The Efficacy and Safety of Tolvaptan in Heart Failure Patients with Congestive Signs: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Abstract

Objective: 

The aim of this study was to investigate the efficacy and safety of tolvaptan, as well as the impact of its treatment dose and duration in heart failure patients with congestive signs.

Methods: 

The PubMed, Embase, Cochrane Library, and ClinicalTrials.gov databases were searched to collect data from all randomized controlled trials (RCT) examining the efficacy and safety of tolvaptan in heart failure patients with congestive signs compared with placebo or blank control until March 4, 2021. Urine volume, change in body weight, improvement in dyspnea, and reduction of edema were evaluated as efficacy indicators. All-cause mortality, worsening heart failure, and adverse events were considered safety indicators. The quality of eligible publications was assessed using the Cochrane risk of bias for RCTs.

Results: 

Ten RCTs with 5,980 patients were included in this analysis. Compared with control, tolvaptan significantly reduced weight in the short term (day 1, 7 RCTs, weighted mean difference (WMD): –1.09, 95% confidence interval (CI): –1.27 to –0.91; day 2, 2 RCTs, WMD: –1.67, 95% CI: –3.00 to –0.33; day 7, 4 RCTs, WMD: –0.95, 95% CI: –1.25 to –0.66), increased urine volume (WMD: 1,825.72, 95% CI: 1,438.38–2,213.07), and relieved dyspnea (risk ratio (RR): 1.12, 95% CI: 1.05–1.19) without increasing the mortality rate (RR: 0.96, 95% CI: 0.87–1.06). Furthermore, the weight loss and increase in urine volume were not dose-dependent effects, and prolonged medication did not lead to sustained weight loss. In addition, there seemed to be more adverse events (RR: 1.17, 95% CI: 1.03–1.32) after treatment with tolvaptan. Further analysis revealed that patients treated with tolvaptan were more likely to report thirst (RR: 6.09, 95% CI: 3.37–11.00) and dry mouth (RR: 6.36, 95% CI: 4.09–9.90), as well as develop hypernatremia (RR: 12.76, 95% CI: 3.52–46.32).

Conclusions: 

The meta-analysis shows that tolvaptan can improve congestion with no increase in mortality rate, but should be used to guard against adverse events. Deserve to be mentioned, the number of RCTs included was limited, suggesting that the observed results should be interpreted with caution. Additional robust clinical studies are warranted to validate the present findings.

CLINICAL PERSPECTIVE

WHAT IS NEW?

• In this meta-analysis, we summarized the dose-dependent efficacy and safety of tolvaptan in heart failure patients with congestive signs.
• Subgroup analysis indicated that increased dose and prolonged administration did not result in a corresponding increase in efficacy.

WHAT ARE THE CLINICAL IMPLICATIONS?

• Tolvaptan is effective in improving congestive symptoms in patients with heart failure, without increasing mortality rate.
• The effect of tolvaptan is not dose-dependent, and prolonged medication do not provide sustained relief from congestion.
• Tolvaptan can cause thirst and dry mouth, which may affect the patient compliance.

1. Introduction

Heart failure (HF) is a complex clinical syndrome caused by the structural or functional impairment of ventricular filling or ejection of blood.^[1,2] Approximately 1% to 2% of the adult population in developed countries has HF, with the prevalence rising to ≥10% among those aged >70 years.^[3] Although survival rates have improved, the absolute death rate from HF within 5 years of diagnosis remains around 50%.^[1] Congestive signs and symptoms caused by volume overload and fluid retention are a major cause of hospitalization in patients with HF. Diuretic therapy remains the mainstay of treatment for HF,^[4] as it rapidly relieves sodium and water retention. However, diuretic therapy (particularly at high doses) has been associated with adverse effects, including electrolyte abnormalities (hyponatremia and hypokalemia), neurohormonal activation, renal dysfunction, and increased mortality.^[5,6] Moreover, approximately one-third of patients with HF develop resistance to diuretics.^[4,7] Thus, it is crucial to develop safe and effective diuretic treatment strategies that can provide relief to patients.^[8]

Tolvaptan is an oral, non-peptide, selective vasopressin V2-receptor antagonist. It increases free-water clearance by inhibiting V2 receptor-mediated water reabsorption in the renal collecting tubule. Numerous clinicians use oral tolvaptan, along with standard therapy, for the treatment of HF. This approach results in a significant decrease in body weight without causing many adverse events. However, the efficacy and safety of tolvaptan remains debatable. The conclusions derived from the existing meta-analyses are not completely consistent. Therefore, we performed a systematic review and meta-analysis of the randomized controlled trials (RCTs) to re-evaluate therapy with tolvaptan. This review was approved by the online PROSPERO International Prospective Register of Systematic Reviews of the National Institute for Health Research (CRD42014013952).

2. Methods

2.1. Literature search

Two investigators systematically searched the PubMed, Embase, Cochrane Library, and ClinicalTrials.gov databases for available relevant RCTs until March 4, 2021. The search strategy included all medical subject headings and free terms such as “Heart failure,” “Tolvaptan,” and “Randomized controlled trial,” according to the population, intervention, comparison, outcomes, and study designs (PICOS) principle.

2.2. Study selection

This meta-analysis included only RCTs that met the following criteria: (1) study population, adult HF patients of both sexes with congestive signs (eg, peripheral edema, dyspnea, and jugular venous distention); and (2) study group, oral tolvaptan with placebo or blank control. Non-English articles, reviews, case reports, conference summaries, and articles with incomplete data were excluded.

2.3. Data extraction and quality assessment

Two investigators independently extracted the following information from each study: first author, year of publication, study design, population characteristics, intervention, sample size, follow-up duration, body weight change, urine volume, dyspnea relief, edema improvement, all-cause mortality, worsening HF (WHF), and adverse events. The quality of the available studies was assessed using the “risk of bias” method recommended by the Cochrane Collaboration.^[9]

2.4. Statistical analysis

The statistical software Stata/SE version 15.1 (StataCorp LLC, Lakeway, Texas, USA) was used to conduct the statistical analysis. The meta-analysis was performed according to the recommendations of the PRISMA guidelines.^[10] When necessary, the means and standard deviations were estimated from the median and confidence interval (CI) limits or range values provided in the studies.^[11] Weighted mean difference for continuous outcomes, risk ratio (RR) for dichotomous outcomes, and 95% CI were selected as effect indicators. To assess the heterogeneity among the studies, we used the I² test and Q statistic,^[12] in which P < 0.05 and I² ≥ 50% were considered to indicate significant outcome heterogeneity. A fixed-effect model was used when non-significant heterogeneity was indicated, and a random-effect model was otherwise selected.

3. Results

3.1. Study characteristics

The initial search strategy resulted in the screening of 283 articles; of those, 108 duplicates were deleted using the EndNote version X7.2 software (Thomson Reuters, New York, New York, USA). A total of 123 reports were considered ineligible based on the information included in the titles and abstracts. Full texts were retrieved from 52 studies, and 41 records were finally excluded. In the end, a total of 5,980 patients with HF from 10 RCTs (11 articles, the EVEREST trial containing short- and long-term treatment) were included in this meta-analysis. The flowchart of the study selection is shown in Figure 1, and the basic characteristics of the included trials are shown in Table 1.^[5,13–22] One open-label and 9 double-blind RCTs were selected. The dosage of tolvaptan varied in the studies, ranging from 15 to 90 mg. The follow-up period ranged from 48 hours to 1 year. The assessment of the methodological quality of the included RCTs is illustrated in Figure 2, and all RCTs were of relatively high quality.

Table 1 - Basic characteristics of included clinical trials

First author (year)	Patient characteristics	Trial design	Intervention		Sample size	Follow-up
			Tolvaptan (mg/d)	Control
Gheorghiade et al (2003)[13]	CHF, volume overload	Ran, DB, PCtr	30, 45, 60	Placebo	254	25 d
Gheorghiade et al (2004)[14]	HFrEF, congestion	Mul, Ran, DB, PCtr	30, 60, 90	Placebo	319	60 d
Gheorghiade et al (2007)[5]	HFrEF, worsening congestive HF	Mul, Ran, DB, PCtr	30	Placebo	4,133	7 d
Konstam et al (2007)[15]	HFrEF, worsening congestive HF	Mul, Ran, DB, PCtr	30	Placebo	4,133	9.9 months
Udelson et al (2007)[16]	HFrEF	Mul, Ran, DB, PCtr	30	Placebo	240	1 year
Matsuzaki et al (2011)[17]	HF, volume overload	Mul, Ran, DB, PCtr	15, 30, 45	Placebo	117	7 d
Udelson et al (2011)[18]	HFrEF, congestion	Mul, Ran, DB, PCtr	TLV 30, TLV 30+FURO 80	Placebo	83	7 d
Matsuzaki et al (2011)[19]	HF, volume overload	Mul, Ran, DB, PCtr	15	FURO 80 mg/day Placebo	110	7 d
Matsue et al (2016)[20]	AHF, RI	Mul, Ran, OL, Ctr	15+Conv	Conv	217	48 h
Felker et al (2017)[21]	AHF, acute congestion	Ran, DB, PCtr	30	Placebo	257	48 h
Konstam et al (2017)[22]	AHF, volume overload	Ran, DB, PCtr	30	Placebo	250	3 d

AHF: Acute heart failure; CHF: Chronic heart failure; Conv: Conventional; Ctr: Controlled; DB: Double-blind; FURO: Furosemide; HF: Heart failure; HFrEF: Heart failure with reduced ejection fraction; Mul: Multicentre; OL: Open label; PCtr: Placebo-controlled; Ran: Randomized; RI: Renal insufficiency; TLV: Tolvaptan.

Figure 1:: Flowchart of the study selection for the meta-analysis.

Figure 2:: Assessment of the methodological quality of included randomized controlled trials (RCTs). The EVEREST trial had 2 components (Gheorghiade et al^{[ 5 ]}: short-term; Konstam et al^{[ 15 ]}: long-term treatment), and we evaluated the short-term one.

3.2. Evaluation of efficacy

3.2.1. Body weight and urine volume

Changes in body weight and urine volume are highly accessible objective indicators that reflect congestion in patients with HF; they are also observation indices commonly used to evaluate the effect of diuretic drugs. All RCTs included in this analysis used weight change and/or urine volume as primary or secondary outcomes. Seven of these RCTs assessed weight change on the first day of treatment,^{[5,13,14,17,18,21,22]} while the others assessed this parameter at different time points. All available data were statistically analyzed, and subgroup analyses were performed for the different doses and time points. The results showed that short-term loss of body weight (≤7 d) was more pronounced in the tolvaptan group versus the control group. Low-dose tolvaptan was effective in achieving weight loss; however, a higher dose and longer duration of treatment did not result in additional weight loss. Hence, the loss in weight did not appear to be a dose-dependent effect. All results regarding weight change are shown in Figure 3. Significant heterogeneity was observed among the studies (I² = 86.8%, P < 0.001); thus, the random-effects model was used for the analysis. Reduced urine output and volume overload in patients with HF can be relieved through the use of diuretics. Six trials reported increased urine volume following the administration of tolvaptan^{[13,14,17–20]}; of those, 5 RCTs provided the required data.^{[13,14,18–20]} The meta-analysis showed that all doses of tolvaptan resulted in a significant increase in urine volume, as shown in Figure 4 (overall weighted mean difference: 1,825.72; 95% CI: 1,438.38–2,213.07).

Figure 3:: Forest plot depicting the effects of tolvaptan on weight loss: (A) All doses of tolvaptan significantly reduced body weight at day 1 compared with control; however, the effect was not dose-dependent. (B) Prolonged treatment with tolvaptan did not sustain weight loss. The left side of the forest plot favors tolvaptan therapy. CI: Confidence interval; WMD: Weighted mean difference.

Figure 4:: Forest plot depicting the effects of tolvaptan on urine volume: all doses of tolvaptan clearly increased urine volume in a dose-independent manner compared with control. The right side of the forest plot favors tolvaptan therapy. CI: Confidence interval; WMD: Weighted mean difference.

3.2.2. Relief of dyspnea and improvement in edema

Dyspnea and edema are the main causes of hospitalization in patients with acute HF. Rapid and effective relief from congestion is an important indicator for evaluating the therapeutic effects against HF. A total of 5 trials reported the number of patients with relief from dyspnea on day 1.^{[4,5,14,20–22]} There was no significant heterogeneity observed among the RCTs (I² = 49.3%, P = 0.096). Therefore, we performed the analysis using the fixed-effects model. Treatment with tolvaptan appeared to be more effective in the relief of dyspnea versus control within a short period of time (RR = 1.12; 95% CI: 1.05–1.19), as shown in Figure 5. Six studies used edema as an endpoint^{[4,5,14,17,19–21]}; the results of the statistical analysis showed that edema did not improve significantly after treatment with tolvaptan (RR = 1.01; 95% CI: 0.98–1.05; I² = 49.1%; P = 0.080) [Figure 6].

Figure 5:: Forest plot depicting the effects of tolvaptan on dyspnea relief: tolvaptan was more effective in the relief of dyspnea compared with control. The right side of the forest plot favors tolvaptan therapy. CI: Confidence interval; RR: Risk ratio.

Figure 6:: Forest plot depicting the effects of tolvaptan on edema improvement: data revealed that there was no significant difference. The right side of the forest plot favors tolvaptan therapy. CI: Confidence interval; RR: Risk ratio.

3.3. Safety evaluation

3.3.1. All-cause mortality

Nine studies provided data on all-cause mortality; of those, 6 assessed short-term mortality (<30 d),^[14,17–21] 4 reported long-term mortality (≥30 d),^[14–16,22] and 1 assessed both.^[14] As shown in Figure 7,^[14–22] the forest plot showed that treatment with tolvaptan did not increase the mortality rate in the short and long term (short-term mortality: RR = 0.67; 95% CI: 0.35–1.26; long-term mortality: RR = 0.97; 95% CI: 0.88–1.07).

Figure 7:: Forest plot depicting the effects of tolvaptan on all-cause mortality: treatment with tolvaptan did not increase the mortality rate both in the short and long term. The left side of the forest plot favors tolvaptan therapy. CI: Confidence interval; RR: Risk ratio.

3.3.2. Worsening HF (WHF)

WHF, defined as worsening signs or symptoms of HF necessitating a treatment adjustment, is associated with a worse prognosis for patients with acute HF. The definitions and procedures used to describe WHF may vary between studies. Five studies included in this meta-analysis provided data on WHF, and 2 studies clearly defined WHF as death, hospitalization, or unscheduled visits.^{[14–16,21,22]} As shown in Figure 8,^{[14–16,21,22]} there was no significant difference in the incidence of WHF between the tolvaptan and control groups (RR = 0.99; 95% CI: 0.92–1.07; I² = 18.2%; P = 0.299).

Figure 8:: Forest plot depicting the effects of tolvaptan on worsening heart failure: the data did not demonstrate significant difference. The left side of the forest plot favors tolvaptan therapy. CI: Confidence interval; RR: Risk ratio.

3.3.3. Adverse events

Eight studies reported safety data, and the overall results showed some increase in the total incidence of adverse events after treatment with tolvaptan (RR = 1.17; 95% CI: 1.03–1.32 I² = 81.2%; P < 0.001; by the random-effects model) [Figure 9].^{[5,13,14,16–20]} In addition, further analysis revealed that patients in the tolvaptan group were more likely to report thirst (RR =6.09; 95% CI: 3.37–11.00 I² = 50.1%; P = 0.075; by the random-effects model) [Supplementary Figure 1, https://links.lww.com/CD9/A29]^{[5,13,14,16–18]} and dry mouth (RR = 6.36; 95% CI: 4.09–9.90; I² = 1.2%; P = 0.386; by fixed-effects model) [Supplementary Figure 2, https://links.lww.com/CD9/A30],^[5,13,14,16] as well as develop hypernatremia (RR = 12.76; 95% CI: 3.52–46.32; I² = 0; P = 0.556; by the fixed-effects model) [Supplementary Figure 3, https://links.lww.com/CD9/A31]^[5,20–22] compared with those in the control group. Tolvaptan add-on therapy did not significantly affect the incidence of atrial fibrillation, ventricular tachycardia, hyperkalemia, renal failure, hyponatremia, or hypokalemia.

Figure 9:: Forest plot depicting the effects of tolvaptan on adverse events: treatment with tolvaptan increased the total incidence of adverse events compared with control. The left side of the forest plot favors tolvaptan therapy. CI: Confidence interval; RR: Risk ratio.

4. Discussion

The systematic review and meta-analysis of 10 RCTs evaluated the dose-dependent efficacy and safety of tolvaptan in HF patients with congestive signs. The present study showed that all doses of tolvaptan (15–90 mg) combined with standard therapy resulted in significant weight loss and increased urine volume. However, this was not a dose-dependent effect. Furthermore, long-term treatment with tolvaptan did not sustain weight loss. Consistent with previous studies, tolvaptan significantly improved dyspnea. Surprisingly, there was no significant difference in improvement in edema between the tolvaptan and control groups; thus, further investigation may be required. Analysis of the safety indicators revealed that short- or long-term treatment with tolvaptan did not increase the mortality rate; however, it did not also significantly reduce the incidence of WHF. Additionally, the addition of tolvaptan was associated with increased thirst, dry mouth, and hypernatremia.

Thus far, diuretic therapy remains the mainstay of treatment for the faster resolution of symptoms and clinical improvement of HF.^[23] However, the use of conventional diuretics in patients with HF is associated with various adverse events. Based on the current situation, the concomitant use of an arginine vasopressin V2 receptor antagonist with a loop diuretic or thiazide may offer an effective approach to controlling fluid volume in patients with HF.^[17] Tolvaptan is a selective arginine vasopressin V2 receptor antagonist whose action on the distal nephron causes loss of electrolyte-free water.^[5] Owing to its unique pharmacological mechanism, tolvaptan may significantly relieve congestion without causing electrolyte imbalance. However, our meta-analysis, based on 10 RCTs, suggested that hypernatremia should be carefully monitored during the administration of tolvaptan. This may be due to its pharmacological properties; tolvaptan has been approved for the treatment of hyponatremia in Europe and the United States.^[24]

The available data suggested that tolvaptan did not affect the rate of all-cause mortality. Treatment with tolvaptan may reduce the dose of loop diuretics and normalize hyponatremia in patients with HF, which may help to improve outcomes.^[25–27]

Nevertheless, several limitations of this meta-analysis need to be considered. The number of RCTs included to evaluate the long-term effects of tolvaptan on the natural course of HF was limited, suggesting that the observed results should be interpreted with caution. Furthermore, the weight of the EVEREST study in the evaluation of certain indicators, such as mortality and improvement in edema, may have affected the accuracy of the results. In addition, we only evaluated the influence of dosage and treatment duration on the efficacy and safety of tolvaptan; other factors (eg, sex,^[28] levels of sodium in the serum, and temperature) should be evaluated. Therefore, additional robust clinical studies are warranted to validate the present findings.

5. Conclusion

This meta-analysis summarizes the dose-dependent efficacy and safety of tolvaptan in HF patients with congestive signs. The results show that tolvaptan is effective in improving congestive symptoms without increasing mortality rate. However, the increased dose and prolonged treatment do not significantly increase the therapeutic effect.

Funding

This work was supported by the State Key Program of National Natural Science Foundation of China (81530014); National Key R&D Plan of China (2017YFC1700502); and National Natural Science Foundation for Young Scientists of China (81700366).

Conflicts of interest

None.