Tolvaptan add‐on therapy in patients with acute heart failure: A systematic review and meta‐analysis

Abstract This study aimed to investigate the short‐term efficacy and safety of tolvaptan as an add‐on to traditional diuretics in patients with acute heart failure (AHF). The PubMed, EMBASE, Cochrane Library, and Web of Science databases were comprehensively searched for all randomized controlled trials (RCTs) that examined AHF patients treated with tolvaptan as a combination therapy with traditional diuretics published on or before December 2, 2019. Efficacy indicators such as improved dyspnea, reduced edema, and changes in urine output and body weight were evaluated. In‐hospital mortality and worsening renal function (WRF) were measured as safety indicators. Data from the published literature included in this study were independently extracted by two reviewers. The Cochrane risk of bias tool was used to evaluate the quality of the included RCTs. Twelve RCTs involving 5577 patients admitted for AHF were included. Compared with traditional diuretics alone, add‐on tolvaptan significantly relieved dyspnea, reduced weight, increased total urine volume and changes in urine volume from baseline, reduced edema, and increased serum sodium concentration in the short term without increasing the mortality. Most importantly, a low dose of tolvaptan (7.5‐15 mg/d) significantly reduced the incidence of WRF, while a high dose (30 mg/d) had the opposite effect. Short‐term add‐on tolvaptan in hospitalized AHF patients could significantly relieve shortness of breath, reduce body weight, improve edema, and increase urine output and serum sodium concentrations without increasing mortality. The protective effects of add‐on tolvaptan against WRF, however, were observed at low doses, but not at high doses.


| INTRODUC TI ON
Fluid retention is the main cause of the signs and symptoms patients with acute heart failure (AHF) experience, and diuretic therapy is currently the only pharmacological treatment that promotes fluid excretion. Approximately 80% of hospitalized patients with AHF require intravenous diuretics, demonstrating the cornerstone role of diuretics in this patient population. 1 Traditional diuretics include thiazides, potassium-sparing diuretics, and loop diuretics, the latter of which have become first-line agents for AHF through their inhibition of the reabsorption of chloride and sodium ions in the ascending loop of Henle. 2 However, about one third of patients with heart failure experience diuretic resistance, that is, the standard dose of diuretics does not achieve ideal urine output or effectively relieve congestion. 3 Although this may be ameliorated by increasing the dose or by adding thiazide diuretics, this could activate the renin-angiotensin-aldosterone system (RAAS) and increase the risk of electrolyte imbalance, renal dysfunction, and in-hospital mortality. [4][5][6] Tolvaptan is a nonpeptide, selective vasopressin V 2 receptor antagonist that exerts a diuretic effect by binding to and blocking the activity of vasopressin V 2 receptors, lowering the expression of aquaporin AQP2 on collecting duct intimal cells, and reducing water reabsorption without affecting the absorption and excretion of sodium and potassium ions. 7 Currently, the efficacy and safety of tolvaptan in the treatment of heart failure remains controversial.
Studies have shown that tolvaptan added to traditional diuretics can significantly increase urine volume without causing electrolyte disturbances, while others have demonstrated that add-on tolvaptan was not superior to conventional diuretics alone in improving the congestive symptoms of heart failure, and there was a risk of worsening renal function (WRF). 8-10 A meta-analysis of the shortterm (≤7 days) efficacy and safety of tolvaptan in AHF patients found that tolvaptan did not reduce the incidence of WRF or short-term all-cause mortality. 11 However, only a limited number of randomized controlled trials (RCTs) were included in that study, and the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST), a pivotal study with the largest sample size, was not included, possibly causing a considerable bias. Therefore, it is necessary to re-evaluate the short-term efficacy and safety of add-on tolvaptan in AHF patients.

| Literature search
The PubMed, EMBASE, Cochrane Library, and Web of Science data-  Table 1. There was one open-label, four single-blind, and seven double-blind RCTs. Four were from North America, and seven from Asia. The remaining EVEREST study was a global multicentre RCT. The Cochrane risk of bias tool was used to evaluate the quality of the included RCTs ( Figure 2). Although some studies had insufficient information about individual items, most items within the tool were considered low risk, indicating that the RCTs included in the meta-analysis were relatively high quality.

| Efficacy evaluation
Dyspnea was one of the main reasons for the admission of AHF patients to the hospital, and a total of six studies reported the number of patients who had relief of dyspnea on the second hospital day. 10,19,[21][22][23][24] No significant heterogeneity was observed between these studies (P = .26, I 2 = 23%; Figure 3), thus the analysis was performed using the fixed-effect model and add-on tolvaptan was shown to be more effective in relieving short-term dyspnea than traditional diuretics alone (RR = 1.12, 95% CI [1.05-1.18], P < .001). Reduced urine output and excessive fluid retention in patients with heart failure often meant they presented with pitting edema and nonnutritional weight gain, which could be improved with diuretics. Five studies reported reduced edema with diuretics after admission. 10,19,[22][23][24] Since no significant heterogeneity was observed among the studies, the fixed-effect model was used for the analysis (P = .46, I 2 = 0%). According to these studies, tolvaptan add-on therapy was more effective at reducing edema than conventional diuretics alone (RR = 1.08, 95% CI [1.02-1.15], P = .009; Figure 4). Body weight changes over 24 hours were discussed in seven clinical trials from six studies (EVEREST was F I G U R E 1 Flow diagram of the study selection process for the meta-analysis divided into Trial A and Trial B), 10,18,19,21,23,24 and the fixed-effect model was used since no significant heterogeneity existed (P = .20, I 2 = 30%). Short-term loss of body weight was more pronounced in the add-on tolvaptan group than in the conventional diuretics group (MD = −0.82, 95% CI [−0.94 to 0.71], P < .001; Figure 5). As a result of the significant heterogeneity found among the five studies that discussed urine volume, however, a subgroup analysis was conducted (P < .001, I 2 = 91%; Figure 6). [18][19][20]22,24 There was no In these studies, add-on tolvaptan was found to be superior to traditional diuretics alone at increasing urine output ( Figure 6). In addition, short-term serum sodium concentration was higher in the add-on tolvaptan group than the traditional diuretics-alone group (MD = 3.57, 95% CI [3.34-3.79], P < .001; Figure 7). 10,18,20,21,23,24

| D ISCUSS I ON
Our meta-analysis demonstrated that add-on tolvaptan could significantly alleviate the signs and symptoms of volume overload and increase the serum sodium concentration in the short term without increasing mortality. Subgroup analysis suggested that low-dose tolvaptan add-on therapy could significantly reduce the incidence of WRF, whereas the opposite was shown in the highdose group.
Most AHF patients are admitted to the hospital with dyspnea, edema, and weight gain caused by volume overload. Therefore, using diuretics to rapidly decrease volume load is essential for heart failure treatment. Consistent with previous studies, 10,25 this meta-analysis found that add-on tolvaptan could significantly reduce volume overload as evidenced by relieved dyspnea, reduced weight, and increased total urine volume and changes in urine volume from baseline.
Electrolyte disturbances such as hyponatremia (serum sodium concentration <135 mmol/L) induced by diuretics are common among patients with heart failure. 26 The rapid correction of hyponatremia could significantly shorten hospital stays and reduce cognitive impairment caused by neurological disorders. 27 Isotonic F I G U R E 8 Forest plot depicting the effects of tolvaptan on mortality: tolvaptan did not increase mortality during hospitalization more than traditional diuretics alone F I G U R E 9 Forest plot depicting the effects of tolvaptan on worsening renal function (WRF): The incidence of WRF was associated with the dose of tolvaptan; a low dose of tolvaptan could significantly reduce the incidence of WRF, while a high dose did the opposite saline can easily correct hypovolemic hyponatremia but not nonhypovolemic hyponatremia. 28 Improvement in hyponatremia has been seen as a benefit of tolvaptan over traditional diuretics. 29,30 Although both our study and the EVEREST study reported that add-on tolvaptan could increase the incidence of hypernatremia, excessive levels of sodium did not require additional intervention. 23 Therefore, the short-term benefit of tolvaptan as an add-on to traditional diuretics among patients with AHF was definite, although an increased sodium concentration within an acceptable range might be encountered.
The EVEREST long-term results suggested that add-on tolvaptan did not increase all-cause mortality. 10,23,24 Similarly, our meta-analysis demonstrated that adding tolvaptan to traditional diuretics did not increase in-hospital mortality. Patients with AHF often have decreased renal perfusion due to circulatory hypovolemia. 14 Traditional diuretics can rapidly improve congestion, but can result in reduced blood volume and progressive renal dysfunction, 31 which could further activate the RAAS and sympathetic nervous system (SNS), two important pathophysiological mechanisms of ventricular remodeling and impaired renal function. 32,33 For instance, loop diuretics can activate RAAS by reducing sodium concentration near the macula densa. 34 Thus, traditional diuretics are thought to lead to WRF. In contrast to traditional diuretics such as loop diuretics, tolvaptan blocked the reabsorption of urea, reduced serum urea nitrogen, 23 and possessed a weaker ability to activate SNS and RAAS. 17 Therefore, there are high hopes for tolvaptan, but whether tolvaptan can reduce renal damage has been debated. The Acute and Chronic Therapeutic Impact of a Vasopressin Antagonist in Chronic Heart Failure study found that tolvaptan tended to protect renal function in patients with AHF, but the EVEREST study, with the largest sample size, demonstrated a slight increase in serum creatinine. 23,24 Interestingly, even with more clinical trials published, this controversy has not been resolved. In the TACTICS study, for example, add-on tolvaptan increased WRF in AHF patients, 10 whereas the K-STAR study showed a significant increase in urine volume and improvement in renal function. 22 In this meta-analysis, low-dose tolvaptan add-on therapy was correlated with a lower incidence of WRF than traditional diuretics alone, which may be due to its protective role in renal function as described above. In addition, some researchers believe that improved WRF might be attributed to the lower loop diuretic dose as a result of add-on tolvaptan, 35 since a positive correlation between WRF and loop diuretic dose has previously been observed. 36 Unfortunately, we could not analyze this further since no accurate loop diuretic doses were provided in any of the included studies. However, the incidence of WRF was higher in AHF patients receiving high-dose tolvaptan add-on therapy than in patients receiving traditional diuretics, although the reason for this was unclear. Additionally, patients with heart failure were sensitive to blood sodium concentrations, with even normal levels stimulating the release of arginine vasopressin (AVP). A single-centre RCT found that a single dose of 15-120 mg of tolvaptan showed a dose-dependent blood sodium concentration, 37 and high doses of tolvaptan might profoundly increase blood sodium concentration, leading to release and subsequent binding of AVP to the V 1 a receptor to cause vasoconstriction and renal hypoperfusion. Conivaptan, a dual V 1 a and V2 receptor antagonist, was able to prevent renal damage in rats that ingested