Circulation Journal
Online ISSN : 1347-4820
Print ISSN : 1346-9843
ISSN-L : 1346-9843
Reviews
Novel Diuretic Strategies for the Treatment of Heart Failure in Japan
Kaoru DohiMasaaki Ito
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2014 Volume 78 Issue 8 Pages 1816-1823

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Abstract

Fluid management is of paramount importance in the treatment strategy of heart failure (HF), but the therapeutic efficacy of loop diuretic-based treatment for HF patients is limited by insufficient response and adverse effects. Clinical data establishing the efficacy and safety of tolvaptan, a selective oral vasopressin V2 receptor antagonist that induces aquaresis, have recently been accumulated over 3 years of daily clinical experience in Japan. Intravenous infusion of carperitide, a synthetic α-human atrial natriuretic peptide, has also been widely used as acute-phase therapy for acute decompensated HF in Japan. Combination therapy using loop diuretics, tolvaptan, and carperitide with differing and complementary mechanisms of action may maximize therapeutic activity, to minimize the dosage of loop diuretics and thereby reduce the adverse effects not only for volume removal but also for the stability of cardiorenal hemodynamics. (Circ J 2014; 78: 1816–1823)

Fluid removal is an important component of heart failure (HF) treatment to improve oxygenation and relieve the signs and symptoms of edema. In this regard, intravenous loop diuretic therapy that can produce significant natriuresis should be initiated without delay, and indeed early intervention has been associated with better outcomes for patients hospitalized with acute decompensated HF (ADHF).14 In addition, HF patients generally require chronic oral loop diuretic treatment to prevent rehospitalization.5 However, clinical data supporting the efficacy and safety of diuretic therapy remain insufficient, and there is very limited evidence from prospective randomized studies to guide the prescription and titration of diuretics.6,7 In Japan, tolvaptan, a vasopressin type 2 (V2) receptor antagonist that induces aquaresis in the collecting duct of the kidney, has been approved for “volume overload in HF patients when adequate response has not been obtained with loop diuretics” since December 2010.813 In addition, intravenous infusion of carperitide, a synthetic α-human atrial natriuretic peptide (ANP), has been widely used as acute-phase therapy for ADHF only in Japan,14 which has been proven to improve patient outcomes.15 This review will describe the current evidence on the risks and benefits of conventional diuretic therapy using loop diuretics and propose a novel therapeutic strategy for HF focusing on optimal use of natriuretic and aquaretic agents.

Decongestion Therapy in ADHF

Aggressive fluid removal therapy is strongly recommended for symptom relief and hemodynamic improvement in ADHF.1,2 The ATTEND registry, a total of 4,842 patients enrolled at 52 hospitals from April 2007 to December 2011 in Japan, demonstrated that the number of cardiac deaths was highest during the first 7 days after admission and then declined over time.16 Hence, hemodynamic stabilization of patients with HF, including rapid decongestion during the acute phase, is undoubtedly important to minimize the incidence of in-hospital cardiac death. At the same time, several previous clinical studies demonstrated that rapid decongestion can cause worsening renal function (WRF), and may contribute to increased length of stay, increased readmission rate and decreased short- and long-term survival.1720 These apparently contradictory observations raise the question of whether aggressive decongestion therapy takes precedence over concerns about WRF and truly improves clinical outcomes. Metra et al21 followed up 594 patients who were hospitalized because of ADHF, and divided them into 4 groups according to the development or not of WRF during hospitalization and the persistence of more than 1 sign of congestion at discharge. They demonstrated that patients with WRF and no congestion had similar outcomes to those with no WRF and no congestion, whereas the risk of death or of death or HF readmission was increased in patients with persistent congestion alone and in those with both WRF and congestion. Those results indicate that persistent fluid overload during hospitalization is one of the most important prognostic factors for poor outcomes, and WRF secondary to successful fluid removal does not lead to harmful clinical outcomes.22 In the Ultrafiltration vs. Intravenous Diuretics for Patients Hospitalized for Acute Decompensated Congestive Heart Failure (UNLOAD) trial, greater weight loss and a trend toward WRF by ultrafiltration compared with conventional diuretic therapy were associated with a reduced rate of rehospitalization for HF.23 Therefore, rapid and aggressive decongestion treatment may precede WRF for better outcomes during hospitalization, irrespective of the decongestion method.

Early post-discharge rehospitalization and mortality rates are extremely high in the United States despite the vast majority of patients symptomatically improving during hospitalization, presumably because of incomplete decongestion during hospital stay (median stay: only 4 days).2426 Hospital stay of ADHF patients is generally much longer in Japan (median stay: 21 days in the ATTEND registry) than in Western registries (median stay: 4–9 days).27 Longer length of stay after achieving hemodynamic stability might lead to greater opportunities to optimize HF management further and to determine individualization of oral diuretic dosage before hospital discharge. Therefore, future evidence regarding optimal in-hospital diuretic strategies will help physicians develop better HF management and yield better patient outcomes.

Loop Diuretics

Loop diuretics have high natriuretic potency by blocking the luminal Na-K-2Cl transporter in the thick ascending limb of the loop of Henle, and they remain the firstline treatment for ameliorating symptoms in the management of ADHF.3,4 Conversely, multiple clinical observations have suggested an association between loop diuretic use and worsening outcomes in patients with HF.18,2832 Loop diuretics cause intravascular volume depletion as well as directly upregulate renin gene expression by blocking sodium chloride uptake at the macula densa, and that activates the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system, both of which play fundamental roles in HF progression.3336 The Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) trial showed a strict correlation between loop diuretic dose and 6-month mortality, with higher doses failing to produce greater reductions in body weight in 395 hospitalized HF patients.29 The ESCAPE investigators revealed that loop diuretic dose predicted mortality even after adjustment for multiple confounders. However, it remains unknown whether higher diuretic requirements are simply a marker of higher risk or whether higher doses of loop diuretics contribute directly to adverse outcomes.30,31,37 In addition, we should pay close attention to the fact that dose-dependent worsening of 6-month mortality did not seem to be observed in patients receiving a maximal in-hospital diuretic dose of less than 300 mg/day (Figure 1).29 Considering that the maximal in-hospital diuretic dose in Japan is gererally lower than 200 mg/day,11 we should recognize that the causal relations between the dose of loop diuretics and clinical outcomes in Japanese populations warrant further investigation.

Figure 1.

Relationship between maximum in-hospital diuretic dose and mortality. (Modified based on figure 2 from Hasselblad V, et al.29)

Now, we revisit the underlying mechanisms that provide the strong relationship between loop diuretic dosage and dismal outcomes. Testani et al38 independently analyzed 2 cohorts: (1) consecutive admissions at the University of Pennsylvania (Penn) with a primary discharge diagnosis of HF (n=657) and (2) patients in the ESCAPE data set (n=390); diuretic efficiency (DE) was estimated as the net fluid output produced per 40 mg of furosemide equivalents, then dichotomized into high vs. low DE based on the median value. They found that low DE was associated with worse survival even after adjusting for in-hospital diuretic dose and fluid output, in addition to baseline characteristics (Penn: hazards ratio [HR], 1.36; 95% confidence interval [CI], 1.04−1.78; P=0.02; ESCAPE: HR, 2.86; 95% CI, 1.53−5.36; P=0.001). In The Diuretic Optimization Strategies Evaluation (DOSE) study,39 a total of 308 patients with ADHF were randomly assigned, in a 1:1:1:1 ratio, to either a low-dose strategy (total intravenous furosemide dose equal to their total daily oral loop diuretic dose in furosemide equivalents) or a high-dose strategy (total daily intravenous furosemide dose 2.5-fold their total daily oral loop diuretic dose in furosemide equivalents) and to administration of furosemide by either intravenous bolus every 12 h or continuous intravenous infusion. In the comparison of the high-dose and low-dose strategies, there was a nonsignificant trend toward greater improvement in patient global assessment of symptoms (mean area under the curve 4,430±1,401 vs. 4,171±1,436, P=0.06). There was a transient WRF with high-dose diuretics, but this disappeared by the time of discharge. Although the study was not powered to detect differences in clinical outcomes, the incidence of the 60-day outcome of death, rehospitalization, or emergency department visit was lower in the high-dose than in the low-dose arm (HR=0.83, P=0.28). These 2 recent studies suggest that transient WRF secondary to volume depletion associated with aggressive and successful loop diuretic therapy does not contribute to poor clinical outcomes, and reduced intrinsic capacity to maximize the diuretic response but not the diuretic dosage itself can directly contribute to poor clinical outcomes (Figure 2).22,38,39

Figure 2.

Pathophysiology of worsening renal function (WRF) or acute kidney injury (AKI) during diuretic therapy and its substantial influence on clinical outcome in acute heart failure. (Reprinted with permission from Dohi K, et al.22)

Loop diuretics remain a mainstay of HF therapy during outpatient follow-up to maintain euvolemia. However, exposure to higher furosemide doses in outpatients is considered to be associated with worse outcomes and is broadly predictive of death and morbidity,40 and therefore current guidelines recommend using the minimum dose of loop diuretic required to keep the patient free from signs and symptoms of congestion.1 In contrast, Núñez et al41 recently demonstrated that high-dose loop diuretics (HDLDs ≥120 mg/day in furosemide equivalent dose) showed an association with increased survival only in patients with high levels of carbohydrate antigen 125 (>35U/ml), a reliable surrogate of systemic congestion, and high blood urea nitrogen (≥24.8 mg/dl), a surrogate of renal dysfunction/neurohormonal activation, at a median follow-up of 21 months in 1,389 consecutive patients discharged for acute HF. Their results suggest that aggressive decongestion would result in a net positive prognostic effect in patients with renal dysfunction associated with systemic and renal congestion. Their findings may underscore the importance of identifying patients who can benefit from HDLDs.

The use of long-acting rather than short-acting loop diuretics may provide better prognoses in patients with chronic HF.42,43 Sustained natriuretic action of long-acting loop diuretics may contribute to minimizing neurohumoral activation and rebound sodium retention, which could favorably influence cardiac remodeling and patient prognoses.

Thiazide Diuretics

Thiazide diuretics can antagonize the renal adaptation to chronic loop diuretic therapy by blocking distal tubule sodium reabsorption, and potentially improve diuretic resistance because of rebound sodium retention.44,45 However, combined loop-thiazide diuretic therapy can lead to powerful neurohormonal activation46 and therefore clinically important adverse effects are common, requiring careful monitoring of serum electrolytes and renal function.47 Hyponatremia can occur because the increase in urine sodium excretion is greater than the increase in urine water excretion, with more hypertonic urine after combined loop-thiazide diuretic therapy than after loop diuretic alone. Importantly, hyponatremia is independently associated with adverse outcomes in patients with HF.48,49 Therefore, minimum necessity use of loop/thiazide diuretics can prevent hyponatremia in HF management.

Tolvaptan Therapy

The therapeutic efficacy of loop diuretic-based treatment is limited by insufficient response and adverse effects. Conventional pharmacological strategies to overcome the ineffectiveness of loop diuretics in the management of volume overload often result in unsatisfactory resolution. The loop diuretic-induced sodium loss contributes to decreased effective arterial blood volume, which in turn stimulates non-osmotic release of arginine vasopressin (AVP)7,50 which activates the V2 receptor and induces water reabsorption via cyclic adenosine monophosphate-stimulated aquaporin (AQP)-2 translocation into the apical plasma membrane of the principal cells in the distal nephron.51 Consequently, non-osmotic stimulation of AVP secretion induces water reabsorption that usually results in hyperosmotic urine, and plays a contributory role in refractoriness to loop diuretics. Tolvaptan is a selective oral vasopressin V2 receptor antagonist that inhibits free water reabsorption in the kidney’s collecting tubules, and has recently been approved for “volume overload in HF patients when adequate response has not been obtained with other diuretics (eg, loop diuretics)” since December 2010 in Japan, and the patient need not be hyponatremic.2,813 Current guidelines in Japan that were updated in 2013 recommend tolvaptan therapy for patients with volume overload and symptoms of right and left HF (Class IIb, Level of Evidence: B).2 Imamura et al demonstrated that baseline urine osmolality >352 mOsm/L was the strongest and an independent predictor of tolvaptan therapy response among 61 study participants with loop-diuretic refractoriness.12 Their findings strongly suggest that most patients with loop-diuretic refractoriness are associated with non-osmotic stimulation of the V2/AQP-2 system with the resultant increased urine osmolality.51

Although large-scale prospective clinical trials have been conducted mainly in Wetern countries,24,5256 clinical data establishing the efficacy and safety of tolvaptan have recently been accumulated over 3 years of daily clinical experience in Japan.813 We previously examined the short-term effects of tolvaptan treatment in patients with chronic HF and excess fluid retention despite receiving appropriate medical therapy including loop and/or thiazide diuretics.9 A 7-day tolvaptan treatment at a dose of 7.5 mg/day significantly increased urinary volume and decreased body weight (Figure 3) without affecting systemic blood pressure and heart rate. Notably, no patients developed overt symptomatic hypernatremia during treatment, mainly because of fluid shift from the interstitial to the intravascular space following adequate water diuresis. Importantly, most patients showed hemodynamic improvement, assessed using right heart catheterization (Figure 4). Matsue et al in Japan demonstrated that tolvaptan therapy achieved more diuresis without WRF in patients at high risk for WRF in a prospective observational study.10 This finding is consistent with previous experimental and clinical data.57

Figure 3.

Daily water intake (blue), urine volume (red), and changes in body weight (green) from baseline over the 7-day treatment period with tolvaptan (n=22). Data are expressed as mean±SD. *P<0.05 vs. baseline. (Modified based on figure 1 from Watanabe K, et al.9)

Figure 4.

Comparisons of hemodynamic parameters before and after tolvaptan treatment (n=22). Data are expressed as mean±SD. *P<0.05 vs. baseline. PCWP, pulmonary capillary wedge pressure; RAP, right arterial pressure; SVRI, systemic vascular resistance index. (Modified based on figure 5 from Watanabe K, et al.9)

Very recently, Shirakabe et al11 prospectively enrolled 183 patients with ADHF who were admitted to the intensive care unit and examined whether the immediate and short-term administration of tolvaptan reduced the amount of furosemide required, prevented worsening acute kidney injury (AKI), and led to a better outcome for patients with severe ADHF. Patients were assigned to receive either tolvaptan (7.5 mg administered within 12 h of hospitalization and then every 12 h until the HF was compensated) or conventional treatment with continuous intravenous furosemide administration at the physician’s discretion. Propensity-matched analysis revealed that urine volumes on days 1 and 2 were significantly higher in the tolvaptan group, and the dose of continuous intravenous furosemide during the first 48 h was significantly lower (30.0 [15.0–47.5] mg vs. 63.3 [25.0–180.0] mg) than in the conventional treatment group. In addition, tolvaptan prevented exacerbation of AKI and improved 180-day mortality.

Consistent with the results from the clinical studies described, post-marketing prospective multicenter surveillance, which enrolled more than 1,000 HF patients with insufficient response to loop diuretics, demonstrated that tolvaptan therapy decreased body weight by −2.3±2.5 kg, and −3.5±4.1 kg at days 7 and 14, respectively, from baseline, with statistical significance associated with improvement of congestive symptoms.8 Accordingly, tolvaptan has marked capacity for aquaresis in HF patients with diuretic-resistant volume overload in real-world clinical settings. Although hypernatremia is a potential complication, and indeed 3.8% of patients experienced it, predictive factors of hypernatremia were found to be the starting dosage of tolvaptan (15 mg/day), serum sodium level (≥142 mEq/L) and serum potassium level (<3.8 mEq/L) at baseline. Therefore, physicians should administer a lower dose of tolvaptan in patients with normonatremia and hypokalemia to prevent hypernatremia. Indeed, two-thirds of patients received low-dose tolvaptan equal to or less than 7.5 mg/day in this post-marketing prospective multicenter surveillance.

The clinical benefits of chronic tolvaptan therapy have not yet been clearly demonstrated.52,54,58 The Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) trial failed to demonstrate clear benefits of long-term tolvaptan treatment in either morbidity or mortality during a median follow-up of 9.9 months, despite sustained improvements in serum sodium levels, overall fluid balance and congestive symptoms.54 Because hyponatremia is not only a marker of increased morbidity and mortality, but also a promising therapeutic target in the treatment of HF,59 it is worth investigating whether long-term administration of tolvaptan has prognostic benefits and identifying the most appropriate dosing strategy in Japanese populations, especially in HF with hyponatremia.

Role of Intravenous Carperitide Infusion

Vasodilators such as intravenous nitroglycerin are a recommended firstline treatment of ADHF associated with elevated systemic blood pressure at presentation.1,2 Intravenous infusion of carperitide, a synthetic α-human ANP, has been widely used as an acute-phase therapy for ADHF, because of its diuretic and vasodilatory effects,14,15 and diuretic therapy using carperitide is recommend in the current Japanese guidelines (Class IIa, Level of Evidence: B).2 ANP binds and activates natriuretic peptide receptor-A (NPRA), which is located in the proximal tubules, as well as in the cortical and inner medullary collecting ducts, and ANP/NPRA signaling promotes the excretion of sodium and water, inhibits RAAS, and enhances the glomerular filtration rate and renal plasma flow in the kidneys.60 Therefore, administration of carperitide can overcome diuretic resistance as well as loop diuretic-induced RAAS activation and WRF. One of the most striking differences in the management of ADHF is the higher use of carperitide in Japanese (34–69%) compared with lower use of nesiritide, a synthetic human brain natriuretic peptide, in the United States (8–11%).2,27 Carperitide elicits natriuretic, diuretic, and vasorelaxant effects, all of which are directed to the reduction of body fluid and the maintenance of blood pressure homeostasis, which consequently increases cardiac output without direct inotropic effects. We previously demonstrated that carperitide infusion increased cGMP generation, decreased afterload and preload, and improved left ventricular systolic and diastolic function in in patients with congestive HF.61,62 Although hypotension is a potential adverse effect of carperitide when administered at a high dose, the administration of low-dose carperitide in patients with ADHF has been demonstrated to improve the long-term (18-month) outcome.15 Intermittent intravenous infusion of carperitide can be given in the outpatient setting and may decrease the length and number of rehospitalizations in patients with advanced HF.63 The efficacy and safety of this promising therapeutic strategy need to be confirmed in large-scale prospective clinical trials.

New Diuretic Strategy in Japan

In general, pharmacological decongestion therapy based on loop diuretics is sometimes insufficient in patients with HF. In addition, hyponatremia can occur as the dosage of the natriuretic agents increases. As hyponatremia is an important and universal risk factor for mortality in hospitalized patients with HF,49,64 we should revisit the importance of an adequate water-sodium balance in volume management. In the intravenous fluid supply treatment for dehydration, the optimal fluid and sodium balance has always been considered on the basis of the patient’s condition. In contrast, we had only been able to use natriuretic agents for the treatment of volume overload, irrespective of the patient’s water–sodium balance, until aquaretic agents emerged. In this respect, a combination of natriuretic and aquaretic drugs as “sequential nephron blockade of sodium and water channels in the kidney” for decongestion therapy in patients with HF is an appropriate volume control strategy to address this issue (Figure 5).

Figure 5.

Water-sodium balance in volume management of heart failure.

Concomitant and aggressive vasodilation therapy with diuresis is necessary especially in ADHF patients without hypotension.1,2 Concomitant use of low-dose carperitide can be useful in addition to water-sodium excretion therapy using loop diuretics and tolvaptan. It is worth investigating further whether the combined use of loop diuretics, tolvaptan, and carperitide may achieve volume control without neurohumoral activation and prevent WRF, minimize the dosage of loop diuretic, and therefore improve patitent prognosis. Pharmacological inhibition of the V2/AQP-2 system that induces aquaresis without direct activation of the RAAS and sympathetic nervous system, and activation of ANP/NPRA signaling that induces natriuresis and RAAS inhibition, could constitute a novel strategy for HF therapy in Japan (Figure 6). The economic effect of this therapeutic strategy for ADHF remains unclear. Up-front costs are definitely greater with this strategy than with incremental doses of loop diuretics alone; but total longitudinal costs could be lower if the length of hospital stay and/or rehospitalization rate is reduced.

Figure 6.

Comparison of loop diuretics, tolvaptan, and carperitide. The use of the 3 diuretic agents may have complementary mechanisms of action for decongestion therapy. RAAS, renin-angiotensin-aldosterone system.

Patients with HF and advanced stages of chronic kidney disease (CKD) frequently manifest diuretic resistance. Because both carperitide and tolvaptan have potential protective effects on renal function in the treatment of ADHF in individuals with CKD and/or at high risk for WRF,2,10,6567 future clinical trials should be performed to confirm the efficacy and safety of combination therapy with these 2 agents with different mechanisms of action in the management of HF at various clinical stages of CKD.

Conclusions

Although many questions remain unanswered about the best approach to using diuretics, they remain an important part of the ADHF armamentarium. Combination therapy with tolvaptan and carperitide with differing and complementary mechanisms of action may maximize therapeutic activity, to minimize the dosage of loop diuretics and therefore reduce the side effects not only for volume removal but also for the stability of cardiorenal hemodynamics. Future clinical trials from Japan should be performed to confirm the efficacy and safety of this strategy.

Disclosures

None.

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