Clinical benefit of tolvaptan in patients with acute decompensated heart failure and chronic kidney disease

Tolvaptan, a vasopressin type 2 receptor antagonist, has an aquaretic effect without affecting renal function. The effects of long-term tolvaptan administration in heart failure patients with renal dysfunction have not been clarified. Here, we assessed the clinical benefit of tolvaptan during a 6-month follow-up in acute decompensated heart failure (ADHF) patients with severe chronic kidney disease (CKD; estimated glomerular filtration rate (eGFR) <45 mL/min/1.73 m²). We compared 33 patients with ADHF and severe CKD who were administered tolvaptan in addition to loop diuretics (TLV group), with 36 patients with ADHF and severe CKD who were administered high-dose loop diuretics (≥40 mg) alone (LD group). Alterations in serum creatinine and eGFR levels from the time of hospital discharge to 6-month follow-up were significantly different between the groups, with those in the TLV group being more favorable. Furthermore, Kaplan–Meier analysis revealed that rehospitalization for heart failure (HF) was significantly lower in the TLV group compared with the LD group. In ADHF patients with severe CKD, tolvaptan use for 6 months reduced worsening of renal function and rehospitalization rates for HF when compared with conventional diuretic therapy. In conclusion, tolvaptan could be a safe and effective agent for long-term management of HF and CKD.     

Rubbing Salt into Wounds: Hypertonic Saline to Assist with Volume Removal in Heart Failure

Traditionally accepted management strategies for patients with heart failure include sodium and fluid restriction, neurohormonal blockade, and the use of loop diuretics to achieve and maintain euvolemia. Despite continued advances in medical and device therapy, fluid management remains a significant problem in patients with the cardiorenal syndrome (manifested as diuretic resistance and worsening renal function with more aggressive attempts at volume removal). This article examines the counterintuitive use of hypertonic saline as a potential therapy to facilitate diuresis in patients with decompensated heart failure and diuretic resistance. Low-volume hypertonic saline administration offsets counterproductive neurohormonal upregulation, transiently improves hemodynamics, and promotes renal sodium excretion with accompanied net water loss and preservation of renal function. This “new” therapeutic tool should be explored further as an adjunct to current medical therapies in the management of patients with refractory volume overload.     

Rational use of diuretics in acute decompensated heart failure

Chronic heart failure poses an enormous health care burden to the United States and other developed countries. Acute decompensated heart failure (ADHF) accounts for nearly half of the morbidity and expense of treating this disease. Most patients presenting with ADHF have symptomatic vascular congestion. Diuretics, especially loop diuretics, are the primary pharmacologic intervention used in this population. Despite their widespread use, scant data from randomized clinical trials are available to guide therapeutic choices. In addition, data from several large registries examining weight loss during hospitalization for ADHF suggest that efficacy with diuretic treatment is far from universal. Aggressive diuresis carries a significant risk of electrolyte and volume depletion, with subsequent arrhythmias, hypotension, and worsening renal function. These complications often translate into worse prognosis. Diuretic regimens used to treat ADHF must be individualized based on general knowledge of potency and pharmacokinetic and pharmacodynamic considerations. This article summarizes older and more recent literature to provide a framework for making rational treatment choices in this difficult patient population.     

Combination of loop diuretics with thiazide-type diuretics in heart failure

Volume overload is an important clinical target in heart failure management, typically addressed using loop diuretics. An important and challenging subset of heart failure patients exhibit fluid overload despite significant doses of loop diuretics. One approach to overcome loop diuretic resistance is the addition of a thiazide-type diuretic to produce diuretic synergy via "sequential nephron blockade," first described more than 40 years ago. Although potentially able to induce diuresis in patients otherwise resistant to high doses of loop diuretics, this strategy has not been subjected to large-scale clinical trials to establish safety and clinical efficacy. We summarize the existing literature evaluating the combination of loop and thiazide diuretics in patients with heart failure in order to describe the possible benefits and hazards associated with this therapy. Combination diuretic therapy using any of several thiazide-type diuretics can more than double daily urine sodium excretion to induce weight loss and edema resolution, at the risk of inducing severe hypokalemia in addition to hyponatremia, hypotension, and worsening renal function. We provide considerations about prudent use of this therapy and review potential misconceptions about this long-used diuretic approach. Finally, we seek to highlight the need for pragmatic clinical trials for this commonly used therapy.     

The role of ultrafiltration in the management of heart failure

Opinion statement In the United States, 90% of one million annual hospitalizations for heart failure are due to symptoms of volume overload. Hypervolemia contributes to heart failure progression and mortality. Treatment guidelines recommend that therapy for patients with heart failure be aimed at achieving euvolemia. Intravenous loop diuretics induce a rapid diuresis that reduces lung congestion and dyspnea. However, loop diuretics’ effectiveness declines with repeated exposure. Unresolved congestion may contribute to high re-hospitalization rates. Furthermore, loop diuretics may be associated with increased morbidity and mortality due to deleterious effects on neurohormonal activation, electrolyte balance, and cardiac and renal function. Ultrafiltration is an alternative method of sodium and water removal, which safely improves hemodynamics in patients with heart failure. Application of this technology has been limited by the need for high flow rates, large extracorporeal blood volumes, and large-bore central venous catheters. A modified ultrafiltration device has overcome these limitations. Ultrafiltration may be a safe and effective alternative to intravenous diuretics in the treatment of decompensated heart failure.     

Therapeutic Dilemmas in Mixed Septic-Cardiogenic Shock

Sepsis is an increasing cause of decompensation in patients with chronic heart failure with reduced or preserved ejection fraction. Sepsis and decompensated heart failure results in a mixed septic-cardiogenic shock that poses several therapeutic dilemmas: Rapid fluid resuscitation is the cornerstone of sepsis management, while loop diuretics are the main stay of decompensated heart failure treatment. Whether inotropic therapy with dobutamine or inodilators improves microvascular alterations remains unsettled in sepsis. When to resume loop diuretic therapy in patients with sepsis and decompensated heart failure is unclear. In the absence of relevant guidelines, we review vasopressor therapy, the timing and volume of fluid resuscitation, and the need for inotropic therapy in patients who, with sepsis and decompensated heart failure, present with a mixed septic-cardiogenic shock.     

Diuretics and ultrafiltration in acute decompensated heart failure

Congestion and volume overload are the hallmarks of acute decompensated heart failure (ADHF), and loop diuretics have historically been the cornerstone of treatment. The demonstrated efficacy of loop diuretics in managing congestion is balanced by the recognized limitations of diuretic resistance, neurohormonal activation, and worsening renal function. However, the recently published DOSE (Diuretic Optimization Strategies Evaluation) trial suggests that previous concerns about the safety of high-dose diuretics may not be valid. There has been a growing interest in alternative strategies to manage volume retention in ADHF with improved efficacy and safety profiles. Peripheral venovenous ultrafiltration (UF) represents a potentially promising approach to volume management in ADHF. Small studies suggest that UF may allow for more effective fluid removal compared with diuretics, with improved quality of life and reduced rehospitalization rates. However, further investigation is needed to completely define the role of UF in patients with ADHF. This review summarizes available data on the use of both diuretics and UF in ADHF patients and identifies challenges and unresolved questions for each approach.     

Intra‐abdominal Hypertension: An Important Consideration for Diuretic Resistance in Acute Decompensated Heart Failure

Fluid accumulation is the hallmark of heart failure decompensation. Fluid overload and congestion are associated with recurrent hospitalizations, poor quality of life, and increased mortality in heart failure. Despite the use of high‐dose intravenous loop diuretic therapy, acutely decompensated heart failure patients may develop diuretic resistance. Diuretic refractoriness can be a result of elevated intra‐abdominal pressure (IAP) in acutely decompensated heart failure. Increased renal venous and interstitial pressures in patients with elevated IAP may lead to renal impairment and diuretic resistance. Routine approaches such as sequential nephron blockade with a combination of loop and thiazide or thiazide‐like diuretics, continuous diuretic infusion, and ultrafiltration may not be sufficient. Presented here is a case illustrating the importance of recognizing intra‐abdominal hypertension in patients with diuretic resistance. Lowering IAP improves renal perfusion, renal filtration, and diuresis. When elevated, IAP is an easily reversible cause of diuretic resistance. Additionally, abdominal perfusion pressure can be used to guide therapy to reverse end‐organ damage and avoid permanent renal replacement therapy.     

Cardiorenal rescue study in acute decompensated heart failure: rationale and design of CARRESS-HF, for the Heart Failure Clinical Research Network

BackgroundWorsening renal function is common among patients hospitalized for acute decompensated heart failure (ADHF). When this occurs, subsequent management decisions often pit the desire for effective decongestion against concerns about further worsening renal function. There are no evidence-based treatments or guidelines to assist in these difficult management decisions. Ultrafiltration is a potentially attractive alternative to loop diuretics for the management of fluid overload in patients with ADHF and worsening renal function.Methods and ResultsThe National Heart, Lung, and Blood Institute Heart Failure Clinical Research Network designed a clinical trial to determine if ultrafiltration results in improved renal function and relief of congestion compared with stepped pharmacologic care when assessed 96 hours after randomization in patients with ADHF and cardiorenal syndrome. Enrollment began in June 2008. This paper describes the rationale and design of the Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARRESS-HF).ConclusionsTreating the signs and symptoms of congestion in ADHF is often complicated by worsening renal function. CARRESS-HF compares treatment strategies (ultrafiltration vs stepped pharmacologic care) for the management of worsening renal function in patients with ADHF. The results of the CARRESS-HF trial are expected to provide information and evidence as to the most appropriate approaches for treating this challenging patient population.     

How to use diuretics in heart failure

Systemic and pulmonary congestion is a central aspect of both acute and chronic heart failure and directly leads to many of the clinical manifestations of these syndromes. Therefore, diuretic therapy to treat congestion plays a fundamental role in heart failure management. However, although diuretics are the most common drugs prescribed for heart failure, there is limited quality evidence to guide their use. Unlike other components of the heart failure armamentarium, such as β-blockers and angiotensin-converting enzyme inhibitors, diuretics (with the exception of aldosterone antagonists) have not been shown to decrease heart failure progression or improve mortality. Additionally, some observational data suggest that diuretics may actually be harmful in heart failure, contributing to neurohormonal activation, renal dysfunction, and potentially mortality. Despite these concerns, diuretics remain ubiquitous in heart failure management because of the need to address symptoms of congestion and the lack of alternative strategies. Recently, the development of a variety of potential adjuncts or alternatives to diuretic therapy has suggested the need for an active reappraisal of diuretic therapy for heart failure. The main classes of diuretics are the loop diuretics, potassium-sparing diuretics, and thiazides. Loop diuretics, the mainstay of acute and chronic therapy for heart failure, are “threshold drugs”; therefore, an adequate dose to achieve a pharmacodynamic effect (ie, to increase urine output) must be prescribed for effective therapy. The minimum dose to achieve diuresis and manage congestion should be used to minimize adverse effects. For patients refractory to initial dosing of intravenous diuretics, options include dose escalation, use of continuous infusion rather than intermittent boluses, or combination therapy with the addition of a thiazide or thiazide-like diuretic (eg, metolazone). Management of chronic heart failure often includes patient-directed titration of diuretics based on changes in symptoms or body weight in an attempt to decrease hospitalizations, although the efficacy of this strategy has not been tested in well-designed trials. Aldosterone antagonists, which are used primarily as neurohormonal agents rather than for their diuretic effects, are indicated for patients with systolic failure and moderate to severe symptoms, as long as renal function and serum potassium are stable and monitored closely. All diuretic therapy requires careful monitoring of electrolytes and renal function. Whether newer modalities for managing congestion (vasopressin antagonists, adenosine A1 antagonists, and ultrafiltration therapy) will be an improvement over diuretic therapy will be determined by the results of multiple ongoing clinical trials.     

Role of vasopressin antagonists in the management of acute decompensated heart failure

Vasopressin antagonists are a class of neurohormonal antagonists with applications in both the short-term and long-term management of patients with acute decompensated heart failure (ADHF). The pharmacologic effects of vasopressin antagonists include changes in fluid balance and hemodynamics that may improve symptoms and outcomes in patients hospitalized with ADHF. With chronic therapy, vasopressin antagonists offer the potential to improve outcomes through a variety of mechanisms, including more effective treatment of congestion, preservation or improvement of renal function, or a reduction in the use of concomitant loop diuretic therapy. Several vasopressin antagonists are currently in advanced clinical trials for the treatment of ADHF, chronic stable heart failure, and hyponatremia.     

Treatment of congestion in heart failure with diuretics and extracorporeal therapies: effects on symptoms, renal function, and prognosis

In the United States and Europe, approximately 90% of heart failure hospitalizations are due to symptoms and signs of sodium and fluid excess. Congestion is associated with heart failure progression. Venous congestion, rather than a reduced cardiac output, may be the primary hemodynamic factor driving worsening renal function in patients with acutely decompensated heart failure. According to data from large national registries, approximately 40% of hospitalized heart failure patients are discharged with unresolved congestion, which may contribute to unacceptably high re-hospitalization rates. Diuretics reduce the symptoms and signs of fluid overload, but their effectiveness can be reduced by excess salt intake, underlying chronic kidney disease, renal adaptation to their action, and neurohormonal activation. In addition, the production of hypotonic urine limits the ability of loop diuretics to reduce total body sodium. Ultrafiltration is the mechanical removal of fluid from the vasculature. Hydrostatic pressure is applied to blood across a semipermeable membrane to separate isotonic plasma water from blood. Because solutes in blood freely cross the semipermeable membrane, fluid can be removed without causing significant changes in the serum concentration of electrolytes and other solutes. Relatively small, mostly single-center clinical studies of ultrafiltration have shown that removal of isotonic fluid may relieve symptoms of congestion and restore diuretic responsiveness in patients with diuretic resistance. These studies have also shown a favorable effect on neurohormonal activation. When compared with intravenous diuretics, ultrafiltration similarly changed dyspnea scores but reduced re-hospitalizations (28 of 87 patients (32%) versus 16 of 89 patients (18%), P < 0.037) in a randomized controlled trial of patients with decompensated heart failure. Future larger controlled clinical trials should evaluate further the effect of ultrafiltration on patients’ outcomes, including survival.     

The Acute Cardiorenal Syndrome Type I: Considerations on Physiology,Epidemiology, and Therapy

Acute cardiorenal syndrome, also known as cardiorenal syndrome type 1, is defined as an abrupt worsening of cardiac function that occurs in at least 30 % of patients with acute decompensated heart failure and can lead to the development of acute kidney injury. The changes in renal function that occur in this setting have variable prognostic implications, as both poorer and better outcomes have been reported when renal function worsens during treatment of heart failure decompensation. Furthermore, it remains unclear when worsening renal function is actually a manifestation of true acute kidney injury or simply an indicator of hemoconcentration. Given these gaps in the understanding of the significance of renal function changes in the setting of decompensated heart failure, it is not surprising that studies on the effects of available therapies, including diuretics, vasoactive drugs, and mechanical fluid removal have yielded inconsistent results. The purpose of this review is to analyze critically the current knowledge on the pathophysiology, epidemiology, prognosis, and treatment of acute cardiorenal syndrome.     

Diuretic usage for protection against end‐organ damage in liver cirrhosis and heart failure

Volume overload is common in liver cirrhosis, heart failure, and chronic kidney disease, being an independent risk factor for mortality. Loop diuretics have been widely used for treating volume overload in these patients. However, there is a tendency to increase the dose of loop diuretics partly because of diuresis resistance. Neurohormonal factors are also enhanced in these patients, which play a role in volume overload and organ ischemia. Loop diuretics cannot improve neurohormonal factors and could result in end‐organ damage. The water diuretic tolvaptan has been approved for use for volume overload in heart failure and liver cirrhosis. Despite causing similar increases in urine volume, its characteristics differ from those of loop diuretics. Renal blood flow is maintained with tolvaptan but decreased with furosemide in heart failure patients. Neurohormonal factors and blood pressure are not markedly altered by tolvaptan administration. It is expected that these mechanisms of tolvaptan can protect against worsening renal function by volume overload diseases compared with loop diuretics. It has also been reported that some patients do not respond well to tolvaptan. Loop diuretics and tolvaptan share the same mechanism with regard to decreasing renal interstitial osmolality, which plays a fundamental role in water diuresis. Thus, a high dose of loop diuretics could result in resistance to tolvaptan, so tolvaptan should be administered before increasing the loop diuretic dose. Therefore, volume control without enhancing end‐organ damage can be achieved by adding tolvaptan to a tolerable dose of Na‐sparing diuretics.     

Diuretic Responsiveness and Its Prognostic Significance in Children With Heart Failure

BackgroundLoop diuretics are considered first-line therapy for congestion in children with heart failure, although some patients remain volume overloaded during treatment. We sought to characterize loop diuretic responsiveness (DR) in children hospitalized with acute decompensated failure and to determine whether a decreased response was associated with worse outcomes.Methods and ResultsDR was calculated for 108 consecutive children ˂21 years of age who were hospitalized with acute decompensated heart failure. DR was defined as net fluid (mL) output per 1 mg of furosemide equivalents during the first 72 hours of treatment with a loop diuretic. The primary outcome was the composite end point of inpatient death or use of mechanical circulatory support. The median DR was 6.0 mL/mg (interquartile range -2.4 to 15.7 mL/mg). Thirty-two percent of patients remained in a positive fluid balance after 72 hours of treatment with a loop diuretic. Death or use of mechanical circulatory support occurred in 29 patients (27%). Low DR was associated with the composite end point, even after adjusting for net urine output and loop diuretic dose indexed to weight (odds ratio 5.3; P = .003). Patients with low DR also experienced longer length of hospital stay than patients with greater DR (median 33 days vs 11 days; P = .002).ConclusionIn children hospitalized with acute decompensated heart failure, early diminished loop DR during decongestion therapy is common and portends a poor prognosis.     

Diuretika bei kardiorenalen Syndromen

Cardiorenal syndromes are well-defined diseases of the heart and kidneys and five forms can be distinguished which are divided into acute and chronic, as well as primary cardiac and primary renal forms. Triggering and predisposing factors contribute to the development of acute renal failure. Diuretics are necessary and indispensible drugs in cases of fluid overload in acute cardiorenal syndromes. In acute decompensated heart failure diuretics are recommended for the symptomatic treatment of hyperhydration. A benefit of diuretics with respect to hard endpoints (e.g. cardiovascular events and mortality) has not been demonstrated in chronic heart failure and chronic cardiorenal syndromes. Loop diuretics, thiazide diuretics, potassium-sparing diuretics and vasopressin V2 antagonist are available with varying mechanisms and sites of action. The maximum recommended dose of diuretics depends on renal function. Major side effects include electrolyte disturbances (e.g. hypokalemia, hyponatremia and hypomagnesemia), disorders of acid-base balance, increased insulin resistance and ototoxicity. The use of diuretics in cases of renal failure reduces the chance of recovery of renal function. A sequential nephron blockade and/or transient ultrafiltration or renal replacement therapy (e.g. hemodialysis and peritoneal dialysis) might be of benefit in cardiorenal syndromes and resistance to conventional treatment but evidence from controlled studies is still lacking.     

Einsatz von Diuretika bei der akut dekompensierten Herzinsuffizienz

Patients with acute heart failure usually present with dyspnea and edema secondary to elevated intracardiac filling pressure resulting from volume overload. Despite significant progress in understanding heart failure, the treatment strategy for acute heart failure did not change in the same way. Diuretics, especially loop diuretics, are the most common drugs used in this setting. Intravenous diuretics act acutely by exerting a modest vasodilatory response and chronically by reducing circulating blood volume. Despite a very common use of diuretics in patients hospitalized with acute heart failure, nearly half of these patients are discharged from the hospital without weight loss. This could be due to inadequate diuresis, overdiuresis with subsequent volume replacement and diuretic resistance. Aggressive diuresis carries a significant risk of electrolyte and volume depletion with subsequent arrhythmias, hypotension, and worsening renal function. Actually, little data from randomized clinical trials are available to guide therapeutic treatment with diuretics. Thus, the choice and dosing of diuretic therapy must be individualized based on general knowledge of potency and pharmacokinetic and pharmacodynamic considerations.     

Acute Decompensated Heart Failure: Update on New and Emerging Evidence and Directions for Future Research

Acute decompensated heart failure (ADHF) is a complex clinical event associated with excess morbidity and mortality. Managing ADHF patients is challenging because of the lack of effective treatments that both reduce symptoms and improve clinical outcomes. Existing guideline recommendations are largely based on expert opinion, but several recently published trials have yielded important data to inform both current clinical practice and future research directions. New insight has been gained regarding volume management, including dosing strategies for intravenous loop diuretics and the role of ultrafiltration in patients with heart failure and renal dysfunction. Although the largest ADHF trial to date (ASCEND-HF, using nesiritide) was neutral, promising results with other investigational agents have been reported. If these findings are confirmed in phase III trials, novel compounds, such as relaxin, omecamtiv mecarbil, and ularitide, among others, may become therapeutic options. Translation of research findings into quality clinical care can not be overemphasized. Although many gaps in knowledge exist, ongoing studies will address issues around delivery of evidence-based care to achieve the goal of improving the health status and clinical outcomes of patients with ADHF.