Acute heart failure (AHF) is a commonly encountered condition that often leads to hospitalization. The wet-warm phenotype, which is characterized by congestive symptoms, is predominant in most AHF patients. Managing congestion through decongestive therapy is a primary focus in patient care (1). Historically, international guidelines have positioned furosemide, a loop diuretic, as the first-line medication for AHF. Despite its recognized benefits, furosemide comes with potential side effects, particularly the activation of the renin–angiotensin–aldosterone (RAA) system, which can have adverse effects on kidney function. This is particularly concerning in patients with heart failure (HF) with ejection fraction, where the RAA system may become overstimulated, thereby posing a potential risk in the presence of comorbid renal function disorders (2). Tolvaptan has been extensively studied for its decongestive effects without worsening renal function (WRF) (3), which formed the basis for conducting this study.

A current meta-analysis conducted by Kansara et al. (4) evaluated the short- and long-term effectiveness of tolvaptan in patients with AHF with standard HF care. The results showed that HF patients in the tolvaptan group experienced superior dyspnea relief, as shown by the Likert score, and a significant mean reduction in weight within the first 48 h (short term). However, it is crucial to acknowledge the potential impact of varying tolvaptan dosages used across the included studies, which could have influenced the results. To address this concern, we conducted an updated systematic review and a meta-analysis of randomized double-blinded tests, comparing tolvaptan add-on therapy with conventional diuretic therapy in hospitalized AHF patients. Our approach used a comprehensive network meta-analysis (NMA) to evaluate the dosage effect of tolvaptan. This meta-analysis aimed to provide insights into the efficacy and safety of tolvaptan add-on therapy in AHF patients, addressing the key questions related to its use in clinical practice.

The meta-analysis showed that tolvaptan add-on therapy significantly alleviated dyspnea by reducing the volume overload. The tolvaptan group showed a substantial reduction in edema and short-term weight within 48 h, but this weight shift was temporary, without significant changes observed within 7 days. Additionally, the tolvaptan group showed an increase in serum sodium during hospitalization in non-Asian studies. Meanwhile, Asian studies suggested that tolvaptan add-on therapy could significantly reduce the incidence of WRF. The NMA of the tolvaptan dosage effect subgroup showed that the intermediate dosage of 15 mg might be considered the optimal dosage for the majority of the outcomes.

In AHF patients presenting with predominant symptoms of fluid overload and congestion, intravenous loop diuretics served as the primary therapy to enhance renal excretion of sodium and fluids, while also acting as a vasodilator to provide rapid relief of congestive symptoms (24). Nevertheless, the acknowledged drawbacks in both effectiveness and safety, such as electrolyte disturbances and renal impairment, compel us to escalate the dosage of diuretics to prevent further neurohormonal activation and overcome resistance to their diuretic effects. It is widely recognized that diuretic effects steadily diminish over successive days of loop diuretic treatment. Hence, it is advisable to promptly adjust diuretic therapies, such as combination therapy, to promote decongestion (25). Tolvaptan, an oral diuretic, competes with vasopressin at the distal nephron V2 receptor. It prevents aquaporin channel activation by blocking the V2 receptor–arginine vasopressin connection. This prevents water from being reabsorbed, resulting in the excretion of free water (26). In line with the observation of Kansara et al., the meta-analysis concluded that adding tolvaptan could greatly reduce volume excess, as evidenced by relieved dyspnea, weight reduction within 48 h, and reduced edema. This suggested that tolvaptan aided in achieving the therapy objectives of HF, such as decreasing congestion, after-load, and neurohormonal activation to enhance hemodynamics and symptoms, potentially reducing in-hospital events, rehospitalizations, and mortality while bypassing therapy toxicities (27).

A drawback of conventional diuretics was the potential development of resistance and adverse effects, including electrolyte abnormalities. The results among non-Asian studies supported by the EVEREST and a previous meta-analysis showed that tolvaptan add-on therapy greatly increased sodium levels compared to conventional therapy. Tolvaptan, a selective non-peptide oral agent rival of the vasopressin receptor, acted on the distal part of the nephron by inhibiting the V2 receptor, suppressing the action of the antidiuretic hormone for reabsorption of free water, thereby resulting in the excretion of diluted urine, and facilitating hypotonic diuresis without adversely affecting the elimination of electrolytes. Furthermore, the mechanism prevented the activation of the aquaporin system, reducing the ability of the kidneys to reabsorb water and leading to an increase in sodium levels in the blood and excretion of water in urine (3, 28).

WRF, a prevalent comorbidity found in AHF patients (29), was described as an increase in creatinine level of ≥0.3 mg/dl in the first 5 days compared to the baseline at hospital admission (30). Traditionally, WRF represented the gold standard for assessing acute kidney failure in patients with AHF (31). This analysis showed that tolvaptan add-on therapy correlated with a more inferior incidence of WRF compared to conventional therapy, as evidenced by a significant disparity in creatinine change between the two levels in Asian studies. Loop diuretics for decongestion may cause WRF by rapidly decreasing blood volume. Stimulation of the RAA and sympathetic nerve systems reduces renal perfusion and glomerular filtration pressure, causing WRF (32). Therefore, the decreased occurrence of WRF can be related to the reduced dosage of loop diuretics, which is assisted by the aquaresis caused by tolvaptan.

Nowadays, a range of therapeutic drugs is employed as standard therapy for HF. The effects of tolvaptan on mortality and morbidity in patients with HF have not been thoroughly explained, unlike ACE-I and beta-blockers, which have been established as medications with a Class I recommendation and A level of evidence (33). This study showed that add-on tolvaptan did not reduce rehospitalization and mortality of patients with HF during therapy, consistent with a previous meta-analysis. While tolvaptan might not reduce long-term mortality, it offers an opportunity for the administration of diuretics at lower dosages, thereby mitigating electrolyte disturbances and enhancing patient safety (34).

A different therapy for AHF utilizes a simultaneous nephron blockade with thiazide diuretics and mineralocorticoid receptor antagonists to allow decongestant use. The addition of these two categories of medications is intended to augment the impact of loop diuretics. Nevertheless, a large-scale clinical trial has systematically assessed the efficacy of combining diuretics. However, alternative combination therapy with diuretics, such as nesiritide or renal dosage dopamine, fails to enhance decongestants or renal function in AHF patients (35). On the other hand, there is a scarcity of data on the effectiveness of tolvaptan when used independently. The first study that examined the possibility of using tolvaptan as a substitute for furosemide was RCT by Udelson et al. (16), which revealed that tolvaptan, as monotherapy or in combination with loop diuretics, increased the urine volume and reduced the body weight of HF patients without changes in the blood electrolyte values. Several guidelines have endorsed the utilization of tolvaptan in patients with AHF (35–38). The 2021 European Society of Cardiology (ESC) Guidelines explicitly state that the therapy of dilutional hyponatremia caused by HF should revolve around controlling the water intake using tolvaptan, a vasopressin antagonist (35). Other Asian country guidelines recommend tolvaptan as a supplementary therapy for AHF patients who continue to experience congestion without distinguishing sodium levels (36–38).

Several clinical outcomes (changes in BW within 48 h and sodium and creatinine levels) suggested that location (non-Asia and Asia) influenced heterogenicity. This might be associated with current (epi)genome-wide connection analyses and HF. Furthermore, it has been identified that genes, metabolites, and pathways are associated with cardiovascular disease traits (39). Scheen et al. (40) reported that pharmacogenomics showed potential in individualized medicine treatment based on genetic and genomic data, thereby contributing to improvements in precision drugs and personalized drug therapy.

To further explore the relationship between tolvaptan dosage and various indicators, the NMA was conducted to compare low, intermediate, and high dosages. The choice of dosage was based on previous studies and consensus. The NMA resulted in diverse results, suggesting that high-dosage tolvaptan tended to have the highest likelihood of effectiveness in relieving dyspnea within 48 h and reducing BW within 48 h and 7 days. Meanwhile, the intermediate dosage indicated the highest probability of effectiveness in relieving dyspnea within 24 h, reducing edema, increasing sodium levels, and lowering the incidence of WRF. Low dosage only showed the best efficacy in mortality outcomes. The NMA findings were consistent with prior meta-analyses and guidelines, indicating that the addition of tolvaptan at intermediate dosages had a protective effect against WRF, but not at high dosages. The recommended initial dose of tolvaptan for general AHF patients is 7.5 mg–15 mg (36, 37, 41). Furthermore, multiple prior RCTs indicate that the occurrence rates of dry mouth, dehydration, and developing hypernatremia were higher in the 30 and 45 mg/day dose groups compared to the 15 mg/day dose group (13, 18). Lower starting dosages of tolvaptan are advised, especially for elderly individuals who are more prone to developing hypernatremia (42). Thus, for AHF add-on therapy, an intermediate dosage of tolvaptan, which is 15 mg/day, may be optimal.

The NMA had several strengths distinct from other meta-analyses. First, a comprehensive search across multiple databases in all languages was conducted, minimizing the chance of overlooking significant studies. Second, subgroup analysis was adopted by grouping studies based on location and year, addressing heterogeneity in various analyses. Third, the NMA was conducted to determine the optimal dosage. The analysis independently assessed the efficacy of each dosage instead of combining multiple dosages into a single therapy group. Finally, sensitivity analysis was performed using the leave-one-out method, facilitating the identification of influential studies and assessing the robustness, particularly in outcomes showing heterogeneity.

This study has several limitations. First, the lack of details regarding conventional therapy, variations in diuretic dosages, and follow-up durations could potentially impact the results. Second, while analyzing the weight change within 7 days and rehospitalization, it was discovered that the investigations had a very high heterogenicity, and subgroup examination with further parameters was precluded due to insufficient data. Third, our study did not provide patient-centered outcomes, such as improvements in the quality of life or functional status. In addition, there are no long-term outcomes that compare tolvaptan's efficacy across different patient demographics in a specific area. These outcomes may provide a more thorough perspective on tolvaptan's benefits and a demographic overview of the research findings. Unfortunately, there is currently no original or primary study that incorporates these outcomes. Further research can be conducted to explore patient-centered outcomes and investigate specific areas, such as performing original research on each continent. Finally, the disparity in the number of studies that used intermediate- and low-dosage tolvaptan compared to high dosage could potentially influence the NMA results.

In conclusion, the tolvaptan add-on therapy for AHF patients proved beneficial for the short-term relief of dyspnea, initial weight reduction, edema reduction, increased sodium levels, and a reduced incidence of WRF; however, it did not lead to a significant benefit in lowering rehospitalization rates and mortality. The results suggested that an intermediate dosage of tolvaptan (15 mg/day) could be considered the optimal dosage for the majority of the outcomes.