Safety and Efficacy of Long-Term Use of Tolvaptan in Patients With Heart Failure and Chronic Kidney Disease

Abstract

Background: We assessed the long-term safety and efficacy of tolvaptan in 102 patients with heart failure (HF) and chronic kidney disease (CKD). Median follow-up duration was 1.6 years (1.0–4.4 years).

Methods and Results: One patient discontinued tolvaptan because of hypernatremia. There were no changes in renal function or electrolytes during the 1-year follow-up. The cardiac-related death-free or HF-related hospitalization-free survival rate was significantly higher in patients receiving tolvaptan than in propensity score-matched patients who did not receive tolvaptan.

Conclusions: In patients with HF and CKD, long-term administration of tolvaptan was well-tolerated, relatively safe and effective, suggesting its utility for long-term management of these conditions.

Tolvaptan is a selective vasopressin type 2 receptor antagonist that blocks the binding of arginine to the vasopressin receptor and increases free-water clearance.^1,2 Previous studies have shown that tolvaptan improves systemic congestion and ameliorates hyponatremia, without activating the renin–angiotensin system or deteriorating renal function.^3–5 Therefore, tolvaptan is a promising agent for the treatment of heart failure (HF) with chronic kidney disease (CKD).

A few studies have reported the safety and efficacy of short- and intermediate-term use of tolvaptan in patients with HF.^3,6–8 Post-marketing surveillance data from Japan also demonstrate the safety of tolvaptan use for short and intermediate periods.⁴ However, it remains unknown whether these favorable effects of tolvaptan are maintained during long-term administration in HF patients with CKD. Here, we assessed the safety and efficacy of long-term tolvaptan administration in patients with HF and CKD in a clinical setting.

Methods

This retrospective study was conducted in hospitalized patients who were administered oral tolvaptan for the treatment of HF between July 2012 and December 2015 in Anjo Kosei Hospital, Japan. Tolvaptan was initiated when the volume overload in these HF patients did not improve despite the use of conventional diuretics. Patients who were administered tolvaptan for >60 days for the treatment of HF were considered eligible. Discontinuation of tolvaptan was defined as no intake of the drug for at least 14 days.

Additional Methods are available in Supplementary File 1.

Results

Baseline Characteristics

Overall, 102 patients who were admitted for the treatment of HF were enrolled (Table S1). All patients were discharged and prescribed tolvaptan in the outpatient clinic at least once. Median follow-up duration was 1.6 years (minimum 1 year, max 4.4 years). The average patient age was 74.1±11.1 years, and 59.8% were male. Most patients were classified into New York Heart Association (NYHA) functional classes III and IV; 64% of the patients had a history of prior hospitalization for HF. All patients had kidney dysfunction (average creatinine and estimated glomerular filtration rate (eGFR) were 1.81±0.91 mg/dL and 32.4±13.3 mL/min/1.73 m², respectively). The median B-type natriuretic peptide (BNP) level was 790.6 pg/mL (interquartile range, 503.5–1,622.2). In 82% of patients, the initial tolvaptan dose was 7.5 mg. Tolvaptan was initiated at a median of 2 days after admission. Mean body weight change from tolvaptan initiation to discharge was −3.8 kg. At discharge, angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers, β-blockers, and mineralocorticoid-receptor antagonists were used by 48.0%, 77.5%, and 37.3% of patients, respectively. Diuretics were used by 97.1% of patients, and the median dose of loop diuretics was 40 mg at discharge. The median duration of hospital stay was 12 days.

Discontinuation of Tolvaptan

During the follow-up period, 29 (28.4%) of the patients who were alive, discontinued tolvaptan (Table S2). Tolvaptan discontinuation was not attributed to thirst, urinary frequency, or dry mouth in any of the cases. All non-cardiac causes that required admission were newly diagnosed, and the diagnosis restricted oral intake in these patients. One patient with colon perforation resumed tolvaptan after recovery. Liver or renal function worsened in 3 patients; 1 patient discontinued tolvaptan because of suspected drug-related hypernatremia, but the hypernatremia was caused by inadequate water restriction by the patient, despite guidance about the drug therapy. There were 7 patients who required maintenance dialysis during follow-up; 6 of them had an eGFR <15 mL/min/1.73 m² at initiation of tolvaptan. Decline in renal function was consistent with the natural course of kidney disease in each case. In 10 patients, cardiologists discontinued tolvaptan because HF stabilized. Among them, 4 patients required resumption of tolvaptan because of relapse of congestion.

Changes in Renal Function, Electrolytes, and Medication Dose

We investigated renal function, electrolytes, and medication dose at the time of hospital admission and discharge, and at 1, 3, 6, and 12 months after discharge (Table). There were no significant changes in serum creatinine levels, eGFR, and the BUN/creatinine ratio during the 1-year follow-up. Plasma BNP levels decreased significantly after discharge together with HF control, whereas serum sodium and potassium levels, systolic blood pressure, and heart rate did not change. NYHA classification and cardiothoracic ratio on chest X-ray also improved during the 1-year follow-up. The doses of tolvaptan and loop diuretics remained statistically unaltered during the 1-year follow-up.

Table. Changes in Clinical Parameters During Tolvaptan Administration

	Baseline (n=102)	Discharge (n=102)	1 month (n=102)	3 months (n=99)	6 months (n=92)	1 year (n=85)
BUN (mg/dL)	38.4±20.3	39.9±23.0	37.6±18.7	41.3±22.8	40.5±23.0	43.0±27.5
Creatinine (mg/dL)	1.81±0.91	1.95±1.75	1.76±0.87	1.81±1.00	1.76±0.82	2.00±1.48
eGFR (mL/min/1.73 m2)	32.4±13.3	33.0±15.5	33.7±15.2	33.2±15.3	33.5±14.8	32.3±15.4
BUN/creatinine ratio	22.2±8.6	23.0±11.0	22.5±8.7	23.7±8.7	23.5±10.2	23.2±11.1
Sodium (mEq/L)	138.8±3.8	139.5±3.7	139.7±3.7	139.3±3.6	139.8±3.6	140.1±3.2
Potassium (mEq/L)	4.1±0.6	4.3±0.6	4.4±0.5	4.4±0.6	4.4±0.6	4.3±0.6
Systolic BP (mmHg)	116±20	112±18	117±21	115±21	115±23	118±26
Heart rate (beats/min)	79.4±18.2	73.5±14.0	78.0±14.5	76.7±16.6	77.5±18.3	75.7±12.7
BNP (pg/mL)	790.6 (1,118.7)	– (–)	469.1 (600.2)*	402.5 (482.3)*	251.7 (504.3)*,#	332.3 (262.7)*,#
NYHA classification	3.1±0.5	1.9±0.6*	1.8±0.7*	1.8±0.8*	1.8±0.8*	1.6±0.7*
Cardiothoracic ratio (%)	62.5±6.9	60.0±7.0	59.3±6.9*	59.4±7.3*	58.7±7.1*	58.2±7.5*
Tolvaptan dose (mg)	7.50 (0.00)	7.50 (3.75)	7.50 (0.94)	7.50 (7.50)	7.50 (7.50)	7.50 (10.3)
Loop diuretic dose (mg)	50.0 (40.0)	40.0 (40.0)	40.0 (40.0)	40.0 (40.0)	40.0 (40.0)	40.0 (40.0)

Data are presented as mean±standard deviation or as median (interquartile range). *P<0.05 vs. baseline, ^#P<0.05 vs. 1 month. BNP, B-type natriuretic protein; BP, blood pressure; BUN, blood urea nitrogen; eGFR, estimated glomerular filtration rate; NYHA, New York Heart Association.

Clinical Outcomes

We lost 3 patients to follow-up. All-cause death and cardiac-related death occurred in 34 (33.3%) and 23 (22.5%) patients, respectively, during the follow-up period (Table S3). During the 1-year follow-up period, all-cause death and cardiac-related death occurred in 11 (10.8%) and 5 (4.9%) patients, respectively. Of the 55 (53.9%) patients who needed re-admission for deterioration of HF, 45 (81.8%) were re-hospitalized within 1 year (Table S3).

Finally, we compared the post-discharge outcomes between patients who did and did not receive tolvaptan. We used patients with HF and CKD who were administered high-dose loop diuretics (≥60 mg) alone between July 2012 and December 2015 as the control group. Propensity score-matching analyses were used to select background-matched patients who did or did not receive tolvaptan (n=56 in each group; Table S4). There were no significant differences in survival rate between the groups. The cardiac-related death-free or HF-related hospitalization-free survival rate was significantly higher in patients receiving long-term tolvaptan treatment than in propensity score-matched patients who did not receive long-term tolvaptan treatment (Figure).

Figure.

Kaplan-Meier estimates of (A) survival rates and (B) cardiac-related death-free or HF-related hospitalization-free survival rates in patients who received tolvaptan and the propensity score-matched patients who did not receive tolvaptan (n=56 in each group).

Discussion

The current study is the first to investigate the safety and efficacy of long-term tolvaptan administration in HF patients with CKD. The incidence of side effects after tolvaptan administration was relatively low in the chronic phase, and renal function was maintained during the long-term follow-up. Thus, long-term administration of tolvaptan in patients of HF with CKD was well tolerated and safe in the clinical setting. In addition, compared with treatment with conventional diuretic agents, tolvaptan treatment resulted in a higher cardiac-related death-free or HF-related hospitalization-free survival rate in HF patients with CKD. Tolvaptan could be a safe and effective agent for long-term management of HF patients with CKD.

Acknowledgments

We gratefully thank Mr. Hiroshi Takahashi, Fujita Health University Graduate School of Medicine, for his advice on statistics.

Funding

This research received no grant from any funding agency in the public, commercial, or non-profit sectors.

Disclosures

Y.U. received lecture fees from Otsuka Pharma Ltd. T.M. received an unrestricted research grant from Otsuka Pharma Ltd. for the Department of Cardiology, Nagoya University Graduate School of Medicine.

Supplementary Files

Supplementary File 1

Supplementary Methods

Table S1. Patients’ characteristics at the initiation of tolvaptan (n=102)

Table S2. Reasons for tolvaptan discontinuation

Table S3. Occurrence of clinical events (n=102)

Table S4. Comparison of post-propensity matched baseline characteristics of patients who did and did not receive tolvaptan (n=56)

Please find supplementary file(s);

http://dx.doi.org/10.1253/circj.CJ-17-0554

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