 128 ± 13 0.29 Diastolic BP (mmHg) 79.3 ± 8.1 79.0 ± 8.3 0.82 81.4 ± 8.7 82.2 ± 8.8 0.16 Mean arterial pressure 98.1 ± 8.4 97.6 ± 8.5 0.67 100.3 ± 9.2 101.2 ± 9.5 0.18 Heart rate (beats per minute) 71 ± 10 68 ± 10 0.07 69 ± 10 69 ± 10 0.98 Hypertension (%) 46 31 0.06 98 98 0.81 Use of AHT (%) 34 22 0.10 97 97 0.84 No. of classes of AHT per patient 0.41 ± 0.62 0.24 ± 0.46 0.05 1.70 ± 0.95 1.79 ± 0.99 0.17 Dosage of AHT per patient (DDD) 0.49 ± 1.02 0.30 ± 0.92 0.19 2.48 ± 1.77 2.52 ± 1.80 0.76 Body weight (kg) 73.7 ± 17.5 68.4 ± 13.7 0.03 82.6 ± 18.6 81.7 ± 17.8 0.49 Plasma sodium (mmol/L) 139.9 ± 2.4 140.5 ± 2.3 0.09 139.8 ± 2.2 140.4 ± 2.4 <0.001 Plasma copeptin (pmol/L) 4.6 [3.2 – 8.8] 6.2 [3.7 – 9.6] 0.09 6.9 [4.2 – 12.4] 7.3 [4.3 – 14.4] 0.20 Differences between groups are tested with Student’s t-test for parametric, Mann-Withney U-test for non-parametric and Fishers’ exact test for categorical data. Year 3 or early end of treatment signifies that this is an intention to treat analysis. Abbreviations: AHT, anti-hypertensive therapy; BP, blood pressure; DDD, defined daily dose; Mean arterial pressure was calculated as diastolic BP + 0.412*(systolic BP – diastolic BP). NB copeptin was not measured in patients with early end of treatment 4

Blood pressure during tolvaptan use

Supplementary Table 3. Distribution of the use of subclasses of RAAS inhibitors and diuretics in the overall study population Tolvaptan (n=734) Placebo (n=407) p-value for Baseline Follow-up p-value Baseline Follow-up p-value difference* RAAS inhibitors ACE inhibitors % of participants 44.4 47.8 0.006 40.5 45.2 0.02 0.58 Defined daily dose 0.76 0.96 <0.001 0.66 0.87 <0.001 0.93 Angiotensin II receptor blockers % of participants 32.0 39.8 <0.001 33.9 40.5 <0.001 0.58 Defined daily dose 0.47 0.62 <0.001 0.48 0.65 <0.001 0.50 Renin inhibitors % of participants 0.1 0.8 0.03 0.2 1.7 0.01 0.24 Defined daily dose 0.003 0.011 0.04 0.003 0.022 0.01 0.15 Mineralocorticoid receptor antagonists % of participants 0 0.3 - 0.2 0.2 - - Defined daily dose 0 0.003 0.16 0.002 0.002 0.32 0.30 Diuretics Loop diuretics % of participants 0.7 1.6 0.03 0.2 1.2 0.05 0.97 Defined daily dose 0.005 0.13 0.05 0.002 0.011 0.12 0.85 Thiazide diuretics % of participants 2.7 2.0 0.32 2.2 1.5 0.41 0.96 Defined daily dose 0.029 0.014 0.08 0.015 0.012 0.01 0.32 Potassium-sparing diuretics % of participants 0.1 0 0.14 0 0 - - Defined daily dose 0.001 0 0.32 0 0 - - In this table the average defined daily dose is calculated in the subjects of whom data was available at both baseline and follow-up visit. Within study arm comparisons were made with a paired t-test or McNemar’s test as appropriate. *p value for difference between the change of antihypertensive treatment in the tolvaptan arm versus the placebo arm tested using Student’s t-test or Chi-square test as appropriate.

Blood pressure during tolvaptan use

Supplementary Figure 1. Mean arterial pressure and average dosage of antihypertensive drugs (in defined daily dosages, DDD) of participants during the TEMPO 3:4 trial. The tolvaptan study arm (n=961) is represented by solid circles ( ) and placebo (n=484) by open circles ( ). Error bars represent 95% confidence intervals of the mean, * indicates p<0.05 calculated with a mixed model repeated measures analysis. Treatment duration is expressed in months with the exception of w3, which indicates week 3, and FU which indicates follow-up. Mean arterial pressure was calculated as diastolic BP + 0.412*(systolic

BP – diastolic BP).

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Blood pressure during tolvaptan use

Supplementary Figure 2. Mean arterial pressure and average dosage of antihypertensive drugs (in defined daily dosages, DDD) in subgroups of the trial participants according to baseline hypertension status. A) includes patients with normotension at baseline (n=258) and B) patients with hypertension at baseline (n=1187). The tolvaptan study arm is represented by solid circles ( ) and placebo by open circles ( ). Error bars represent 95% confidence intervals of the mean, * indicates p<0.05. Treatment duration is expressed in months with the exception of w3, which indicates week 3 and FU which indicates follow-up. Mean arterial pressure was calculated as diastolic BP + 0.412*(systolic BP – diastolic

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Blood pressure during tolvaptan use

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