Conventional Diuretics Research Articles

Copeptin and Body Fluid Responses to the Combined Use of an SGLT2 Inhibitor and Conventional Diuretics in Patients with CKD: The DAPA-BODY Trial

Copeptin and Body Fluid Responses to the Combined Use of an SGLT2 Inhibitor and Conventional Diuretics in Patients with CKD: The DAPA-BODY Trial

The Effect of Tolvaptan on Metabolism and Electrolyte Homeostasis in Patients with Heart Failure: A Systematic Review and Meta-Analysis.

This study aimed to investigate the effect of tolvaptan on metabolism and electrolyte homeostasis in patients with heart failure (HF). Literature databases, such as PubMed, EMBASE, the Cochrane Library, China National Knowledge Infrastructure, VIP, and WanFang Data, were systematically searched for relevant trials from inception to November 4, 2023. We used the fixed effect model to combine the effect sizes and used I2 to test heterogeneity. Funnel plots were plotted to assess publication bias. 16 studies were eligible for further analysis. No significant differences were identified in the incidence of hyperuricemia between the tolvaptan group and the placebo group (odds ratio (OR) = 1.23, 95% confidence interval (CI) = 0.97 to 1.55, p = 0.09). Tolvaptan decreased the levels of blood uric acid compared to traditional diuretics (mean difference (MD) = -82.8, 95% CI = -96.48 to -69.13, p < 0.00001). There was no significant difference in hypernatremia (OR = 1.62, 95% CI = 0.66 to 3.96, p = 0.29) and hyperkalemia (OR = 1.17, 95% CI = 0.93 to 1.48, p = 0.18) between the tolvaptan and control groups. Tolvaptan reduced the level of blood uric acid compared to conventional diuretics, and could be used as a substitute for traditional diuretics for HF patients with a high risk of gout.

Short-term impact of kampo goreisan in patients with congestive heart failure refractory to tolvaptan-incorporated medical therapy.

We often encounter patients with congestive heart failure refractory to conventional diuretics therapy. Kampo goreisan (Tsumura &Co. Tokyo, Japan) is receiving great concern in mediating body water balance, particularly for such a cohort. However, its detailed biological mechanism remains uncertain. Patients who received goreisan to treat congestive heart failure refractory to tolvaptan-incorporated medical therapy were prospectively included and observed for one week during the therapeutic period. The change in urine biomarkers during the first 24h was assessed as a primary concern. Baseline factors associated with an increase in urine volume during the first 24h were investigated as a secondary concern. A total of 18 patients were included. Median age was 81 (77, 86) and 12 (67%) were men. During the first 24h after the initiation of goreisan, urine cyclic AMP tended to decrease, urine aquaporin-2 decreased significantly, urine osmolality decreased significantly, and urine volume tended to increase. Baseline higher common logarithm of plasma B-type natriuretic peptide was associated with any increases in urine volume during the first 24h with an odds ratio of 73.2 (95% confidence interval 1.04-5149, p = 0.048). Baseline plasma B-type natriuretic peptide level had a positive correlation with a change in urine volume between baseline and day 1 (r = 0.533, p = 0.026). Goreisan may increase urine volume even in patients with congestive heart failure refractory to tolvaptan-incorporated medical therapy by modulating aquaporin-2 systems in the collecting duct, particularly in individuals with advanced heart failure accompanying significant congestion. Goreisan may have a regulatory effect on body fluid, rather than just forcing aquaresis.

Sodium-Glucose Cotransporter 2 Inhibitor Combined with Conventional Diuretics Ameliorate Body Fluid Retention without Excessive Plasma Volume Reduction.

We previously reported that sodium-glucose cotransporter 2 (SGLT2) inhibitors exert sustained fluid homeostatic actions through compensatory increases in osmotic diuresis-induced vasopressin secretion and fluid intake. However, SGLT2 inhibitors alone do not produce durable amelioration of fluid retention. In this study, we examined the comparative effects of the SGLT2 inhibitor dapagliflozin (SGLT2i group, n = 53) and the combined use of dapagliflozin and conventional diuretics, including loop diuretics and/or thiazides (SGLT2i + diuretic group, n = 23), on serum copeptin, a stable, sensitive, and simple surrogate marker of vasopressin release and body fluid status. After six months of treatment, the change in copeptin was significantly lower in the SGLT2i + diuretic group than in the SGLT2i group (-1.4 ± 31.5% vs. 31.5 ± 56.3%, p = 0.0153). The change in the estimated plasma volume calculated using the Strauss formula was not significantly different between the two groups. Contrastingly, changes in interstitial fluid, extracellular water, intracellular water, and total body water were significantly lower in the SGLT2i + diuretic group than in the SGLT2i group. Changes in renin, aldosterone, and absolute epinephrine levels were not significantly different between the two groups. In conclusion, the combined use of the SGLT2 inhibitor dapagliflozin and conventional diuretics inhibited the increase in copeptin levels and remarkably ameliorated fluid retention without excessively reducing plasma volume and activating the renin-angiotensin-aldosterone and sympathetic nervous systems.

The role of tolvaptan add-on therapy in patients with acute heart failure: a systematic review and network meta-analysis.

Several conflicting reviews have concluded that the use of loop diuretics is associated with poorer clinical and safety outcomes. Therefore, this study aimed to investigate the efficacy and safety of tolvaptan as an adjunct to conventional diuretic therapy in patients with acute heart failure (AHF). A comprehensive search was conducted on PubMed, Embase, ProQuest, EBSCO, and Cochrane Library until 24 May 2023 to identify randomized controlled trials that compared the effects of tolvaptan with conventional therapy and placebo in patients with AHF. The quality assessment of the included trials was conducted using the Cochrane risk of bias. A network meta-analysis (NMA) was conducted to examine the dosage effect of tolvaptan. A total of 17 studies with 18 reports, involving 10,039 patients, were selected. The tolvaptan add-on therapy significantly alleviated dyspnea [24 h: RR 1.16 (1.04, 1.29), 48 h: RR 1.18 (1.04, 1.33)], reduced body weight within 48 h [Asian group, MD -0.93 (-1.48, -0.38); non-Asian group, MD -2.76 (-2.88, -2.65)], reduced edema [RR 1.08 (1.02, 1.15)], increased serum sodium [non-Asian group, MD 3.40 (3.02, 3.78)], and resulted in a change in serum creatinine [MD -0.10 (-0.18, -0.01)]. No significant differences were observed in mortality and rehospitalization. The NMA suggested that an intermediate dosage (15 mg/day) might offer the best efficacy in reducing dyspnea within 24 h, reducing edema, increasing serum sodium, and lowering the incidence of worsening renal function (WRF). In conclusion, the meta-analysis showed that tolvaptan contributed to the short-term alleviation of congestive symptoms, elevated sodium levels, and a lower incidence of WRF. However, no significant benefits were observed in long-term symptoms, rehospitalization rates, and mortality. An intermediate dosage of tolvaptan might be considered the optimal choice for various clinical outcomes. https://www.crd.york.ac.uk/, PROSPERO (CRD42023420288).

Diagnosis and Management of Ureteropelvic Obstruction in Kidney Transplant Recipients and Outcomes of Foley Y-V Pyeloplasty.

To evaluate the etiology and diagnostic tools for ureteropelvic obstruction in kidney transplant recipients, we investigated the short-term and long-term outcomes of Foley Y-V pyeloplasty. We retrospectively reviewed 10 patients who underwent kidney transplant followed by additional interventions to treat obstructive ureteral pathologies between 2016 and 2020. We enrolled 4 patients who had received intervention to treat ureteropelvic obstruction. For these 4 patients, serum creatinine and estimated glomerular filtration rate levels were recorded at baseline, during the symptomatic period, and long-term. In this single center study, we investigated diagnostic tools and management strategies for ureteropelvic obstruction and assessed performance of Foley Y-V nondismembered pyeloplasty in kidney transplant recipients. Among 4 patients, graft function (assessed by serum creatinine and estimated glomerular filtration rate) worsened significantly (P = .03) in the symptomatic period of ureteropelvic obstruction in all patients; however, graft function levels improved rapidly to levels similar to baseline (P = .07) after Y-V pyeloplasty. In addition, no statistically significant difference was detected between baseline and longterm graft functions afterY-V pyeloplasty in follow-up (P = .28). Diagnosis and management of ureteropelvic obstruction in kidney transplant recipients are challenging due to rarity and lack of an ideal management algorithm.There is no specific diagnostic tool to discriminate this pathology from other ureteral pathologies; therefore, a regimen of conventional imaging modalities and diuretic renogram combined with endoscopic evaluation is more reliable. Moreover, nondismembered Foley Y-V pyeloplasty is effective and safe for graft function in the short-term and long-term.

Preliminary Report of Intravenous Tolvaptan Sodium Phosphate (Samtas®) Treatment in Decompensated Heart Failure

Background: Tolvaptan sodium phosphate (Samtas®; Otsuka Pharmaceutical, Tokyo, Japan) is a novel intravenous aquaretic diuretic aimed at individuals experiencing advanced congestion refractory to conventional diuretics and having difficulty with oral intake. Despite its potential, the true efficacy and practicality of this compound within real-world clinical settings remain obscure. Methods: A retrospective analysis of clinical data was conducted, examining trends among consecutive in-hospital patients diagnosed with congestive heart failure who underwent treatment with tolvaptan sodium phosphate at a prominent academic medical center between June 2022 and June 2023. Results: Twenty-one patients were enrolled (median age: 75 years, serum N-terminal pro B-type natriuretic peptide: 8941 pg/mL). Among them, 14 patients (67%) received non-invasive/invasive positive-pressure ventilation, and 17 patients (81%) concurrently received intravenous inotropes. Subsequent to the initiation of tolvaptan sodium phosphate treatment, a significant increase in urine volume was observed on the following day (p = 0.036). Urine osmolality decreased from 356 (318, 443) at baseline to 247 (176, 333) mOsm/kg after 4 h (p = 0.002). No occurrences of hypernatremia were recorded during the therapeutic period. Notably, two patients transitioned from tolvaptan sodium phosphate treatment to continuous hemodiafiltration due to insufficient efficacy. Conclusions: In routine clinical practice, intravenous tolvaptan sodium phosphate exhibits potential efficacy and practicability in the majority of congestive heart failure patients exhibiting refractory congestion, unstable hemodynamics, and challenges with oral intake.

Role of Conventional and Novel Classes of Diuretics in Various Diseases

Abstract: Diuretics are advised as the initial course of action for hypertension because they are successful in lowering hypervolemia and resolving electrolyte abnormalities. The most popular diuretics are included with their main characteristics in this summary. The primary line of treatment for common cardiovascular and non-cardiovascular diseases is diuretics. Patients with hypertension, oedema, heart failure, as well as a variety of renal disorders are frequently treated with conventional diuretics. The usage of the various types of diuretics that are now licensed for therapeutic use generally has a favourable risk/benefit ratio. Nevertheless, they are not without drawbacks. Pharmaceutical scientists have thus been working to develop new drugs with an enhanced pharmacological profile. SGLT2 inhibitors (sodium-glucose-linked cotransporter 2 inhibitors) have altered how hypoglycaemic medications are thought to affect heart failure. Despite the presence or absence of diabetes, the sodiumglucose-linked cotransporter subtype 2-inhibitor class, which was first developed as a therapy for T2DM (Type 2 Diabetes mellitus), has shown considerable promise in lowering cardiovascular risk, particularly in relation to heart failure (HF) outcomes. The immediate and substantial improvements observed in clinical studies do not appear to be attributable to the drug's fundamental mechanism, which involves inducing glycosuria and diuresis by blocking receptors in the renal nephron. Among patients with chronic heart failure and cirrhosis, hyponatremia is a risk factor for death.

Examination about clinical efficacy and safety of active use of tolvaptan for decompensated congestive heart failure cases

Abstract Background In Japan, Tolvaptan is approved for use as a potent oral diuretic, mainly for severe congestive heart failure. However, over time since the launch of Tolvaptan, there have been many reports of its usefulness when used earlier in milder cases. Based on this background, in August 2015, our facility introduced a clinical pathway (PATH) for acute care for cases with decompensated congestive heart failure (DCHF), in which immediate use of tolvaptan with conventional diuretics ware stipulated to keep patient’s activity by early diuresis. Purpose In this study, we verified the clinical usefulness and safety of PATH for DCHF that prescribes the active use of tolvaptan. Methods From April 2014 to July 2022, 846 DCHF cases admitted to our hospital for the first time were included. They were divided into two groups, N-group(154 cases before introduction of PATH) and P-group(692 cases introduced PATH and prescribed Tolvaptan as stipulated). We investigated their implementation status of each medical treatment in acute phase and hospitalization period(HP), and compared the difference between the two groups. And in P-group, we investigated the occurrence of adverse event(AE), deterioration of renal function (R-event) and hypernatremia (N-event) that required unplanned discontinuation of tolvaptan use, and we investigated the clinical features about the cases with each adverse event. Results There was almost no difference in the patient background before admission or the patient's condition at admission. In P-group, the performance rate of each acute medical care for DCHF was lower and their performance period was shorter compared in N-group. The performance rate of cardiac rehabilitation was higher and its starting time was earlier in P-group. (Figure 1) As a result, HP was significantly shorter in P-group. AE incidence in P-group were 2.2%(R-event) and 4.8%(N-event). Mean age tended to be higher and cognitive function was lower in both AE cases. Cases with R-event were more likely to have pre-existing renal insufficiency. In N-event cases, their activity level before admission was lower and blood sodium level at admission was higher. Most of the N-event(85%) occurred within 7 days.(Figure 2) Conclusions With the introduction of unique clinical pathway that stipulates the active use of tolvaptan, the acute care of cases with decompensated congestive heart failure had been greatly simplified and streamlined, and the hospitalization period had been shortened. Although it is unlikely that all the results were due to the medicinal effects of Tolvaptan, it was thought that the realization of early mobilization due to its strong diuretic effect was linked to these results. A certain rate of feared adverse events, especially hypernatremia, was found to occur, but the rate appeared to be acceptable. However, in elderly and cognitively impaired cases, special caution seemed to be required for several days after the start of tolvaptan use.Figure 1Figure 2

Efficacy and safety of early ultrafiltration in patients with acute decompensated heart failure: a meta-analysis.

The objective of this study is to investigate the efficacy and safety of early ultrafiltration in patients with acute decompensated heart failure. A systematic search was conducted on PubMed, Cochrane Library, and EMbase databases from inception to April 2023 to identify randomized controlled trials that compared the efficacy and safety of early ultrafiltration and conventional diuretics in patients with acute decompensated heart failure. Two investigators independently screened all eligible studies and extracted relevant data. The primary outcomes of interest were changes in body weight and creatinine levels, as well as the rate of readmission and mortality within 30 days. Meta-analysis was conducted using RevMan 5.4 software. This meta-analysis included eight studies and found that early ultrafiltration was effective in reducing body weight in patients with acute decompensated heart failure (RR = 1.45, 95% CI: 0.54-2.35, P = 0.002), but it also increased serum creatinine (RR = 0.1, 95% CI: 0.03-0.17, P = 0.003). However, it did not reduce the 30-day rehospitalization rate or mortality rate (30-day rehospitalization rate: RR = 0.84, 95% CI: 0.62-1.14, P = 0.28; Mortality: RR = 0.90, 95% CI: 0.57-1.44, P = 0.67). Although early ultrafiltration is more effective in reducing body weight in patients with acute decompensated heart failure, it is associated with an increase in serum creatinine levels and does not reduce the rate of readmission or mortality within 30 days. identifier: CRD42023416152.

Safety and Efficacy of Empagliflozin and Diuretic Use in Patients with Heart Failure and Preserved Ejection Fraction

The diuretic effect of sodium-glucose cotransporter 2 inhibitors may result in interaction with background diuretic therapy in patients with heart failure and preserved ejection fraction (HFpEF). To assess the safety and efficacy of empagliflozin in combination with background diuretic therapy and the association of empagliflozin with the need for conventional diuretics. This was a post hoc analysis of the Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Preserved Ejection Fraction (EMPEROR-Preserved). EMPEROR-Preserved was a phase 3, randomized, placebo-controlled, double-blind clinical trial conducted from March 2017 to April 2021. Patients with class II to IV heart failure and left ventricular ejection fraction greater than 40% were included. Of 5988 patients enrolled, 5815 (97.1%) had baseline data on diuretic use and were included in this analysis, which was conducted from November 2021 to August 2022. Participants in EMPEROR-Preserved were randomized to empagliflozin or placebo. In this analysis, participants were divided into 4 subgroups: no diuretics and furosemide-equivalent diuretic dose of less than 40 mg, 40 mg, and greater than 40 mg at baseline. The main outcomes of interest were first hospitalization for heart failure (HHF) or cardiovascular death (CV death) and its components. Association of empagliflozin vs placebo with outcomes by baseline diuretic status (no diuretic vs any dose) and dose (no diuretic, <40 mg, 40 mg, and > 40mg) was assessed. Association of empagliflozin use with changes in diuretic therapy was also studied. Among 5815 patients (mean [SD] age, 71.9 [9.4] years; 2594 [44.6%] female) with known baseline diuretic use, 1179 (20.3%) were not taking diuretics, 1725 (29.7%) were taking less than 40 mg, 1772 (30.5%) were taking 40 mg, and 1139 (19.6%) were taking greater than 40 mg. In the placebo arm, patients with higher diuretic doses had worse outcomes. Empagliflozin decreased the risk of HHF or CV death, regardless of background diuretic status (hazard ratio [HR], 0.81; 95% CI, 0.70-0.93] for the diuretic group vs HR, 0.72; 95% CI, 0.48-1.06 for the nondiuretic group; P for interaction = .58). Similarly, diuretic status was not associated with changes in improvements in first HHF, total HHF, rate of decline in estimated glomerular filtration rate, and Kansas City Cardiomyopathy Questionnaire 23 clinical summary score with empagliflozin. Findings were consistent when patients were categorized by diuretic dose. Empagliflozin was associated with a decreased likelihood of diuretic dose escalation (HR, 0.74; 95% CI, 0.65-0.84) and an increased likelihood of de-escalation (HR, 1.15; 95% CI, 1.02-1.30). Empagliflozin was associated with an increased risk of volume depletion in patients taking diuretics (HR, 1.34; 95% CI, 1.13-1.59). In this study, treatment with empagliflozin was similar regardless of diuretic use or dose. Empagliflozin use was associated with decreased conventional diuretic dosing. ClinicalTrials.gov Identifier: NCT03057951.

First reports of clinical effects of transjugular intrahepatic portosystemic shunt in four patients with cirrhotic ascites refractory to tolvaptan

ObjectiveAscites in patients with decompensated cirrhosis can lead to abdominal distention and decrease quality of life. Tolvaptan, a vasopressin V2 receptor antagonist, is an effective agent in the treatment of...

Impact of urine cyclic AMP relative to plasma arginine vasopressin on response to tolvaptan in patients with chronic kidney disease and heart failure.

The clinical utility of tolvaptan in chronic kidney disease (CKD) patients with heart failure remains uncertain. The level of urine cyclic adenosine monophosphate (AMP) relative to plasma arginine vasopressin (AVP) indicates the residual function of the collecting ducts in response to AVP stimulation and might be a key to predicting response of tolvaptan. CKD patients who were hospitalized to treat their congestive heart failure refractory to conventional loop diuretics were considered to receive tolvaptan and included in this prospective study. The impact of urine cyclic AMP/plasma AVP ratio for prediction of response to tolvaptan, which was defined as any increase in urine volume at day 7 from day 0, was investigated. A total of 30 patients (median 75years old, 24 men, and median estimated glomerular filtration rate 14.4mL/min/1.73 m2) were included. As compared to baseline, urine volume increased at day 7 in 17 responders, whereas urine volume decreased at day 7 in 13 non-responders. Baseline urine cyclic AMP/plasma AVP ratio distributed between 0.25 and 4.01 with median 1.90. The urine cyclic AMP/plasma AVP ratio was a significant predictor of response to tolvaptan, which was adjusted for 6 potential confounders with a cutoff of 1.24. Baseline urine cyclic AMP/plasma AVP ratio is an independent predictor of response to tolvaptan in advanced CKD patients with heart failure. UMIN000022422.

Efficacy and safety of tolvaptan for refractory fluid collection and edema in the terminal cancer patients.

Tolvaptan, a vasopressin V2 receptor antagonist, is an oral diuretic. Patients with terminal cancer develop marked fluid retention, and oral diuretics other than tolvaptan have been used as treatments without clear therapeutic effects. Herein, we aimed to study the efficacy and safety of tolvaptan in patients with terminal cancer. Tolvaptan was administered at a dose of 7.5mg/day to 29 patients (median, 72 years) between August 2017 and February 2020. The duration of tolvaptan treatment ranged from 1 to 85 days (mean, 18.5 days). Median albumin (Alb) and transthyretin (TTR) levels on admission were 2.3g/dL (1.2-4.2g/dL) and 8.9mg/dL (2.1-38.2g/dL), respectively. Median Alb and TTR levels 1 month after treatment initiation remained at 2.3g/dL (0.8-2.9g/dL) and 8.6mg/dL (0.8-23.7mg/dL), respectively. Regarding renal function indicators, median blood urea nitrogen (BUN) and creatinine levels on admission were 19.9mg/dL (8.6-49.3mg/dL) and 0.81mg/dL (0.38-2.25mg/dL), respectively. Median BUN and creatinine levels 1 month after treatment initiation were 23.4mg/dL (13.5-34.0mg/dL) and 0.91mg/dL (0.39-2.41mg/dL), respectively. No patients had hypernatremia on admission, and no effects of tolvaptan on the blood sodium level were found 1 month after treatment initiation. The median potassium level on admission was 4.2mEq/dL (2.9-5.0mEq/dL); tolvaptan treatment had no effects on blood potassium level. Tolvaptan is effective and safe for treating fluid retention refractory to conventional diuretics in patients with terminal cancer.

Cardiovascular and renal effects of SGLT2 inhibitor initiation in acute heart failure: a meta-analysis of randomized controlled trials.

We sought to compare cardiovascular outcomes, renal function, and diuresis in patients receiving standard diuretic therapy for acute heart failure (AHF) with or without the addition of SGLT2i. Systematic search of three electronic databases identified nine eligible randomized controlled trials involving 2,824 patients. The addition of SGLT2i to conventional therapy for AHF reduced all-cause death (odds ratio [OR] 0.75; 95% CI 0.56-0.99; p = 0.049), readmissions for heart failure (HF) (OR 0.54; 95% CI 0.44-0.66; p < 0.001), and the composite of cardiovascular death and readmissions for HF (hazard ratio 0.71; 95% CI 0.60-0.84; p < 0.001). Furthermore, SGLT2i increased mean daily urinary output in liters (mean difference [MD] 0.45; 95% CI 0.03-0.87; p = 0.035) and decreased mean daily doses of loop diuretics in mg of furosemide equivalent (MD -34.90; 95% CI [- 52.58, - 17.21]; p < 0.001) without increasing the incidence worsening renal function (OR 0.75; 95% CI 0.43-1.29; p = 0.290). SGLT2i addition to conventional diuretic therapy reduced all-cause death, readmissions for HF, and the composite of cardiovascular death or readmissions for HF. Moreover, SGLT2i was associated with a higher volume of diuresis with a lower dose of loop diuretics.

A Cost-effectiveness Model Comparing Urinary Biomarkers with Diuretic Renogram in Diagnosing Ureteropelvic Junction Obstruction in Children.

In this cost-effectiveness model, we compared the cost-effectiveness of commonly used urinary biomarkers with conventional diuretic renogram (DR) in diagnosing ureteropelvic junction obstruction (UPJO). We hypothesized that urinary biomarkers are as effective as DR. We used incremental cost-effectiveness ratio (ICER) as a tool for our cost-effectiveness analysis model. The cost of biomarker assay and renogram were sourced from the same center while the accuracy data of DR and urinary biomarkers from the relevant pubications. As the accuracy of individual biomarker increased, the ICER also got better. As a panel of biomarker was introduced, the ICER went to the negative range suggesting cost saving as well. ICER of most urine biomarkers is currently less expensive and less effective. When a biomarker panel was applied ICER became more expensive and effective. With higher samples, test running cost is likely to go down in future and thus biomarkers are likely become less expensive and more effective. Individual urine biomarkers are currently less expensive and less effective compared to DR in predicting UPJO. In future, biomarker panel is likely to be more cost-effective and reduce the need for invasive renogram thus reducing the radiation exposure.

Effects of Low-Dose Tolvaptan for Fluid Management After Cardiovascular Surgery.

Background: Perioperative management of body fluid levels after cardiovascular surgery with cardiopulmonary bypass is essential. Fluid management using tolvaptan with conventional diuretics is effective in maintaining urine output without worsening renal function. This study aimed to improve the in-out balance in the early perioperative phase using low-dose tolvaptan (3.75 mg/day). Methods and Results: This prospective, single-center, randomized, open-label study included 199 patients who underwent cardiovascular surgery with cardiopulmonary bypass in Kobe City Medical Center General Hospital between September 2018 and December 2020. Treatment with tolvaptan and loop diuretics (tolvaptan group; 99 patients) was compared with treatment with loop diuretics alone (control group; 100 patients) to evaluate achievement of preoperative body weight as the primary outcome. Secondary outcomes were urine volume, the incidence of worsening renal function (WRF), and postoperative paroxysmal atrial fibrillation (POAF). There was no significant difference between groups in the return to preoperative body weight on postoperative Day 6. The tolvaptan group had significantly increased urine volume (2,530 vs. 2,150 mL/day) and decreased total furosemide dose (24 vs. 32 mg) compared with the control group. No significant differences were observed in the development of WRF and POAF between the 2 groups. Conclusions: Although low-dose tolvaptan administration did not shorten the time to achieving preoperative body weight, it did significantly increase urine volume without WRF and POAF.

Canagliflozin independently reduced plasma volume from conventional diuretics in patients with type 2 diabetes and chronic heart failure: a subanalysis of the CANDLE trial.

Sodium-glucose cotransporter 2 inhibitors (SGLT2is) reduce the risk of heart failure progression and mortality rates. Moreover, osmotic diuresis induced by SGLT2 inhibition may result in an improved heart failure prognosis. Independent of conventional diuretics in patients with type 2 diabetes (T2D) and chronic heart failure, especially in patients with heart failure with preserved ejection fraction (HFpEF), it is unclear whether SGLT2i chronically reduces estimated plasma volume (ePV). As a subanalysis of the CANDLE trial, which assessed the effect of canagliflozin on N-terminal pro-brain natriuretic peptide (NT-proBNP), we examined the change (%) in ePV over 24 weeks of treatment based on the baseline level associated with diuretic usage. In the CANDLE trial, nearly all patients were clinically stable (NYHA class I-II), with approximately 70% of participants presenting a baseline phenotype of HFpEF. A total of 99 (42.5%) patients were taking diuretics (mostly furosemide) at baseline, while 134 (57.5%) were not. Relative to glimepiride, canagliflozin significantly reduced ePV without worsening renal function in patients in both groups: -4.00% vs. 1.46% (p = 0.020) for the diuretic group and -6.14% vs. 1.28% (p < 0.001) for the nondiuretic group. Furthermore, canagliflozin significantly reduced serum uric acid without causing major electrolyte abnormalities in patients in both subgroups. The long-term beneficial effect of SGLT2i on intravascular congestion could be independent of conventional diuretic therapy without worsening renal function in patients with T2D and HF (HFpEF predominantly). In addition, the beneficial effects of canagliflozin are accompanied by improved hyperuricemia without causing major electrolyte abnormalities.

The Efficacy and Safety of Short-Term Tolvaptan Usage in Patients with Acute Decompensated Heart Failure.

Patients admitted with acute decompensated heart failure (ADHF) have a poor prognosis and poor quality of life due to dyspnea and edema. Tolvaptan, a vasopressin V2 receptor antagonist, is an effective water diuretic. This study aimed to evaluate the efficacy and safety of a short course of tolvaptan to treat volume overload in patients with ADHF. We conducted a phase III, multicenter, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of a short course of tolvaptan (15 mg/day for 4 days) in hospitalized ADHF patients with volume overload despite the use of conventional diuretics. The primary end-point was the change in body weight after 4 days of treatment. The secondary end-points were the change in intake/output balance, change in serum sodium/potassium concentrations, physician/patient assessed signs and symptoms of heart failure after 4 days of treatment, and all-cause mortality in 1 month. A total of 110 patients were screened, and 91 were randomized to receive 15 mg/day of tolvaptan for 4 days (n = 46) or matching placebo (n = 45). Compared to the placebo-treated patients, tolvaptan significantly reduced body weight (-1.36 ± 2.13 kg in the tolvaptan group vs. -0.59 ± 1.27 kg in the placebo group, p = 0.0394). The tolvaptan group also had a negative intake/urine volume balance compared to the placebo group (-509.3 ± 2788.2 ml vs. 975.5 ± 1903.1 ml, p = 0.0059). The safety profile of tolvaptan was acceptable. Tolvaptan significantly reduced volume overload in hospitalized ADHF patients with volume overload despite the use of conventional diuretics.

Impact of Goreisan upon aquaporin-2-incorporated aquaresis system in patients with congestive heart failure.

We often encounter patients with congestive heart failure refractory to conventional diuretics therapy, and Kampo Goreisan is receiving great concern to mediate body water balance particularly for such a cohort. However, its detailed biological mechanism remains uncertain. We had two hospitalized patients with congestive heart failure receiving tolvaptan. Following the administration of Goreisan, both urine cyclic adenosine monophosphate concentration and urine aquaporin-2 concentration decreased, accompanied by incremental diluted urine volume. Although further studies are warranted to establish therapeutic strategy, Goreisan might be a promising therapeutic tool for those with congestive heart failure refractory to conventional diuretics including tolvaptan, via pleiotropic effects including suppression of aquaporin-incorporated water reabsorption system.