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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

Due to the number of contributing authors, the affiliations are listed at the end of this article.

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: ccc–ccc, 2021. doi: https://doi.org/10.1681/ASN.2020101512

Vasopressin and antidiuretic hormone are names receptor, although indispensable for water homeo- that refer to the pleiotropic effects of this peptide. stasis, can also be damaging in a variety of kidney Although the former name is most often used, the disorders, including autosomal dominant poly- latter may be more appropriate because decreasing cystic kidney disease (ADPKD).7 The V2 receptor urinary output is the principal function of vaso- regulates water permeability of the tubular cell pressin. Effects of vasopressin are facilitated by three types of receptors, the V1a, V1b, and V2 re- ceptors, present on various cell types.1 The V2 re- Received October 27, 2020. Accepted March 1, 2021. ceptor, 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, Correspondence: Dr. Ron T. Gansevoort, Department of Ne- 4–6 responsible for vasoconstriction, requires con- phrology, University Medical Center Groningen, Hanzeplein 1, siderably higher vasopressin levels.3 PO Box 30.001, 9700 RB Groningen, The Netherlands. Email: r.t. Not all of the effects of vasopressin are beneficial. [email protected] It has been recognized that activation of the V2 Copyright © 2021 by the American Society of Nephrology

JASN 32: ccc–ccc, 2021 ISSN : 1046-6673/3207-ccc 1 CLINICAL RESEARCH www.jasn.org membrane via an intracellular second messenger, cAMP.8 In Significance Statement patients with ADPKD, growth of kidney cysts is stimulated by an increase in intracellular cAMP, leading to loss of kidney Patients with autosomal dominant polycystic kidney disease are function and ultimately, resulting in ESKD.9 Patients with treated with tolvaptan, a V2 receptor antagonist, to slow pro- ADPKD are therefore treated with tolvaptan, a selective V2 gression toward ESKD. In theory, tolvaptan could have both BP-increasing and BP-decreasing effects. To investigate the mag- receptor antagonist, which has been shown to slow the rate nitude and time course of the effect of tolvaptan use on BP, the of disease progression in patients at risk of rapid kidney func- authors conducted a post hoc analysis of data from the TEMPO 3:4 tion decline.10,11 By preventing binding of vasopressin to the trial, which randomized 1445 patients with autosomal dominant V2 receptor, tolvaptan induces nephrogenic diabetes insipidus, polycystic kidney disease to tolvaptan or placebo. Their analysis which causes a compensatory rise in plasma vasopressin.12 It is shows that directly after start of tolvaptan therapy, BP does not change, but in the long term, BP gradually becomes lower in patients important to note that tolvaptan has a high selectivity for the with tolvaptan compared with placebo. This observation might be V2 receptor and does not block the effect of vasopressin on the attributed to the beneficial effect of tolvaptan on disease progres- V1a receptor.13 Consequently, given the higher levels of vaso- sion, a sustained natriuretic effect, or both. pressin induced by treatment, the V1a receptor is activated more than usual. This could have undesired off-target effects, summary, 1445 patients were enrolled for 2:1 randomization of which a change in BP 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 increase in BP.14,15 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 excretion, thereby potentially decreasing BP.16 In addition, to confound study end points, such as poorly controlled di- preventing vasopressin binding to the V2 receptor could result abetes mellitus. Participants allocated to the treatment arm in a reduction of BP because of loss of V2 receptor–mediated ENaC channel activation and therefore, sodium reabsorption, were started on a dosage regimen of 45 mg in the morning loss of renin angiotensin aldosterone system (RAAS) activa- and 15 mg in the late afternoon, which was increased to tion due to a decrease of V2 receptor–dependent renin pro- 60/30 mg after 1 week and thereafter, to 90/30 mg in the third duction, and loss of circulating volume due to aquaresis.17,18 week if tolerated. Participants remained on the highest toler- Finally, in the long term, tolvaptan ameliorates the rate of ated dose for 36 months. Primary outcome was the annual rate disease progression, possibly also reducing the develop- of change in TKV, and secondary outcomes included annual fi ment of secondary symptoms of kidney disease, such as rate of change in eGFR. Tolvaptan ef cacy was studied on top hypertension. of standard clinical care, which included optimal BP control. fi The original publication of the TEMPO 3:4 trial disclosed Study recommendations de ned in 2007, at the start of the trial, only limited information on the effect of tolvaptan on BP.10 considered optimal control to start antihypertensive treatment Change in BP was expressed as worsening hypertension, de- at a systolic BP of 130 mm Hg or a diastolic BP of 85 mm Hg. fined as a change in BP category, or as worsening of hyperten- Adjustments in antihypertensive therapy could be made during sion requiring an increase in hypertensive treatment. No effect the entire study period in case BP exceeded the limits on two was found. However, the use of a categorical variable as out- consecutive visits. RAAS inhibitors were recommended as first- come measure may have resulted in a loss of power to find line antihypertensive drug. The choice for second-line therapy differences between the two study groups. Therefore, this was left to the discretion of the treating physician. Long-term study investigates the magnitude and time course of the effect use of diuretics was discouraged for safety reasons. of tolvaptan on BP expressed as a continuous variable, not This study was approved by all local ethics committees of only taking into account measured values but also, use of the participating sites and was conducted according to the BP-lowering medication. International Conference of Harmonization Good Clinical 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 month 3, and thereafter, after every 4 months for 36 months. A prospective, 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

2 JASN JASN 32: ccc–ccc,2021 www.jasn.org CLINICAL RESEARCH validated oscillometric device. BP was measured twice, and if baseline disease severity–related characteristics (sex, median these values varied by .5 mm Hg, they were repeated two age, Mayo htTKV class, median eGFR, and median copeptin more times. Mean of these two or four values was documen- value). In all of these analyses, a P value ,0.05 was considered ted. In addition, review of medication use and laboratory as- to indicate statistical significance. Statistical analyses were per- sessment was performed. Plasma sodium, cholesterol, and formed using SAS 9.4 and GraphPad Prism 8.4.2. glucose were measured using standard methodology. Copep- tin was measured as a surrogate marker for vasopressin, with an automatic immunofluorescence assay with coefficients of RESULTS variation of 8.0% and 10.0%, respectively (BRAHMS GmbH, Henningsdorf, Germany).20 TKV was measured by manual Population at Baseline tracing of magnetic resonance images taken without use of a In this study, 1445 patients were included, of which 961 were contrast agent. TKV was corrected for height (height-adjusted randomized to tolvaptan and 484 were randomized to pla- total kidney volume [htTKV]) and age to determine Mayo cebo. There were no significant differences in baseline char- htTKV class, a classification system designed to predict future acteristics between both study arms (Table 1). Table 2 shows disease progression.21 BP and BP-related patient characteristics. At baseline, pres- sures were comparable in both study arms, with systolic and BP-Related Patient Characteristics diastolic BPs of 129614 over 82.569.9 mm Hg for tolvaptan Mean arterial pressure was calculated as diastolic BP and 128614 over 82.469.3 mm Hg for placebo. Hypertension 10.4123(systolic BP – diastolic BP).22 Hypertension was de- was present in 81% of the patients randomized to receive tol- fined as either having a systolic BP $140 mm Hg or diastolic vaptan and 84% of the patients randomized to receive placebo. BP $90 mm Hg or use of antihypertensive medication. Anti- In both study arms, 77% of the patients were at baseline on hypertensive drugs were divided into five classes: RAAS inhib- antihypertensive therapy, mostly RAAS inhibitors. Average itors, b-blocking agents, calcium channel blockers, diuretics, dosages of these antihypertensives were similar in both study and others. To be able to compare dosages between different arms, namely 1.4461.38 versus 1.4061.34 defined daily classes of antihypertensives, these were expressed as defined doses, respectively. Plasma copeptin, as a marker of vasopres- daily dose. Reference values to calculate defined daily doses sin, did also not differ between the two study arms at baseline were obtained from the World Health Organization Collabo- (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- Statistical Analyses domized to receive tolvaptan (n5179) had a significantly BP and BP-related patient characteristics were evaluated at higher body mass index, used a cholesterol-lowering drug baseline, after short-term useoftolvaptan(3weeks),after more often, and had a higher htTKV compared with patients longer-term use (36 months), and at the post-treatment whoweretoreceiveplacebo(n579) in this subpopulation follow-up visit. Change between the baseline and 36 months (Table 1). In patients diagnosed with hypertension at baseline, visits was studied as intention to treat analysis, including the there were no significant differences in BP or other baseline last study visits of patients who ended their participation in the patient characteristics between tolvaptan- (n5782) and study prematurely. Depending on distribution, data were pre- placebo-treated (n5405) 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 After 3 weeks of study treatment, copeptin was significantly t 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 compar- At this time point in the study, there were no significant dif- ison of the change of BP over time between the study arms in ferences in BP-related patient characteristics, such as systolic the overall study population presented in figures, mixed model and 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. Use parametric data, and McNemar test for categorical data. As of tolvaptan caused body weight to decrease from 79.7618.3 secondary analysis, patients were divided into two subgroups to 78.8618.2 kg and plasma sodium to increase from on the basis of hypertension status at baseline (e.g., hyperten- 140.462.1 to 142.662.6 mmol/L (both P,0.001). Changes sion, as defined above, or normotension). To test the robust- in copeptin levels were significantly associated with the acute ness of primary findings, effect of use of tolvaptan on mean changes in body weight (R50.08; P50.02) and plasma so- arterial pressure was assessed in several subgroups defined by dium (R50.16; P,0.001) but not with BP in the tolvaptan

JASN 32: ccc–ccc, 2021 BP during Tolvaptan Use 3 CLINICAL RESEARCH www.jasn.org

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. arm. In the placebo arm, weight increased significantly P50.83). In Supplemental Figure 1, it is shown that after (P50.007), and plasma sodium remained stable (P50.85). 28 months of treatment, average mean arterial pressure was In the subgroup with normotension at baseline, diastolic also significantly lower in the tolvaptan arm compared with BP after 3 weeks was slightly but statistically significantly placebo (99.769.4 versus 100.9610.2 mm Hg, respectively; higher in the tolvaptan arm when compared with the placebo P50.04). Of note, throughout the study, plasma sodium and arm (79.768.9 versus 77.168.2 mm Hg, respectively; copeptin levels of the tolvaptan-treated patients were higher P50.03), despite start of antihypertensive therapy dosed at an than those of the placebo-treated patients (P,0.001). Body average of 0.1260.66 defined daily doses in the tolvaptan arm weight did not differ (Table 2). versus 0.0160.06 in the placebo arm (P50.12). No differences In subjects with normotension at baseline, no difference in in systolic BP were noted. In the subgroup with hypertension at systolic BP, diastolic BP (Figure 2), and mean arterial pressure baseline, no differences were found between the two study arms (Supplemental Figure 2) was observed between both study arms after 3 weeks in diastolic BP, in systolic BP, or in number and during the trial period, whereas average dose of antihypertensive dose of antihypertensive drugs (Supplemental Table 2). drugs was slightly higher in the tolvaptan-treated subjects at months 20 and 24 but not at week 3 or at the last visit. After Long-Term Effects of Tolvaptan 3 years, 42% and 33% of the patients who did not have an Figure 1 shows systolic and diastolic BP and dose of antihy- elevated BP at baseline had developed hypertension in the pertensive drugs over the course of the trial. Over time, a small tolvaptan-treated and placebo-treated study arms, respectively difference in BP between the two study arms occurred, namely (P50.13). In the subgroup of patients diagnosed with hyperten- asignificant decrease in systolic BP after 28 months and di- sion at baseline, similar observations as in the overall study pop- astolic BP after 32 months. At the end of the treatment period ulation were made, with a lower systolic BP after 28 month, a both systolic and diastolic BP were lower in the tolvaptan arm lower diastolic BP after 32 months (Figure 2), and a lower mean compared to placebo arm, with a systolic BP of 129 6 14 arterial pressure after 32 months (Supplemental Figure 2). versus 126 6 13, respectively, P50.002 and diastolic BP of 82.6 6 10 versus 81.2 6 9.5 mmHg, respectively, P50.01. Shortly after Ending Long-Term Use of Tolvaptan Meanwhile, a similar average number of antihypertensive Approximately 3 weeks after withdrawal of study medica- drugs (1.46 6 1.01 in the tolvaptan arm versus 1.48 6 1.07 tion, data were available for 734 patients participating in the in the placebo arm, P50.68) was given at a similar dose (2.07 tolvaptan arm and 407 patients participating in the placebo 6 1.77 versus 2.05 6 1.84 defined daily doses, respectively, 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.

JASN 32: ccc–ccc, 2021 BP during Tolvaptan Use 5 CLINICAL RESEARCH www.jasn.org

135

130 * * **

125 Systolic blood pressure (mmHg) 120

85 **

80

75 Diastolic blood pressure (mmHg) 70

3

2

1 Antihypertensives (DDD)

0 0 w34 8 12162024283236FU 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 with medications that were used in both arms remained similar. In baseline in the tolvaptan arm (P50.007 and P50.001,

6 JASN JASN 32: ccc–ccc,2021 www.jasn.org CLINICAL RESEARCH

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, 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 di- pressure after 36 months of treatment did not differ between uretics, 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 to DISCUSSION 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 was the magnitude and time course of the effect of tolvaptan on BP,

JASN 32: ccc–ccc, 2021 BP during Tolvaptan Use 7 CLINICAL RESEARCH www.jasn.org

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 weight and increase in plasma sodium after start of study variable but also, use of BP-lowering medication. We did not medication in the tolvaptan arm but not in the placebo arm. find an acute effect but observed a gradually developing dif- This effect on total body water has been studied previously as a ference in BP between study arms in favor of tolvaptan that therapeutic modality in patients with heart failure or hypona- was not explained by a difference in antihypertensive treat- tremia as an alternative for diuretics.23–25 Notably, in our ment. This difference leveled off after stopping study tolvaptan-treated subjects, change in copeptin was associated medication. with change in sodium concentration and body weight but not The acute effect of a V2 receptor antagonism was studied with change in BP, possibly reflecting the opposing mecha- after a 3-week titration period in which the highest tolerated nisms that are at play. It might be suggested that a decreasing dose of medication was reached. At this visit, none of the effect on BP is counteracted by activation of the RAAS system parameters assessed to monitor changes in BP were signifi- due to intravascular volume depletion. However, it has been cantly different between tolvaptan- and placebo-treated sub- showninbothexperimentalaswellashumanstudiesthat jects. In both arms, BP had decreased. This may be explained tolvaptan, in contrast to other diuretics, does not increase re- by the higher dosages of antihypertensive drugs that were used nin or aldosterone levels.13,26–28 Given that markers of the at week 3, prescribed by physicians aiming to reach adequate RAAS were not measured, this could not be further addressed BP control. Alternatively, it could also be that participants had in our study. Three small-scale studies with crossover designs grown more familiar with the study setting, which could have have previously investigated the acute effects of tolvaptan in resulted in reduction of stress and consequently, a lower BP. In patients with ADPKD. These studies, which included 18, 20, the tolvaptan-treated subjects, two additional opposing mech- and 27 patients, also found no acute effect on BP after a single anisms may have been in action, as set out in the introduction. dose or 1–3 weeks of tolvaptan treatment.29–31 Of note, given Use of tolvaptan led to a more than three-fold increase in that in our overall population the BP effect of tolvaptan might copeptin, measured as a surrogate marker for vasopressin, as have been obscured by the use of BP-lowering medication, we central compensation for the loss of renal urine concentrating also studied the normotensive subgroup separately that did capacity. This hormone has regulatory functions that can in- not use such medication as baseline. In this specific subgroup, crease as well as decrease BP. Although V1a receptors on the there was a suggestion of an effect of tolvaptan on vascular vascular wall induce vasoconstriction and thus, increase in BP, tone, given that diastolic BP was significantly higher in the V1a receptors present in various segments of the kidneys have treatment arm versus the placebo arm and slightly more pa- a counterbalancing effect via natriuresis.16,17 These effects, in tients in the tolvaptan arm had started antihypertensive ther- combination with aquaresis mediated by tolvaptan blocking apy. However, after 3 weeks of treatment, no effect on systolic the V2 receptor, can lead to a reduction in total body water and BP was observed in this normotensive subgroup, and in the in circulating volume. Indeed, we observed a decrease in body hypertensive subgroup, an effect on diastolic BP was not

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

JASN 32: ccc–ccc, 2021 BP during Tolvaptan Use 9 CLINICAL RESEARCH www.jasn.org concurrent changes in antihypertensive therapy. Simulta- sustained natriuretic effect, possibly in combination with the neously, body weight increased, and plasma sodium decreased 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 betheresultofanincreaseincirculatingvolume.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 V2- week 3. It should be noted that after cession of medication, mediated antidiureris and sodium reabsorption, resulting in plasma sodium in the tolvaptan arm was significantly lower an excess of circulating volume. This acute effect of stopping compared with the placebo arm, which may indicate that there 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. Torres 32,33 SIADH as well as psychogenic polydipsia. We expect 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,andJ.Ouyangareemployeesof not available, but this line of reasoning matches our clinical Otsuka. Additionally, A.B. Chapman reports consultancy agreements with fi experience that after stopping tolvaptan, patients report that and/or research funding from and/or honoraria from Otsuka, Janssen, P zer 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, and fades out over a couple of weeks to months. membership of the Special Emphasis Panel and Review Panel, NIH/National Some limitations of our study should be acknowledged, Institute of Diabetes and Digestive and Kidney Diseases, and SBIR. O. Devuyst mostly those inherent to the post hoc design. BP would ideally reports consultancy agreements with Alnylam, Galapagos, and Sanofi and re- fi have been studied over time without changing antihyperten- search funding from Otsuka and Roche; and scienti c advisor or membership via editorial boards of CJASN, Kidney International, Nephrology Dialysis sive therapy to answer our study question irrefutably. Such a Transplantation, OJRD, Peritoneal Dialysis International, and Pflügers Archiv. strategy is, however, not possible in clinical practice because R.T. Gansevoort reports consultancy agreements with and/or research funding subjecting a patient to suboptimal BP control during a 3-year from and/or honoraria from AstraZeneca, Bayer, Galapagos, and Sanofi- period would be unethical. Second, the choice of BP therapy Genzyme, Otsuka, and scientific advisor or membership of the American was dependent on the discretion of the treating physician, a Journal of Kidney Disease, CJASN, Journal of Nephrology, Kidney360, Ne- phrology Dialysis Transplantation,and Nephron Clinical Practice. J. Lee has given that may have introduced variability in our outcomes. ownership interest in Pfizer. R.D. Perrone reports consultancy agreements Becausewedidnotfind differences between the two study with and/or research funding from and/or honoraria from Navitor, Palladio- arms in the number or dose of antihypertensives overall nor bio, Reata, Sanofi-Genzyme, Kadmon, Otsuka, and scientificadvisorand of specific classes of antihypertensives, this is unlikely to have membership of UpToDate. V. Torres reports consultancy agreements with induced bias. Third, BP could have been assessed more accu- and/or research funding from Acceleron Pharma, Blueprint Medicines, Mironid,Otsuka,PalladioBiosciences,Reata,andSanofi, honoraria from rately with home measurements or even 24-hour measure- Otsuka (to institution); and scientific advisor or membership with Mironid, ments, instead of measurement during an outpatient clinic Otsuka, and Sanofi. The remaining author has nothing to disclose. visit.34 In the clinic, BP was measured after 5 minutes of rest with either a manual or oscillometric device. Despite the rel- ative insensitivity of our BP measurement method, we still FUNDING observed changes in BP during long-term tolvaptan use. Given that tolvaptan induces a profound polyuria and thirst, thus The TEMPO 3:4 trial was funded by Otsuka Pharmaceutical (Tokyo, Japan) possibly deblinding the study groups to the researchers, one and Otsuka Pharmaceutical Development and Commercialization, Inc. may argue that the decrease in BP is merely produced by an (Rockville, MD). Measurement of copeptin was sponsored by the manufac- observer bias.35 Then again, all participants were encouraged turer of the copeptin proAVP KRYPTOR assay (BRAHMS GmbH, Hennings- to increase their fluid 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 that This post hoc analysis of the TEMPO 3:4 study was conceptualized by A.B. Chapman and R.T. Gansevoort; statistical analyses were performed by J. Lee, cancel out. During prolonged use, however, gradually BP be- H. Li, and J. Ouyang; data interpretation was done by all authors; figures were comes lower in patients on tolvaptan compared with patients made by J.E. Heida; the manuscript draft was written by R.T. Gansevoort and on placebo. This observation can likely be attributed to a J.E. Heida; the manuscript was revised by all authors; and all authors approved

10 JASN JASN 32: ccc–ccc,2021 www.jasn.org CLINICAL RESEARCH

the final version of the manuscript and can be held accountable for all aspects predict disease progression and tolvaptan efficacy in autosomal dom- of the work. inant polycystic kidney disease. Kidney Int 96: 159–169, 2019 13.MiyazakiT,FujikiH,YamamuraY,NakamuraS,MoriT: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 271: This article contains the following supplemental material online at http:// 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 vasopressin DCSupplemental. receptor stimulation on medullary blood flow and arterial pressure. Am Supplemental Table 1. Conversion table for antihypertensive medication JPhysiol275: 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. JAmSocNephrol19: 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 Renal itors and diuretics in the overall study population. Physiol 299: F917–F928, 2010 Supplemental Figure 1. Mean arterial pressure and average dosage of anti- 18. Gonzalez AA, Cifuentes-Araneda F, Ibaceta-Gonzalez C, Gonzalez- hypertensive drugs (in defined daily dosages) of participants during the Vergara A, Zamora L, Henriquez R, et al.: Vasopressin/V2 receptor TEMPO 3:4 trial. stimulates renin synthesis in the collecting duct. Am J Physiol Renal Supplemental Figure 2. Mean arterial pressure and average dosage of anti- Physiol 310: F284–F293, 2016 hypertensive drugs (in defined daily dosages) in subgroups of the trial partic- 19. Torres VE, Meijer E, Bae KT, Chapman AB, Devuyst O, Gansevoort RT, ipants according to baseline hypertension status. et al.: Rationale and design of the TEMPO (tolvaptan efficacy and safety in management of autosomal dominant polycystic kidney disease and its outcomes) 3-4 study. AmJKidneyDis57: 692–699, 2011 REFERENCES 20. Morgenthaler NG, Struck J, Alonso C, Bergmann A: Assay for the measurement of copeptin, a stable peptide derived from the precursor of vasopressin. Clin Chem 52: 112–119, 2006 1. Koshimizu TA, Nakamura K, Egashira N, Hiroyama M, Nonoguchi H, 21. Irazabal MV, Rangel LJ, Bergstralh EJ, Osborn SL, Harmon AJ, Tanoue A: Vasopressin V1a and V1b receptors: From molecules to Sundsbak JL, et al.; CRISP Investigators: Imaging classification of au- physiological systems. Physiol Rev 92: 1813–1864, 2012 tosomal dominant polycystic kidney disease: A simple model for se- 2. Andersen LJ, Andersen JL, Schütten HJ, Warberg J, Bie P: Antidiuretic lecting patients for clinical trials. J Am Soc Nephrol 26: 160–172, 2015 effect of subnormal levels of arginine vasopressin in normal humans. 22. Papaioannou TG, Protogerou AD, Vrachatis D, Konstantonis G, Am J Physiol 259: R53–R60, 1990 Aissopou E, Argyris A, et al.: Mean arterial pressure values calculated 3. Bankir L: Antidiuretic action of vasopressin: Quantitative aspects and using seven different methods and their associations with target organ interaction between V1a and V2 receptor-mediated effects. Cardiovasc deterioration in a single-center study of 1878 individuals. Hypertens Res 51: 372–390, 2001 Res 39: 640–647, 2016 4. Henderson KK, Byron KL: Vasopressin-induced vasoconstriction: Two 23. Gheorghiade M, Niazi I, Ouyang J, Czerwiec F, Kambayashi J, Zampino concentration-dependent signaling pathways. J Appl Physiol (1985) M, et al.; Tolvaptan Investigators: Vasopressin V2-receptor blockade 102: 1402–1409, 2007 with tolvaptan in patients with chronic heart failure: Results from a 5. Mackie AR, Brueggemann LI, Henderson KK, Shiels AJ, Cribbs LL, double-blind, randomized trial. Circulation 107: 2690–2696, 2003 Scrogin KE, et al.: Vascular KCNQ potassium channels as novel targets for the control of mesenteric artery constriction by vasopressin, based 24. Schrier RW, Gross P, Gheorghiade M, Berl T, Verbalis JG, Czerwiec FS, on studies in single cells, pressurized arteries, and in vivo measure- et al.; SALT Investigators: Tolvaptan, a selective oral vasopressin V2- – ments of mesenteric vascular resistance. J Pharmacol Exp Ther 325: receptor antagonist, for hyponatremia. NEnglJMed355: 2099 2112, 475–483, 2008 2006 6. Nyvad J, Mazur A, Postnov DD, Straarup MS, Soendergaard AM, Staehr 25. Konstam MA, Gheorghiade M, Burnett JC Jr, Grinfeld L, Maggioni AP, fi C, et al.: Intravital investigation of rat mesenteric small artery tone and Swedberg K, et al.; Ef cacy of Vasopressin Antagonism in Heart Failure blood flow. JPhysiol595: 5037–5053, 2017 Outcome Study With Tolvaptan (EVEREST) Investigators: Effects of oral 7. Meijer E, Boertien WE, Zietse R, Gansevoort RT: Potential deleterious tolvaptan in patients hospitalized for worsening heart failure: The EV- – effects of vasopressin in chronic kidney disease and particularly auto- EREST outcome trial. JAMA 297: 1319 1331, 2007 somal dominant polycystic kidney disease. Kidney Blood Press Res 34: 26. Hirano T, Yamamura Y, Nakamura S, Onogawa T, Mori T: Effects of the 235–244, 2011 V(2)-receptor antagonist OPC-41061 and the loop diuretic furosemide – 8. Knepper MA, Kwon TH, Nielsen S: Molecular physiology of water bal- alone and in combination in rats. J Pharmacol Exp Ther 292: 288 294, ance. NEnglJMed372: 1349–1358, 2015 2000 9. Torres VE, Harris PC, Pirson Y: Autosomal dominant polycystic kidney 27. Veeraveedu PT, Watanabe K, Ma M, Palaniyandi SS, Yamaguchi K, disease. Lancet 369: 1287–1301, 2007 Kodama M, et al.: Effects of V2-receptor antagonist tolvaptan and the 10. Torres VE, Chapman AB, Devuyst O, Gansevoort RT, Grantham JJ, loop diuretic furosemide in rats with heart failure. Biochem Pharmacol Higashihara E, et al.; TEMPO 3:4 Trial Investigators: Tolvaptan in pa- 75: 1322–1330, 2008 tients with autosomal dominant polycystic kidney disease. NEngl 28. Jujo K, Saito K, Ishida I, Furuki Y, Kim A, Suzuki Y, et al.: Randomized JMed367: 2407–2418, 2012 pilot trial comparing tolvaptan with furosemide on renal and neuro- 11. Torres VE, Chapman AB, Devuyst O, Gansevoort RT, Perrone RD, Koch G, humoral effects in acute heart failure. ESC Heart Fail 3: 177–188, 2016 et al.; REPRISE Trial Investigators: Tolvaptan in later-stage autosomal 29. Al Therwani S, Malmberg MES, Rosenbaek JB, Bech JN, Pedersen EB: dominant polycystic kidney disease. NEnglJMed377: 1930–1942, 2017 Effect of tolvaptan on renal handling of water and sodium, GFR and 12. 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placebo-controlled, double blind, crossover study. BMC Nephrol 18: 33. Smith D, Moore K, Tormey W, Baylis PH, Thompson CJ: Downward 268, 2017 resetting of the osmotic threshold for thirst in patients with SIADH. Am 30. Irazabal MV, Torres VE, Hogan MC, Glockner J, King BF, Ofstie TG, J Physiol Endocrinol Metab 287: E1019–E1023, 2004 et al.: Short-term effects of tolvaptan on renal function and volume in 34. Drawz PE, Abdalla M, Rahman M: Blood pressure measurement: patients with autosomal dominant polycystic kidney disease. Kidney Int Clinic, home, ambulatory, and beyond. Am J Kidney Dis 60: 80: 295–301, 2011 449–462, 2012 31. Boertien WE, Meijer E, de Jong PE, ter Horst GJ, Renken RJ, van der 35. Howard JP, Shun-Shin MJ, Hartley A, Bhatt DL, Krum H, Francis DP: Jagt EJ, et al.: Short-term effects of tolvaptan in individuals with auto- Quantifying the 3 biases that lead to unintentional overestimation of somal dominant polycystic kidney disease at various levels of kidney the blood pressure-lowering effect of renal denervation. Circ Cardio- function. Am J Kidney Dis 65: 833–841, 2015 vasc Qual Outcomes 9: 14–22, 2016 32. Thompson CJ, Edwards CR, Baylis PH: Osmotic and non-osmotic 36. Heida JE, Boesten LS, Ettema EM, Kobold ACM, Franssen CFM, regulation of thirst and vasopressin secretion in patients with compul- Goosevoort RT, et al.: Comparison of ex vivo stability of copeptin and sive water drinking. Clin Endocrinol (Oxf) 35: 221–228, 1991 vasopressin. Clin Chem Lab Med 55: 984–992, 2016

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, Université 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

12 JASN JASN 32: ccc–ccc,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

1

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

2

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

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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.

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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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