Holly B. Krasa

Tolvaptan in Patients with Autosomal Dominant Polycystic Kidney Disease

BACKGROUND The course of autosomal dominant polycystic kidney disease (ADPKD) is often associated with pain, hypertension, and kidney failure. Preclinical studies indicated that vasopressin V(2)-receptor antagonists inhibit cyst growth and slow the decline of kidney function. METHODS In this phase 3, multicenter, double-blind, placebo-controlled, 3-year trial, we randomly assigned 1445 patients, 18 to 50 years of age, who had ADPKD with a total kidney volume of 750 ml or more and an estimated creatinine clearance of 60 ml per minute or more, in a 2:1 ratio to receive tolvaptan, a V(2)-receptor antagonist, at the highest of three twice-daily dose regimens that the patient found tolerable, or placebo. The primary outcome was the annual rate of change in the total kidney volume. Sequential secondary end points included a composite of time to clinical progression (defined as worsening kidney function, kidney pain, hypertension, and albuminuria) and rate of kidney-function decline. RESULTS Over a 3-year period, the increase in total kidney volume in the tolvaptan group was 2.8% per year (95% confidence interval [CI], 2.5 to 3.1), versus 5.5% per year in the placebo group (95% CI, 5.1 to 6.0; P<0.001). The composite end point favored tolvaptan over placebo (44 vs. 50 events per 100 follow-up-years, P=0.01), with lower rates of worsening kidney function (2 vs. 5 events per 100 person-years of follow-up, P<0.001) and kidney pain (5 vs. 7 events per 100 person-years of follow-up, P=0.007). Tolvaptan was associated with a slower decline in kidney function (reciprocal of the serum creatinine level, -2.61 [mg per milliliter](-1) per year vs. -3.81 [mg per milliliter](-1) per year; P<0.001). There were fewer ADPKD-related adverse events in the tolvaptan group but more events related to aquaresis (excretion of electrolyte-free water) and hepatic adverse events unrelated to ADPKD, contributing to a higher discontinuation rate (23%, vs. 14% in the placebo group). CONCLUSIONS Tolvaptan, as compared with placebo, slowed the increase in total kidney volume and the decline in kidney function over a 3-year period in patients with ADPKD but was associated with a higher discontinuation rate, owing to adverse events. (Funded by Otsuka Pharmaceuticals and Otsuka Pharmaceutical Development and Commercialization; TEMPO 3:4 ClinicalTrials.gov number, NCT00428948.).

Continental differences in clinical characteristics, management, and outcomes in patients hospitalized with worsening heart failure results from the EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study with Tolvaptan) program.

OBJECTIVES Our aim was to examine continental and regional differences in baseline characteristics and post-discharge clinical outcomes in the EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study with Tolvaptan) trial. BACKGROUND Continental and regional differences in clinical trials of acute heart failure syndromes (AHFS) have not been well studied. METHODS We analyzed data from the EVEREST trial, which randomized 4,133 patients hospitalized for worsening (HF) and left ventricular ejection fraction < or =40% to oral tolvaptan, a vasopressin antagonist, or placebo and followed for a median of 9.9 months. Baseline characteristics, mortality, and outcomes were analyzed across North America (n = 1,251), South America (n = 688), Western Europe (564 patients), and Eastern Europe (n = 1,619). RESULTS There were major differences between the 4 groups in the severity, etiology, and management of HF. Unadjusted 1-year mortality and cardiovascular mortality/HF hospitalization were 30.4% and 52.5% in North America, 27.2% and 41.6% in South America, 27.1% and 47.3% in Western Europe, and 20.5% and 35.3% in Eastern Europe. After adjustment, South American patients had the highest overall mortality (hazard ratio: 1.42, 95% confidence interval: 1.15 to 1.76), while Eastern European patients had the lowest cardiovascular death and HF hospitalization rate (hazard ratio: 0.84, 95% confidence interval: 0.73 to 0.97), compared with patients in North America. CONCLUSIONS Major continental and regional differences in HF severity, etiology, and management exist among AHFS patients, resulting in varied post-discharge outcomes, despite pre-defined selection criteria. These differences should be taken into account when planning global trials in AHFS. (Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study with Tolvaptan [EVEREST]; NCT00071331).

Acute Hemodynamic Effects of Tolvaptan, a Vasopressin V2 Receptor Blocker, in Patients With Symptomatic Heart Failure and Systolic Dysfunction : An International, Multicenter, Randomized, Placebo-Controlled Trial

OBJECTIVES This study sought to assess the acute hemodynamic effect of vasopressin V(2) receptor antagonism. BACKGROUND In decompensated heart failure (HF), tolvaptan, a vasopressin V(2) receptor antagonist, has been shown to improve congestion. It has not yet been established whether these improvements may be associated with the hemodynamic effects of tolvaptan. METHODS A total of 181 patients with advanced HF on standard therapy were randomized to double-blind treatment with tolvaptan at a single oral dose (15, 30, or 60 mg) or placebo. RESULTS Tolvaptan at all doses significantly reduced pulmonary capillary wedge pressure (-6.4 +/- 4.1 mm Hg, -5.7 +/- 4.6 mm Hg, -5.7 +/- 4.3 mm Hg, and -4.2 +/- 4.6 mm Hg for the 15-mg, 30-mg, 60-mg, and placebo groups, respectively; p < 0.05 for all tolvaptan vs. placebo). Tolvaptan also reduced right atrial pressure (-4.4 +/- 6.9 mm Hg [p < 0.05], -4.3 +/- 4.0 mm Hg [p < 0.05], -3.5 +/- 3.6 mm Hg, and -3.0 +/- 3.0 mm Hg for the 15-mg, 30-mg, 60-mg, and placebo groups, respectively) and pulmonary artery pressure (-5.6 +/- 4.2 mm Hg, -5.5 +/- 4.1 mm Hg, -5.2 +/- 6.1 mm Hg, and -3.0 +/- 4.7 mm Hg for the 15-mg, 30-mg, 60-mg, and placebo groups, respectively; p < 0.05). Tolvaptan increased urine output by 3 h in a dose-dependent manner (p < 0.0001), without changes in renal function. CONCLUSIONS In patients with advanced HF, tolvaptan resulted in favorable but modest changes in filling pressures associated with a significant increase in urine output. These data provide mechanistic support for the symptomatic improvements noted with tolvaptan in patients with decompensated HF. (Heart Pressure Assessment Study With Tolvaptan to Treat Congestive Heart Failure; NCT00132886).

Clinical Implications of QRS Duration in Patients Hospitalized With Worsening Heart Failure and Reduced Left Ventricular Ejection Fraction

CONTEXT Hospitalization for heart failure is associated with high postdischarge mortality and morbidity. The predictive value of the QRS duration during admission for heart failure has not been well studied. OBJECTIVE To investigate the predictive value of the QRS duration in patients hospitalized for heart failure with reduced left ventricular ejection fraction (LVEF). DESIGN, SETTING, AND PARTICIPANTS Retrospective, post hoc analysis from the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST), an event-driven, randomized, double-blind, placebo-controlled study in patients hospitalized for heart failure and having an LVEF of 40% or less. A total of 4133 patients were enrolled at 359 North American, South American, and European sites between October 7, 2003, and February 3, 2006. After excluding 1029 patients with a pacemaker, implantable cardioverter-defibrillator, or both at enrollment and 142 patients without a reported baseline QRS duration, 2962 patients were included in the analysis: 1641 had a normal QRS duration (< 120 ms) and 1321 had a prolonged QRS duration (> or = 120 ms). MAIN OUTCOME MEASURES Dual primary end points were all-cause mortality and the composite of cardiovascular death or hospitalization for heart failure. RESULTS During a median follow-up of 9.9 months, all-cause mortality was 18.7% for patients with a normal baseline QRS duration and 28.1% for patients with a prolonged baseline QRS duration (hazard ratio [HR], 1.61; 95% confidence interval [CI], 1.38-1.87). The composite of cardiovascular death or hospitalization for heart failure was 32.4% for patients with a baseline QRS duration less than 120 ms and 41.6% for patients with a baseline QRS duration of 120 ms or greater (HR, 1.40; 95% CI, 1.24-1.58). The increased risk associated with prolonged QRS duration was confirmed after adjusting for multiple variables for all-cause mortality (HR, 1.24; 95% CI, 1.02-1.50) and the composite of cardiovascular death or hospitalization for heart failure (HR, 1.28; 95% CI, 1.10-1.49). Only 105 patients (3.6%) who presented with a prolonged baseline QRS duration had a normal QRS duration on their last inpatient electrocardiogram. CONCLUSION A prolonged QRS duration appears common in patients with reduced LVEF who are hospitalized for heart failure and is an independent predictor of high postdischarge morbidity and mortality.

Tolvaptan in Autosomal Dominant Polycystic Kidney Disease: Three Years' Experience

BACKGROUND AND OBJECTIVES Autosomal dominant polycystic kidney disease (ADPKD), a frequent cause of end-stage renal disease, has no cure. V2-specific vasopressin receptor antagonists delay disease progression in animal models. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS This is a prospectively designed analysis of annual total kidney volume (TKV) and thrice annual estimated GFR (eGFR) measurements, from two 3-year studies of tolvaptan in 63 ADPKD subjects randomly matched 1:2 to historical controls by gender, hypertension, age, and baseline TKV or eGFR. Prespecified end points were group differences in log-TKV (primary) and eGFR (secondary) slopes for month 36 completers, using linear mixed model (LMM) analysis. Sensitivity analyses of primary and secondary end points included LMM using all subject data and mixed model repeated measures (MMRM) of change from baseline at each year. Pearson correlation tested the association between log-TKV and eGFR changes. RESULTS Fifty-one subjects (81%) completed 3 years of tolvaptan therapy; all experienced adverse events (AEs), with AEs accounting for six of 12 withdrawals. Baseline TKV (controls 1422, tolvaptan 1635 ml) and eGFR (both 62 ml/min per 1.73 m(2)) were similar. Control TKV increased 5.8% versus 1.7%/yr for tolvaptan (P < 0.001, estimated ratio of geometric mean 0.96 [95% confidence interval 0.95 to 0.97]). Corresponding annualized eGFR declined: -2.1 versus -0.71 ml/min per 1.73 m(2)/yr (P = 0.01, LMM group difference 1.1 ml/min per 1.73 m(2)/yr [95% confidence interval 0.24 to 1.9]). Sensitivity analyses including withdrawn subjects were similar, whereas MMRM analyses were significant at each year for TKV and nonsignificant for eGFR. Increasing TKV correlated with decreasing eGFR (r = -0.21, P < 0.01). CONCLUSION ADPKD cyst growth progresses more slowly with tolvaptan than in historical controls, but AEs are common.

Rationale and design of the TEMPO (Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and its Outcomes) 3-4 Study.

BACKGROUND Current management of autosomal dominant polycystic kidney disease (ADPKD) is focused on treating disease complications, not on slowing cyst development or preventing progression to kidney failure. Tolvaptan, a selective vasopressin V2 (vasopressin 2) receptor antagonist, has been proved to inhibit kidney cyst growth and preserve kidney function in multiple animal models of polycystic kidney disease. The TEMPO (Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes) 3-4 Study will examine the long-term effectiveness and safety of tolvaptan in patients with ADPKD. We report baseline characteristics and revised power calculations for the trial. STUDY DESIGN A prospective, 3-year, multicenter, double-blind, placebo-controlled trial of tolvaptan, a selective V2 receptor antagonist. Primary outcome is total kidney volume percentage of change from baseline for tolvaptan relative to placebo. Secondary outcome parameters include time to ADPKD-associated complications (kidney function decrease, blood pressure control, renal pain, and albuminuria) and safety end points. SETTING & PARTICIPANTS This trial includes patients with ADPKD with relatively preserved kidney function (baseline estimated creatinine clearance ≥60 mL/min), aged 50 years or younger, and with total kidney volume measured using magnetic resonance imaging ≥750 mL. INTERVENTION Administration of placebo or tolvaptan, dose titrated to tolerance. OUTCOMES Number of subjects enrolled and baseline characteristics. MEASUREMENTS Total kidney volume, kidney function, albuminuria, kidney pain, and vital signs. RESULTS 1,445 patients with ADPKD were enrolled between March 2007 and January 2009. Preliminary baseline median total kidney volume was 1.46 L, and estimated creatinine clearance was 105 ± 34 mL/min. A prespecified blinded sample-size recalculation at two-thirds enrollment confirmed the likely power of the study to detect 20% differences from placebo in the primary and key secondary end points at P < 0.05. LIMITATIONS This is a preselected ADPKD population chosen for its risk of progression to kidney failure and may not represent the general ADPKD population. If study results are positive with regard to the primary end point, positive effects on other secondary clinical outcomes will be required to assess overall benefit. CONCLUSIONS This randomized trial is the largest clinical study of a proposed ADPKD intervention to date. It targets patients with ADPKD with early disease who are projected to have rapid cyst growth and accelerated outcomes. Blockade of vasopressin V2 receptor is hypothesized to inhibit cyst growth, thereby delaying additional adverse clinical outcomes.

Short-term renal hemodynamic effects of tolvaptan in subjects with autosomal dominant polycystic kidney disease at various stages of chronic kidney disease

Vasopressin V2-receptor antagonists may delay disease progression in ADPKD. Trials with V2-receptor antagonists have been performed predominantly in patients with an estimated creatinine clearance of 60 ml/min or more. Here we determined renal hemodynamic effects of the V2-receptor antagonist tolvaptan in 27 patients with ADPKD at various stages of chronic kidney disease: group A: >60, group B: 30-60, and group C: <30 ml/min per 1.73 m(2). Measurements were performed before, after 3 weeks of tolvaptan (up titration to 90/30 mg/day, split dose), and 3 weeks after the last dose of tolvaptan. With tolvaptan, a minor, reversible decrease in GFR ((125)I-iothalamate clearance) was found that reached significance in groups A and B: -7.8 (interquartile range -13.7 to -1.3) and -4.3 (-9.7 to -0.9) ml/min per 1.73 m(2), respectively, but not in group C (GFR decrease -0.7 (-1.1 to 1.5) ml/min/1.73 m(2)). The percentage change in GFR, ERPF ((131)I-hippuran clearance), and filtration fraction with tolvaptan did not differ between the three study groups. No differences between the three study groups were found in other main efficacy variables, besides smaller increases in urine volume in group C during tolvaptan treatment. Tolvaptan was well tolerated, with only two patients withdrawing. Thus, doses of tolvaptan typically used in patients with ADPKD do not produce a difference in renal hemodynamic profile in chronic kidney disease stages 1 through 4, but minor GFR drops may be observed in individual patients.

Short-term Effects of Tolvaptan in Individuals With Autosomal Dominant Polycystic Kidney Disease at Various Levels of Kidney Function

BACKGROUND A recent study showed that tolvaptan, a vasopressin V2 receptor antagonist, decreased total kidney volume (TKV) growth and estimated glomerular filtration rate (GFR) loss in autosomal dominant polycystic kidney disease (ADPKD) with creatinine clearance≥60mL/min. The aim of our study was to determine whether the renal hemodynamic effects and pharmacodynamic efficacy of tolvaptan in ADPKD are dependent on GFR. STUDY DESIGN Clinical trial with comparisons before and after treatment. SETTING & PARTICIPANTS Patients with ADPKD with a wide range of measured GFRs (mGFRs; 18-148 mL/min) in a hospital setting. INTERVENTION Participants were studied at baseline and after 3 weeks of treatment with tolvaptan given in increasing dosages, if tolerated (doses of 60, 90, and 120mg/d in weeks 1, 2, and 3, respectively). OUTCOMES Change in markers for aquaresis (free-water clearance, urine and plasma osmolality, 24-hour urine volume, and plasma copeptin) and kidney injury (TKV and kidney injury biomarkers). MEASUREMENTS GFR was measured by (125)I-iothalamate clearance; TKV, by magnetic resonance imaging; biomarker excretion, by enzyme-linked immunosorbent assay; and osmolality, by freezing point depression. RESULTS In 27 participants (52% men; aged 46±10 years; mGFR, 69±39mL/min; TKV, 2.15 [IQR, 1.10-2.77] L), treatment with tolvaptan led to an increase in urine volume and free-water clearance and a decrease in urine osmolality, TKV, and kidney injury marker excretion. Changes in urine volume and osmolality with treatment were less in participants with lower baseline mGFRs (both P<0.01). However, change in fractional free-water clearance was greater at lower baseline mGFRs (P=0.001), suggesting that participants with decreased GFRs responded more to tolvaptan per functioning nephron. LIMITATIONS Limited sample size, no control group. CONCLUSIONS In patients with ADPKD with decreased kidney function, response to tolvaptan is lower for TKV, urinary volume, and osmolality, but larger for fractional free-water clearance. This latter finding suggests that patients with ADPKD with lower GFRs might benefit from long-term treatment with tolvaptan, as has been observed for patients with preserved GFRs.

Prevalence of autosomal dominant polycystic kidney disease in the European Union.

Background Autosomal dominant polycystic kidney disease (ADPKD) is a leading cause of end-stage renal disease, but estimates of its prevalence vary by >10-fold. The objective of this study was to examine the public health impact of ADPKD in the European Union (EU) by estimating minimum prevalence (point prevalence of known cases) and screening prevalence (minimum prevalence plus cases expected after population-based screening). Methods A review of the epidemiology literature from January 1980 to February 2015 identified population-based studies that met criteria for methodological quality. These examined large German and British populations, providing direct estimates of minimum prevalence and screening prevalence. In a second approach, patients from the 2012 European Renal Association‒European Dialysis and Transplant Association (ERA-EDTA) Registry and literature-based inflation factors that adjust for disease severity and screening yield were used to estimate prevalence across 19 EU countries (N = 407 million). Results Population-based studies yielded minimum prevalences of 2.41 and 3.89/10 000, respectively, and corresponding estimates of screening prevalences of 3.3 and 4.6/10 000. A close correspondence existed between estimates in countries where both direct and registry-derived methods were compared, which supports the validity of the registry-based approach. Using the registry-derived method, the minimum prevalence was 3.29/10 000 (95% confidence interval 3.27-3.30), and if ADPKD screening was implemented in all countries, the expected prevalence was 3.96/10 000 (3.94-3.98). Conclusions ERA-EDTA-based prevalence estimates and application of a uniform definition of prevalence to population-based studies consistently indicate that the ADPKD point prevalence is <5/10 000, the threshold for rare disease in the EU.

Effect of serum sodium concentration and tolvaptan treatment on length of hospitalization in patients with heart failure

PURPOSE The effect of serum sodium concentration and tolvaptan treatment on length of stay (LOS) in patients hospitalized with heart failure (HF) was evaluated. METHODS Data for this study were derived from a large, international, Phase III trial of patients hospitalized for HF. Two distinct post hoc analyses were performed, analyzing the association between serum sodium concentration and index hospitalization LOS in normonatremic patients and hyponatremic patients treated with placebo plus standard of care versus tolvaptan. Analysis of covariance models were constructed to adjust for potential variation in care delivery and adjusted for hyponatremia status or treatment. RESULTS Patients with a baseline serum sodium concentration of <135 meq/L who received placebo had an adjusted mean LOS that was 3.06 days longer than did normonatremic patients (p < 0.001). More severely hyponatremic patients had an adjusted mean LOS 5.18 days longer than did normonatremic patients (p < 0.001). In an analysis of all hyponatremic patients, those receiving tolvaptan had an adjusted mean LOS that was 1.72 days shorter than patients receiving placebo, though this difference was not significant. In more severely hyponatremic patients (serum sodium concentration of <130 meq/L), patients treated with tolvaptan had an adjusted mean LOS 2.12 days shorter than those receiving placebo, but this difference was not significant. CONCLUSION A secondary analysis of a large, international, Phase III trial of patients hospitalized for HF demonstrated that comorbid hyponatremia was associated with a significant increase in hospital LOS. Treatment of hyponatremia with tolvaptan was associated with reductions in LOS that were not significant.