Short-Term Efficacy and Safety of Tolvaptan in Patients with Left Ventricular Assist Devices

Abstract

Tolvaptan is an effective therapy for heart failure patients with symptomatic congestion and hyponatremia. The efficacy of its use in patients with continuous-flow left ventricular assist devices (LVADs) is unknown. The aim of this study was to assess the clinical efficacy and safety of tolvaptan in LVAD patients. We retrospectively reviewed medical records of patients who underwent LVAD implantation between January 2014 and August 2018. Among 217 consecutive LVAD patients, tolvaptan was used in 20 patients. Mean age was 46 ± 14 years old and 14 patients were males. The duration of tolvaptan therapy was 4 (interquartile range 1–8) days. Urine volume significantly increased from 2,623 ± 1,109 ml/day before tolvaptan to 4,308 ± 1,432 ml/day during tolvaptan therapy (p < 0.001). Serum sodium increased from 127 ± 3 to 133 ± 3 mEq/L at the end of tolvaptan therapy (p < 0.001). No patients developed hypernatremia (serum sodium >150 mEq/L). The 90-day overall survival following tolvaptan therapy was 89% in both the tolvaptan group and a propensity score-matched non-tolvaptan group (p = 0.918). Survival free of heart failure readmissions was also comparable between the groups (p = 0.751). In conclusion, short-term use of tolvaptan following LVAD implantation is a safe and effective therapy to augment diuresis and improve hyponatremia.

Continuous-flow left ventricular assist devices (LVADs) have become a mainstay of therapy for advanced heart failure (HF) patients, both as a bridge to transplantation and destination therapy.¹ In addition to improving survival, LVADs improve patient hemodynamics, allowing for a potential reduction or discontinuation of diuretics following implantation.² However, elevated filling pressures are common following LVAD implantation, and acute decompensated HF is one of the most frequent causes of readmission, which may be left-sided, right-sided, or both.^3,4 Especially, right ventricular failure (RVF) in LVAD patients is a challenging development and associated with increased morbidity and mortality.^5–8 It has been reported that diuretics were prescribed to almost half of LVAD patients at index discharge, and even 2 years following LVAD implantation.^9,10 Loop diuretics are used as first-line agents for decongestion; however, diuretic resistance is common in LVAD patients due to long-term loop diuretic exposure and concomitant chronic kidney disease. Furthermore, loop diuretics are known to increase neurohormonal activation, and have been demonstrated to worsen renal function and induce hyponatremia.^11–14

Tolvaptan, an arginine vasopressin Type 2 antagonist, is an aquaretic that has been approved since 2009 for use with hypervolemic and euvolemic hyponatremia.¹⁵ Reports have demonstrated efficacy of short-term use of tolvaptan for acute HF patients with symptomatic congestion and hyponatremia.^16,17 However, the use of tolvaptan in LVAD patients has only been described in case reports.¹⁸ The aim of this study is to investigate the clinical efficacy and safety of tolvaptan in LVAD patients.

Materials and Methods

We retrospectively reviewed the medical record of patients who underwent LVAD implantation at our institution between January 2014 and August 2018. Tolvaptan was indicated for the treatment of hypervolemic hyponatremia or euvolemic hyponatremia and was used at the discretion of the attending cardiologist. The study protocol was approved by the Institutional Review Board at the University of Chicago.

Background characteristics, laboratory, echocardiographic, and hemodynamic data were obtained from the medical record. The dimensions and volumes of chambers were measured in the standard manner by echocardiography.¹⁹ Valvular regurgitation (tricupid and mitral) was defined as significant if reported as moderate or greater by echocardiography. Hemodynamic data were collected, including right atrial pressure (RAP), pulmonary artery pressure (PAP), pulmonary capillary wedge pressure, and cardiac index. Pulmonary arterial pulsatility index (PAPi) was calculated as PAPi = (systolic PAP – diastolic PAP)/mean RAP. Urine volume and diuretic dose on the day before starting tolvaptan were used as the pre-tolvaptan values. Values during tolvaptan therapy were calculated as an average of the 24-hour urine volume or dose of diuretics on the days that tolvaptan was administered. Dose of diuretics is reported as intravenous furosemide equivalent, with oral bumetanide 1 mg equaling oral furosemide 40 mg and intravenous bumetanide 1 mg equaling intravenous furosemide 20 mg.²⁰ Laboratory data on the day of starting tolvaptan were used as the pre-tolvaptan values, and those on the day following the last use of tolvaptan were used as the post-tolvaptan values. All patients were followed prospectively until October 2018. HF readmissions and mortality were recorded during the observational period. Ninety-day outcomes were compared between the tolvaptan group and a propensity score-matched non-tolvaptan group.

Statistical Analyses

The distribution of continuous variables was assessed by Shapiron-Wilk test, and they were presented as mean and standard deviation for normally distributed data and median with interquartile range (IQR) for data without a normal distribution. Continuous data were compared using the unpaired t-test or Mann-Whitney U test, as appropriate. Categorical variables were compared between groups using the χ² test or Fisher’s exact test as appropriate. Changes in continuous data were compared by the paired t-test. Changes in categorical variables were compared by McNemar’s test. Propensity score matching analysis was performed to adjust the background data in the tolvaptan group and the non-tolvaptan group. Considering the number of patients in the tolvaptan group, we matched three parameters; age, gender, and serum sodium before LVAD implantation. We matched each patient in the tolvaptan group with two patients in the non-tolvaptan group according to each propensity score, and compared clinical outcomes during the 90-day period after the postoperative day when tolvaptan was started. Clinical outcomes were assessed using Kaplan-Meier analyses and compared by the log-rank test. Statistical analysis was performed using SPSS Statistics 23 (SPSS Inc, Chicago, IL). A two-tailed p-value <0.05 was considered significant.

Results

Baseline Characteristics

Among 217 consecutive LVAD patients, tolvaptan was used in 20 patients (9%). Characteristics of the study population are shown in Table 1. Mean age was 46 ± 14 years old and 14 patients (70%) were males. Before LVAD implantation, mean RAP was 15 ± 7 mmHg and PAPi was 1.7 ± 1.0 (Table 1).

Table 1.

Baseline Data of Patients Treated with Tolvaptan

	n = 20
Baseline characteristics
Age, years	46 ± 14
Male, n	14 (70%)
Race, n
African American	10 (50%)
White	9 (45%)
Others	1 (5%)
Ischemic etiology, n	5 (25%)
Destination therapy, n	15 (75%)
Diabetes mellitus, n	8 (40%)
Atrial fibrillation, n	7 (35%)
History of stroke, n	3 (15%)
Device type, n
HeartMate II	6 (30%)
HeartMate 3	5 (25%)
HVAD	9 (45%)
Data before LVAD implantation
Body surface area, m2	2.1 ± 0.3
Mean blood pressure, mmHg	79 ± 13
Heart rate, bpm	102 ± 16
LVEDD, mm	73 ± 13
LVEF, %	19.3 ± 7.3
TAPSE, mm	13.3 ± 5.2
Significant MR, n	10 (50%)
Significant TR, n	11 (55%)
Mean RAP, mmHg	15 ± 7
Mean PAP, mmHg	38 ± 10
Mean PCWP, mmHg	27 ± 11
Cardiac index, L/min/m2	1.9 ± 0.5
PAPi	1.7 ± 1.0

LVAD, left ventricular assist device; bpm, beats per minute; LVEDD, left ventricular end-diastolic diameter; LVEF, left ventricular ejection fraction; MR, mitral regurgitation; PAP, pulmonary arterial pressure; PAPi, pulmonary arterial pulsatility index; PCWP, pulmonary capillary wedge pressure; RAP, right atrial pressure; TAPSE, tricuspid annular plane systolic excursion; TR, tricuspid regurgitation.

Data of tolvaptan therapy are shown in Table 2. The initial dose of tolvaptan was 15 mg in all patients, and increased to 30 mg in 5 (25%) patients. The duration of tolvaptan therapy during the hospitalization was 4 (IQR 1–8) days (Table 2). All patients were successfully discharged after the treatment with tolvaptan. Two patients (10%) continued taking tolvaptan after discharge and the others were discharged 7 (IQR 4–11) days after the last use of tolvaptan.

Table 2.

Data of Patients at Tolvaptan Therapy

	n = 20
Timing of starting tolvaptan, n
Index hospitalization	13 (65%)
Readmission	7 (35%)
Reason for starting tolvaptan, n
Hypervolemic hyponatremia	18 (90%)
SIADH	2 (10%)
LVAD duration before tolvaptan therapy, days	16 (8, 374)
Initial dose of tolvaptan, n
15 mg	20 (100%)
Last dose of tolvaptan, n
15 mg	15 (75%)
30 mg	5 (25%)
Duration of tolvaptan therapy, days	4 (1, 8)

LVAD, left ventricular assist device; SIADH, syndrome of inappropriate secretion of antidiuretic hormone.

Physical and Laboratory Data

Urine volume significantly increased from 2,623 ± 1,109 ml/day before starting tolvaptan to 4,308 ± 1,432 ml/day during tolvaptan therapy (Figure 1A, p < 0.001). Body weight significantly decreased following tolvaptan therapy (99 ± 30 to 97 ± 30 kg, p = 0.018, Table 3). LVAD pump speeds were comparable between pre- and post-tolvaptan therapy. Serum sodium increased from 127 ± 3 to 133 ± 3 mEq/L at the end of tolvaptan therapy (Figure 1B and Table 3, p < 0.001). Blood urine nitrogen and serum creatinine remained unchanged (blood urine nitrogen, 31 ± 22 to 25 ± 19 mg/dl, p = 0.182; creatinine, 1.3 ± 0.6 to 1.2 ± 0.4 mg/dl, p = 0.698, Table 3). No patients developed hypernatremia (serum sodium >150 mEq/L) or hypovolemia requiring volume resuscitation during tolvaptan therapy.

Figure 1.

The changes of urine volume (A) and serum sodium (B) with tolvaptan therapy. A: The left box (blue) shows 24-hour urine volume before tolvaptan therapy, and the right box (orange) shows the average of 24-hour urine volume on the days that tolvaptan was administered. B: The left box (blue) shows serum sodium before tolvaptan therapy, and the right box (orange) shows serum sodium one day after the last use.

Table 3.

Comparison of Patients’ Data Between Pre- and Post-Tolvaptan

	Pre-tolvaptan (n = 20)	Post-tolvaptan (n = 20)	p
Physical and Pump Data
Body weight, kg	99 ± 30	97 ± 30	0.018
Mean blood pressure, mmHg	77 ± 11	77 ± 8	0.919
Heart rate, bpm	98 ± 13	100 ± 13	0.645
Pump speed, rpm			0.451
HeartMate II (n = 6)	9,466 ± 242	9,500 ± 210
HeartMate 3 (n = 5)	5,500 ± 292	5,580 ± 311
HVAD (n = 9)	2,776 ± 283	2,757 ± 158
Laboratory data
White blood cell/μl	13,500 ± 5,300	10,400 ± 3,700	0.010
Hemoglobin, g/dl	10.0 ± 1.4	10.1 ± 1.4	0.676
Platelet, 104/μl	29.0 ± 14.8	32.3 ± 16.0	0.089
Blood urine nitrogen, mg/dl	31 ± 22	25 ± 19	0.182
Serum creatinine, mg/dl	1.3 ± 0.6	1.2 ± 0.4	0.698
Serum sodium, mEq/L	127 ± 3	133 ± 3	<0.001
Serum potassium, mEq/L	4.1 ± 0.7	4.2 ± 0.5	0.820
Serum chloride, mEq/L	87 ± 4	94 ± 4	<0.001

bpm, beats per minute; rpm, rotations per minute.

The median intravenous furosemide-equivalent dose of diuretics was 170 mg (IQR 40–240 mg) before starting tolvaptan. During tolvaptan therapy, the median diuretic dose decreased to 80 mg (IQR 40–180 mg), but the change was not statistically significant (p = 0.127, Figure 2).

Figure 2.

The change of diuretics dose with tolvaptan therapy. The left box (blue) shows intravenous furosemide-equivalent dose of loop diuretics before tolvaptan therapy. The right box (orange) shows the average of that on the days that tolvaptan was administered.

Outcomes

We compared echocardiographic data and survival following tolvaptan therapy in the tolvaptan group and a propensity score-matched non-tolvaptan group. Two patients in the tolvaptan group could not be matched because their propensity scores were outliers. The remaining 18 patients in the tolvaptan group were matched to 36 control patients for the purpose of outcome analyses.

There were no significant differences in the baseline characteristics, laboratory, echocardiographic, and hemodynamic data before LVAD implantation (see Table, Supplemental Digital Content 1, http://links.lww.com/ASAIO/A459). As shown in Table, Supplemental Digital Content 2, http://links.lww.com/ASAIO/A460, left ventricular end-diastolic diameter (LVEDD) and left atrial volume (LA volume) did not significantly decrease with tolvaptan therapy (LVEDD, 65 ± 16 to 64 ± 12 mm, p = 0.708; LA volume, 73 ± 28 to 61 ± 21 ml, p = 0.096). However, right ventricular end-diastolic area (RVEDA) and right atrial volume (RA volume) as well as inferior vena cava (IVC) diameter significantly decreased with tolvaptan therapy (RVEDA, 35 ± 9 to 30 ± 11 cm2, p = 0.033; RA volume, 84 ± 37 to 63 ± 28 ml, p < 0.001; IVC diameter, 23 ± 5 to 19 ± 9 mmHg, p < 0.001).

The 90-day survival rate following tolvaptan therapy was 89% in the tolvaptan group and in the non-tolvaptan group(p = 0.918; Figure 3A). Survival free of HF readmissions was also comparable between the groups (78% in the tolvaptan group and 83% in the non-tolvaptan group, p = 0.751; Figure 3B).

Figure 3.

Comparison of clinical outcomes. Overall survival (A) and HF readmission-free survival (B) following tolvaptan therapy in the tolvaptan group (n = 18, red line) and a propensity score-matched non-tolvaptan group (n = 36, black line). HF, heart failure.

Discussion

This is the first study that assessed the short-term efficacy and safety of tolvaptan in LVAD patients. The main findings of this study were: 1) tolvaptan therapy effectively augmented diuresis in LVAD patients; 2) tolvaptan therapy increased serum sodium significantly in LVAD patients; and 3) no serious adverse effects occurred during tolvaptan therapy.

Although LVAD implantation has improved the survival of advanced HF patients, LVAD patients experience high readmission rates. One of the most frequent causes of readmission is acute decompensated HF, which may be left-sided in cases of inadequate left ventricular unloading, right-sided, or both.^3,4 Left-sided HF can be caused by inadequate speed setting, poor cannula position, aortic insufficiency, or high afterload.^2,21,22 The etiology of RVF is more complicated and multifactorial, including intraoperative factors, intrinsic RV dysfunction, pulmonary hypertension, interventricular interaction, and worsening tricuspid regurgitation.^8,23 RVF can occur early or late after LVAD implantation and is related to poor clinical outcomes.^1,5–8

Recently, our group reported that almost half of clinically stable LVAD patients have abnormal hemodynamics and that these are associated with worse clinical outcomes.^2,22,24,25 In addition, it was found that optimization of hemodynamics was associated with reduced hospital readmission rates.²⁶ However, RVF cannot be addressed simply with speed optimization, and aggressive diuresis may be required for certain patients even after LVAD implantation.^9,10

Aggressive diuresis may lead to diuretic resistance over time. Overcoming loop diuretic resistance may require escalating diuretic doses, the addition of a thiazide diuretic, or the use of ultrafiltration.²⁷ Tolvaptan has emerged as an alternative method to attain effective diuresis without significant adverse effects. The use of tolvaptan has been studied as an adjunct to diuretic therapy in chronic systolic HF patients with a HF hospitalization. Owing to its unique aquaretic effect, evidence for the efficacy of tolvaptan therapy for hospitalized HF patients has been accumulating as it leads to improvement in congestive symptoms and ameliorates hyponatremia.^15–17 Despite this, in the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan trial, tolvaptan therapy increased weight loss during hospitalization, but had no effect on long-term mortality or HF hospitalizations.^16,28 Adding tolvaptan to conventional diuretic therapy may decrease the dose of loop diuretics and prevent worsening renal function during decongestion.^29,30 However, there are no studies to date evaluating the efficacy of tolvaptan in LVAD patients.

In this study, adding tolvaptan to high dose loop diuretics led to a >50% increase in urine volume while also improving serum sodium levels. These changes occurred in the presence of lower diuretic doses (not statically significant) and did not produce any changes in renal function. Echocardiographic data showed that right-sided volume significantly decreased with tolvaptan therapy. Furthermore, in this study, no patients suffered from hypernatremia or any other adverse events during tolvaptan therapy. Similar to other tolvaptan studies, tolvaptan therapy was not associated with statistically significant differences in the 90-day survival and HF readmission-free survival when compared with the non-tolvaptan group.^28,31 Similar to previous studies, in this study tolvaptan was used in combination with loop diuretics in most patients.^16,29,31 We need further studies to investigate the difference of efficacy and safety of tolvaptan with or without other diuretics, especially in LVAD patients.

Study Limitations

Several potential limitations of this study should be considered. First, the cohort is a small population from a single center. As there were only 20 patients in the tolvaptan group and 18 of them were enrolled for outcome analyses, the strength of statistical precision and power is limited for the comparison of outcomes. In addition, the dosage response of tolvaptan cannot be established in this small study. Larger studies are needed to investigate the optimal dosage of tolvaptan in LVAD patients. Second, due to the nature of this retrospective analysis, unmeasured factors other than tolvaptan may have affected the change in urine volume or laboratory data. Also, undetectable selection bias may have affected the clinical outcomes of the tolvaptan group despite the propensity score matching analysis. Because of the limited number of patients, we used only age, gender, and serum sodium before LVAD implantation for propensity score matching. Accordingly, a randomized, prospective study would be required to validate our findings and the implications for clinical practice. Third, we could not predict responders to tolvaptan in our cohort because of the small population. Finally, as noted above, this report described the short-term effect of tolvaptan therapy, and the results cannot be extrapolated to long-term tolvaptan use.

Conclusions

Short-term use of tolvaptan following LVAD implantation was an effective therapy to augment diuresis and improve hyponatremia. Further investigations of the clinical utility of tolvaptan in LVAD patients are needed.