Effects of Additive Tolvaptan vs. Increased Furosemide on Heart Failure With Diuretic Resistance and Renal Impairment　― Results From the K-STAR Study ―

Abstract

Background: Although diuretic resistance leading to residual congestion is a known predictor of a poorer heart failure (HF) prognosis, better therapeutic strategies for effective and safe decongestion have not been established.

Methods and Results: In this study, 81 HF patients with fluid retention (despite taking ≥40 mg/day furosemide (FUR)), with an estimated glomerular filtration rate <45 mL/min/1.73 m², were randomized into 2 groups and administered either ≤15 mg/day additive tolvaptan (TLV) or ≤40 mg/day increased FUR for 7 days. Changes in urine volume between baseline and mean urine volume during treatment were significantly higher in the TLV than FUR group (P=0.0003). Although there was no significant decrease in body weight or improved signs and symptoms of congestion between the 2 groups, the increase in serum creatinine on Day 7 from baseline was significantly smaller in the TLV than FUR group (P=0.038). Multiple logistic regression analysis revealed that additive TLV (odds ratio 0.157, 95% confidence interval 0.043–0.605, P=0.001) was an independent clinical factor for improved renal function during treatment compared with increased FUR.

Conclusions: In HF patients with residual congestion and renal dysfunction refractory to standard therapy, additive TLV increased urine volume without further renal impairment compared with patients who received an increased dose of FUR.

Heart failure (HF) is characterized by neurohumoral activation and sodium retention, which leads to excessive fluid accumulation in the systemic and pulmonary circulation. In patients admitted to hospital due to acute decompensated HF, the degree of congestion is of prognostic relevance, with residual congestion at discharge a risk factor for early readmission and mortality.¹ Excess fluid needs to be removed to both relieve patient discomfort and improve HF prognosis.

Diuretic resistance, defined as a failure to achieve the therapeutically desired reduction in fluid overload despite adequate dosing of a diuretic,² has a crucial role in residual congestion. Several recent studies have investigated the relationship between diuretic efficacy and clinical outcome in HF patients.³ Despite differences in study design, the results consistently demonstrate that outcomes are poor in patients with diuretic resistance.^3,4 Although loop diuretics continue to comprise the mainstay therapy to remove volume overload, it has been found that patients with diuretic resistance have lower underlying glomerular filtration rates (GFRs).⁴ The potential pharmacokinetic causes of diuretic resistance could be addressed by increasing the dose of the loop diuretic.⁵ In the Diuretic Optimization Strategies Evaluation (DOSE) trial, the use of higher doses of furosemide (FUR) was associated with higher net fluid and weight loss at the cost of an increased incidence of rising serum creatinine in acute HF.⁶

The vasopressin V₂ receptor antagonist tolvaptan (TLV) improves HF signs and symptoms by increasing water excretion, which occurs via a reduction in the aquaporin system in the distal portion of the nephron.⁷ The efficacy and safety of TLV as a treatment for HF has only been evaluated in clinical trials targeting an acute setting.^8–11 Few of these studies have focused on HF patients with diuretic resistance and residual congestion, unrelated to acute or chronic clinical settings.¹² To address this clinical question, the aim of the Kanagawa Aquaresis Investigators Trial of Tolvaptan on Heart Failure Patients with Renal Impairment (K-STAR) was to demonstrate the superiority of additive TLV compared with increased FUR doses in loop diuretic-resistant HF patients with residual congestion and renal insufficiency (Figure 1).

Figure 1.

Design of the Kanagawa Aquaresis Investigators Trial of Tolvaptan on Heart Failure Patients with Renal Impairment (K-STAR). In all, 81 heart failure (HF) patients with residual congestion and renal impairment were assigned to either additive tolvaptan (TLV) or an increased dose of furosemide (FUR). eGFR, estimated glomerular filtration rate.

Methods

Study Population

K-STAR was a multicenter open-labeled randomized controlled prospective clinical study that evaluated the short-term efficacy and safety of additive TLV compared with an increased dose of FUR in HF patients with residual congestion, despite optimal medical therapy including loop diuretics. The study included 81 patients from 18 hospitals in Kanagawa, Japan, from December 2012 to August 2014. HF patients over 20 years of age with at least 1 subjective symptom (dyspnea or orthopnea) and 1 sign (leg edema, jugular vein dilatation, pulmonary rales, or pulmonary vascular congestion on chest X-ray) of fluid retention despite taking ≥40 mg/day FUR or equivalents (bumetanide ≥1 mg/day, piretanide ≥6 mg/day, azosemide ≥60 mg/day, torasemide ≥8 mg/day), either in a hospital or outpatient setting, and with a baseline estimated GFR (eGFR) <45 mL/min/1.73 m², which indicates high cardiovascular risk,^13,14 were included in the study. In addition, patients received conventional pharmacotherapy, including angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers, β-blockers, and mineral corticoid receptor antagonists. Exclusion criteria included anuria, hypernatremia, use of intravenous agents for HF management, cardiac mechanical support, hemofiltration or dialysis, a previous history of TLV use, hypersensitivity to vaptan derivatives, pregnancy, acute coronary syndrome, scheduled coronary intervention, and subjects who were unable to drink or sense thirst. The study protocols were approved by the ethics committees at Kitasato University School of Medicine and at each participating institution, in compliance with the ethical guidelines of the 1975 Declaration of Helsinki. Written informed consent was obtained from all patients prior to their enrollment in the study.

Treatment Protocol and Data Collection

Patients were randomized into 2 groups and administered either ≤15 mg/day additive TLV or an increased (≤40 mg/day) FUR dose for 7 days in hospital. Dosing of added TLV or increased FUR was determined within the upper limit at the discretion of the treating physician. In addition, any physician could decide to terminate diuretic enhancement before Day 7 if the fluid overload was relieved. Patients in both groups were fed a salt-restricted diet with no restrictions on water intake during the treatment period. Within 24 h before the initiation of the treatment interventions, baseline clinical variables were obtained, including demographic and physiologic characteristics, concomitant medications, results of blood and urine tests, chest X-ray, electrocardiography, and echocardiography. The outcomes studied included congestion-associated signs and symptoms, vital signs, urinary volume per day, body weight (BW), and blood and urinary tests. Outcomes were assessed daily for 7 days and again on Day 9, which represented the 1-day washout period of the additive treatment. On Days 1–7, investigators assessed jugular vein dilation, hepatomegaly, pulmonary rales, and whether the third heart sound was present. Leg edema was assessed according to the standard 4-point scale as absent, mild, moderate, or severe.

Endpoints

The primary endpoint for the present study was the average change in urine output during the treatment period for 7 days or less (if earlier) compared with baseline values, according to previous studies.^15,16 Secondary endpoints were changes in BW, congestive signs and symptoms, renal function, and free water clearance (CH₂O). Worsening renal function (WRF) was defined as serum creatinine ≥0.3 mg/dL from baseline at any time during the observation period.^17,18

CH₂O (mL/min) was calculated as follows:

CH₂O=UV−COsm

where UV is urine volume (mL/min) and COsm is osmolar clearance (mL/min) and was calculated using the following equation:

COsm=UV×urine osmolality (mOsmol/L) / serum osmolality (mOsmol/L)

Adverse events were assessed throughout the inpatient period. Adverse events were defined as: (1) worsening HF requiring further treatment intensification, including higher doses of diuretics (which exceeded the doses used in the study protocol), intravenous agents, or mechanical cardiopulmonary support; (2) hypernatremia with levels >12 mEq/mL during 24 h or exceeding the reference value in each institute, most commonly serum Na >147 mEq/L;¹⁹ and (3) any events interfering with study continuation, determined at the discretion of the attending physician.

Statistical Analysis

Continuous variables are reported as the mean±SD or as the median with interquartile range (IQR) for those that were not normally distributed. Continuous variables were compared using Student’s t-test if normally distributed or the Wilcoxon rank-sum test if the distribution assumption was not met. Categorical variables are presented as proportions, with comparisons performed using Fisher’s exact test. Linear regression analysis was used to elucidate relationships between clinical parameters and primary endpoints. Logistic regression analysis was used to determine predictors for the incidence of WRF. Clinical variables with a significance level of P<0.05 in univariate analyses were included in the multivariate analyses with backward stepwise selection. Differences were considered significant at P<0.05. All statistical analyses were performed using JMP 10.0 software for Windows (SAS Institute, Cary, NC, USA).

Results

Demographic and Clinical Characteristics at Baseline

In all, 81 patients were randomized in the present study. Baseline characteristics of the patients are summarized in Table 1. Patients were predominantly male, with age ranging from 65 to 85 years. Most patients suffered from moderate HF, with New York Heart Association (NYHA) Functional Class II–III and a clinical profile of “wet & warm” with a previous history of repeated hospitalizations for HF. The HF phenotype presented as right ventricular failure with or without left ventricular (LV) failure and with a wide variation in LV ejection fraction (LVEF). Renal dysfunction was observed to be complicated with an eGFR of 29±10 mL/min/1.73 m². Before randomization, the mean dose of FUR was 51±25 mg/day. Patients were well treated with angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, β-blockers, and mineral corticoid receptor blockers. The only significant differences in baseline clinical characteristics between the 2 treatment groups were pulmonary rales, LVEF, and the pressure gradient in tricuspid regurgitation.

Table 1. Baseline Characteristics in All Subjects and According to Treatment With Additive TLV or an Increased Dose of FUR

	All subjects (n=81)	TLV (n=40)	FUR (n=41)	P value
Age (years)	76 [72–81]	77 [72–81]	76 [72–80]	0.663
No. males	45 (59)	24 (60)	24 (59)	0.893
NYHA functional class				0.598
I	7 (9)	4 (10)	3 (7)
II	30 (37)	16 (40)	14 (34)
III	38 (47)	16 (40)	22 (54)
IV	6 (7)	4 (10)	2 (5)
Ischemic heart disease	37 (46)	15 (38)	22 (54)	0.144
Hypertension	52 (64)	28 (70)	24 (59)	0.282
Atrial fibrillation	38 (47)	21 (53)	17 (41)	0.319
Diabetes mellitus	52 (64)	25 (63)	27 (66)	0.752
HF phenotype				0.087
Left	20 (25)	9 (23)	11 (27)
Right	18 (22)	13 (33)	5 (12)
Biventricular	43 (53)	18 (45)	25 (61)
Acute HF on enrollment	31 (38)	17 (43)	14 (34)	0.497
Nohria-Stevenson classification				0.366
Dry-warm	4 (5)	3 (8)	1 (2)
Wet-warm	71 (88)	33 (83)	38 (93)
Dry-cold	0 (0)	0 (0)	0 (0)
Wet-cold	6 (7)	4 (10)	2 (5)
No. previous HF admissions	2±3	2±2	3±4	0.340
Drugs at baseline
Thiazides	4 (5)	3 (8)	1 (2)	0.393
ACEi/ARB	63 (78)	34 (85)	29 (71)	0.122
β-blockers	57 (70)	25 (63)	32 (78)	0.125
MRA	43 (53)	23 (58)	20 (49)	0.431
Digitalis	11 (14)	5 (13)	6 (15)	0.779
FUR (mg/day)	40 [40–60]	40 [40–60]	40 [40–40]	0.299
Physical examination
Leg edema	64 (79)	31 (78)	31 (80)	0.741
Jugular vein dilatation	47 (58)	23 (58)	24 (59)	0.924
Hepatomegaly	29 (36)	13 (33)	16 (39)	0.540
Pulmonary rales	22 (27)	6 (15)	16 (39)	0.015
Gallop-S3	17 (21)	11 (28)	6 (15)	0.155
Body weight (kg)	61 [50–69]	62 [50–71]	61 [50–67]	0.548
Urine volume (mL/day)	1.6 [1.4–2.0]	1,306±494	1,251±540	0.424
Laboratory data
Serum albumin (mg/dL)	3.4 [3.1–3.8]	3.5 [3.1–3.9]	3.4 [3.1–3.8]	0.213
Serum BUN (mg/dL)	32 [22–44]	35 [23–44]	29 [21–43]	0.215
Serum creatinine (mg/dL)	1.6 [1.4–2.0]	1.5 [1.4–2.1]	1.6 [1.4–2.0]	0.835
eGFR (mL/min)	31 [23–38]	31 [24–39]	31 [22–37]	0.913
Plasma BNP (pg/mL)	487 [187–769]	346 [164–589]	622 [214–969]	0.132
Urine osmolality (mOsmol/kgH2O)	361 [308–407]	349 [298–409]	367 [312–409]	0.927
Pulmonary congestion on CXR				0.614
None		12 (30)	7 (17)
Mild		18 (45)	22 (54)
Moderate		9 (23)	10 (24)
Severe		1 (3)	2 (5)
Echocardiography
LVEDV (mL/m2)	89 [63–122]	76 [62–119]	98 [64–133]	0.182
LVESV (mL/m2)	50 [24–82]	35 [23–74]	67 [27–96]	0.079
LVEF (%)	43 [30–59]	50 [35–65]	42 [28–54]	0.013
SV (mL/m2)	32 [26–44]	32 [26–45]	37 [25–43]	0.864
TR-PG (mmHg)	35 [26–43]	30 [23–40]	36 [28–49]	0.043
IVC (mm)	20±6	21±7	20±6	0.518

Data are given as the mean±SD, n (%), or as the median [interquartile range]. ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; BNP, B-type natriuretic peptide; BUN, blood urea nitrogen; CXR, chest X-ray; eGFR, estimated glomerular filtration rate; FUR, furosemide; HF, heart failure; IVC, inferior vena cava; LVEDV, left ventricular end-diastolic volume; LVEF, left ventricular ejection fraction; LVESV, left ventricular end-systolic volume; MRA, mineralocorticoid receptor antagonist; NYHA, New York Heart Association; SV, stroke volume; TLV, tolvaptan; TR-PG, tricuspid regurgitation pressure gradient.

Treatment Protocol and Safety Profile

The dose of additive TLV or increased FUR measured on Day 7 was 10±4 or 28±12 mg/day, respectively. Prior to Day 7, 17 (43%) patients with additive TLV and 12 (29%) patients with increased FUR discontinued the treatment protocol. Among these, 7 (18%) and 8 (20%) discontinuations were due to adverse events, whereas 10 (25%) and 4 (10%) discontinued the study due to improvement in congestion as determined by the attending physicians. The analyses described below were performed using cumulative clinical data in all subjects, including those who discontinued intervention due to either beneficial or adverse reasons before Day 7. For adverse events, 3 uncontrolled HFs necessitating intensified treatment exceeding the study protocol were observed, but only in the FUR group. The treatment protocol was terminated by the attending physician for the following 3 reasons: (1) WRF in 1 patient in the TLV group and 3 patients in the FUR group; (2) consciousness disturbance in 1 patient in the TLV group; and (3) complaints from 2 patients in the TLV group of marked thirst. Hypernatremia, as defined above, was observed in 3 patients in the TLV group and 2 patients in the FUR group. In summary, adverse events were equally observed in the 2 groups, including hypernatremia. More patients discontinued in the TLV group because of resolved congestion; however, this difference between the 2 groups did not reach statistical significance.

Primary Endpoint

Urine output per day was significantly increased from Day 1 to Day 7 in the TLV group (Figure 2B). Changes in UV between baseline and mean UV during treatment over the 7 days (or less if discontinued) were significantly greater in the TLV than FUR group (P=0.0003; Figure 2A). Among the candidate variables identified by univariate analysis (P<0.05), multiple regression analysis showed that additive TLV (β = 0.353, 95% confidence interval [CI] 71.08–256.8, P=0.0008) and eGFR at baseline were independent clinical factors predictive of increased UV output (Table 2).

Figure 2.

Change in urine output per day after treatment with either additive tolvaptan (TLV) or an increased dose of furosemide (FUR) was the primary endpoint in the present study. (A) The changes in urine volume between baseline and mean output during treatment over a period of 7 days were significantly higher in the TLV than FUR group. (B) Daily urine output over the 7-day treatment period in the TLV and FUR groups. WO, wash out. Data are the mean±SD.

Table 2. Independent Predictors of Increased Urine Output

Covariate	β (95% CI)	P value
Additive TLV	0.353 (71.08, 256.8)	0.0008
eGFR at baseline	0.286 (3.931, 22.90)	0.006
Urine osmolality at baseline	0.176 (−0.135, 2.100)	0.089

CI, confidence interval. Other abbreviations as in Table 1.

Secondary Endpoints

BW continued to decrease in both groups during the study, with no significant difference between the 2 groups (Figure 3A-b). BW reductions in the TLV and FUR groups were 2.1±1.8 and 2.1±2.6 (NS, Figure 3A-a), respectively. Similarly, changes in patient-assessed dyspnea and fatigue were gradually relieved equally in both groups during the study, as shown in Figure 3B-a,b. In addition, investigator-assessed physical status, such as leg edema, jugular vein dilatation, hepatomegaly, pulmonary rales, and the third heart sound, steadily decreased in both groups to a similar extent (Figure 3B-c–g).

Figure 3.

Secondary endpoints and vital signs. Fluid overload, measured as body weight (BW, A), symptoms (B-a,b), and signs (B-c–g), was relieved similarly in both treatment groups (tolvaptan (TLV) and furosemide (FUR)). Changes in serum creatinine (C-a,b) and the cumulative incidence of worsening renal function (WRF; C-c) during the treatments were significantly increased in the FUR group than in the TLV group. The free water clearance (CH₂O) was significantly increased from days 1 to 7 in the TLV group than in the FUR group (D). There was no significant difference in mean blood pressure or pulse rate during the treatments in either group (E). Data are the mean±SD. WO, wash out.

Serum creatinine levels increased gradually in the FUR group during the study, but not in the TLV group. Differences in serum creatinine levels between the 2 groups were observed after Day 3, with significant differences in serum creatinine levels after Day 5 (Figure 3C-b). The changes in serum creatinine at day 7 or the last day of the treatment from baseline were +(0.06±0.32) and +(0.20±0.27) mg/dL in the TLV and FUR groups, respectively (Figure 3C-a). The cumulative incidence of WRF was significantly lower in the TLV than FUR group (Figure 3C-c). Among the candidate variables identified by univariate analysis (P<0.05), multiple logistic regression analysis revealed that additive TLV (odds ratio 0.157, 95% CI 0.043–0.605, P=0.001) and eGFR at baseline were independent clinical factors for reducing WRF, whereas male gender and hypertension were risk factors for increasing WRF (Table 3). CH₂O was significantly increased from Day 1 to Day 9 in the TLV group (Figure 3D-b) and the change from baseline was significantly higher on the last day of treatment period in the TLV than FUR group (P=0.008; Figure 3D-a). There were no significant differences in blood pressure and pulse rate during the treatments in either group (Figure 3E).

Table 3. Independent Predictors of Worsening Renal Function

Covariate	OR (95% CI)	P-value
Additive TLV	0.157 (0.043–0.605)	0.001
Male sex	5.632 (1.652–23.00)	0.004
Hypertension	3.725 (1.057–15.47)	0.040
eGFR at baseline (for each 10-mL/min/1.73 m2 increment)	0.442 (0.229–0.787)	0.004

OR, odds ratio. Other abbreviations as in Tables 1,2.

Discussion

K-STAR has a distinctive study protocol that focuses on the efficacy of TLV to relieve residual congestion by only using diuretic-resistant HF patients. Previous studies of TLV use were tested in acute HF without accounting for diuretic resistance.^8–11 There are 3 main findings of the present study. First, additive TLV resulted in significantly higher UV than increased FUR, primarily through increased urinary water excretion in HF patients with residual congestion despite concomitant FUR. Second, additive TLV prevented renal dysfunction during the course of equivalent decongestion compared with increased FUR. Finally, additive TLV was one of the independent predictors for preventing WRF during the course of treatment.

Efficacy and Safety of Pharmacotherapeutic Decongestion in Diuretic-Resistant HF

There are many reasons for loop diuretic resistance,²⁰ with scant evidence from high-quality randomized clinical trials. Particularly in HF patients, diuretic resistance may occur when renal perfusion decreases, likely from low cardiac output.²¹ However, renal hypoperfusion at baseline as a causative factor of diuretic resistance in the present study is unlikely because the exclusion criteria included intravenous administration of inotropes. In fact, only 7% of the study population exhibited “cold” clinical status.

The addition of TLV resulted in congestion relief equivalent to increased FUR despite greater urine output, presumably because of increased water intake,²² although we failed to demonstrate such differences because water intake volume description was lacking from the study protocol. However, more patients ended the study protocol earlier due to sufficient fluid removal in the TLV than FUR group (25% and 10%, respectively). Intensified treatment was needed only in the FUR group, suggesting that TLV use was a more successful intervention for decongestion. Furthermore, the increased urine output and WRF incidence (see below) showed similar tendencies even after excluding the subjects who withdrew from the study (data not shown). Focusing on safety, the overall rate of adverse events was similar, with few serious complications in either group. A key point is that additive TLV showed no excess of hypernatremia, a potential serious complication with the use of this type of drug,²³ compared with increased FUR.

An alternative interpretation of these results is that increased FUR also ameliorated residual congestion compared with the additive TLV. In terms of the effectiveness of additional therapies leading to decongestion, we also acknowledge that evaluation of the signs and symptoms as secondary endpoints has clinical significance equivalent to urine output as the primary endpoint in the present study.

The results of the present study are consistent with the interpretation of the DOSE trial.⁶ Sufficient plasma concentrations of FUR are needed to enable secretion to the luminal side of the renal tubule, especially in this study population with chronic kidney diseases.²¹ Considering the comparable clinical efficacy among the therapeutic tools, one must choose the best strategy based on the effect on renal function during decongestion, as discussed below.

Effect of Therapy on WRF During Decongestion

Renal impairment is often seen in the process of relieving congestion and is associated with a worse prognosis in HF, widely known as WRF.²⁴ Although there is an unmet need to develop a better treatment to overcome this issue, no therapy has been proven to be more efficacious and safe regarding renal protection.^25–27 The present study is the first to demonstrate the beneficial effect of additive TLV to prevent WRF during decongestion in relatively stable HF patients with loop diuretic resistance. Both diuretic efficacy and GFR represent different aspects of kidney function, because the association between diuretic resistance and adverse clinical outcome remains strong even after correction for GFR.^3,28 Because renal dysfunction in the present study was worse (eGFR 29±10 mL/min/1.73 m²) than in previous trials of TLV use,^8,9 the study population may be harder to treat for fluid removal in conjunction with renal protection.^3,28 Notably, although hyperdiuresis has a potential risk of hypotension, partly leading to “prerenal” renal dysfunction,²⁹ additive TLV did not lower blood pressure during the process of fluid removal (data not shown). From previous studies, a possible explanation for more frequent WRF in the FUR group is that aggressive fluid removal with FUR use caused intravascular volume depletion without refilling from the extravascular space.³⁰ In future studies, a focus on differences in renal function during equivalent decongestion between the 2 treatment strategies is warranted.

Clinical Implications

In patients with HF, especially within a hospital setting, congestion is an important therapeutic target, not only for symptomatic relief, but also for prevention of rehospitalization and mortality.¹ That is, patients with persistent congestive symptoms at the time of discharge or even in stable outpatient settings are at higher risk of readmission. Because the present study population included few patients with NYHA Functional Class 4, residual fluid overload despite FUR of approximately 50 mg, and a history of repeated hospitalization for HF, these patients’ characteristics at baseline imply obstinate resistance to diuretics, leading to residual congestion persistent on chronic compromise rather than on the acute exacerbation. We emphasize that the study protocol resembles the generic clinical scenario for diuretic resistance based on therapeutic indications applicable for public insurance in Japan.¹⁹ Furthermore, the Samsca Post-Marketing Surveillance In Heart faiLurE (SMILE) study demonstrated that real-world clinical treatment conditions at baseline for additive TLV were similar (≤3.75 mg/day in 8.5% of patients, 7.5 mg/day in 56.1%, and ≥15 mg/day in 35.4%) to those used in the present study, namely high age (75±9 vs. 76±13 years, respectively), NYHA Functional Class II–III (84% vs. 66%, respectively), dominant leg edema (79% vs. 83%, respectively), and decreased eGFR (29±10 vs. 43±27 mL/min/1.73 m², respectively) and FUR (51±25 mg vs. 69±66 mg, respectively). This suggests that the predominance of TLV use for kidney function during decongestion in FUR-resistant HF patients can be applied in real-world clinical practice.

Study Limitations and Future Prospects

K-STAR has several limitations. First, the data were drawn from a small number of patients with a wide variation of clinical settings from acute to chronic. Although the present study was a prospective multicenter observation, all possibilities of selection bias were not excluded. Second, subjective data for decongestion, such as dyspnea, were limited by the lack of blinding in the study design of open-label examination. Finally, some recent reports have demonstrated that not all types of WRF are necessarily associated with poor outcomes in the acute HF setting: transient WRF, as opposed to persistent WRF, may not affect prognosis.³¹ Regrettably, we could not determine whether the occurrence of WRF was transient or persistent, because the study design only included data collected during treatment for 7 days.¹¹

We used simple treatments to add a relatively low dose of TLV or FUR to standard therapy, representing residual congestion to be continued in 10–20% of subjects (Figure 3B). Although the recent clinical trial of TLV in Japan has set comparative doses of increased FUR and additive TLV that resemble those used in the present study,⁹ the clinical figures after the treatments provided in the present study underscore the ongoing unmet need to develop better strategies for aggressive decongestion in diuretic-resistant HF patients. There have been some reports that short-term declines in GFR may even track with better prognosis when accompanied by successful fluid removal.³² Hence, future work will investigate whether and how additive TLV, associated with greater urine output increase to relieve congestion without compromising WRF, can lead to prognostic improvement such as length of stay, incidence of worsening HF, or post-discharge outcome in chronic HF.

Conclusions

In HF patients with residual congestion and renal dysfunction refractory to standard therapy including loop diuretics, additive TLV increased UV without further renal impairment compared with patients receiving an increased dose of FUR.

Acknowledgments

K-STAR study was funded by The Kidney Foundation, Japan. The authors express their deep gratitude to the following clinical sites and their investigators for enrolling study patients: Kitasato University Hospital, St. Marianna University School of Medicine Hospital, Yokohama City University Hospital, Yokohama City University Medical Center, Tokai University Hospital, Showa University Fujigaoka Hospital, Nippon Medical School Musashi-Kosugi Hospital, Yokohama General Hospital, Kanagawa Cardiovascular and Respiratory Center, Teikyo University School of Medicine University Hospital, Yokosuka General Hospital Uwamachi, Kawasaki Municipal Hospital, Nippon Kokan Hospital, Yamato Municipal Hospital, Sagamihara Kyodo Hospital, National Hospital Organization Sagamihara National Hospital, JCHO Yokohama Chuo Hospital, National Hospital Organization Yokohama Medical Center, Yokosuka City Hospital, Japanese Red Cross Hadano Hospital, Tokai University Oiso Hospital, Isehara Kyodo Hospital, St. Marianna University School of Medicine, Yokohama City Seibu Hospital and Toyoko Hospital, Kawasaki Municipal Tama Hospital, Ebina General Hospital, and Yokohama Sakae Kyosai Hospital. In addition, the authors thank Kazuko Nakamura, Secretary of the Kanagawa Aquaresis Investigators management office, for collecting data and Kitasato Academic Research Organization for managing this study.

Conflict of Interest

T. Inomata has received lecture honoraria from Otsuka Pharmaceutical Co. and Daiichi-Sankyo Pharmaceutical. Y.S. has received lecture honoraria from Otsuka Pharmaceutical and Novartis Pharma, as well as research funding from Otsuka Pharmaceutical, Teijin Pharma, and Kyowa-Hakko Kirin. N.S. has received consultancy fees from Novartis and Terumo, lecture honoraria from Otsuka, Daiichi-Sankyo, Ono, Eisai, Bayer, Boehringer-Ingelheim, Roche Diagnostics-Japan, Astellas, and Teijin, and institutional research support from Roche-Japan and Astellas. The other authors have nothing to disclose.

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