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.     

Diuretika und extrakorporale Verfahren zur Behandlung des kardiorenalen Syndroms

Acute or chronic heart failure can lead to a reduction in kidney function presenting as cardiorenal syndrome (CRS). A substantial clinical problem in such patients is hypervolemia in combination with deteriorating renal function. The treatment initially consists of diuretics at this clinical stage; however, development of resistance against diuretics often limits successful therapy. The aim of this overview is to provide an overview of extracorporeal treatment options, such as peritoneal dialysis (PD), hemodialysis (HD), and mechanical ultrafiltration alone. In patients with manifest CRS the use of PD can result in improvement in the quality of life and improve cardiac function as well as reduction in the number of hospital stays. The HD is also an option in the treatment of such patients; however, it is often related to unfavorable effects, such as hypotension and a reduction in diuresis. Mechanical ultrafiltration alone does not seem to provide any advantages as compared to diuretic treatment in patients with CRS.     

Is There Still a Role for Ultrafiltration in the Management of Acute Heart Failure? CARRESS and Beyond

The Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARRESS-HF) trial was a prospective, randomized study comparing ultrafiltration versus pharmacological therapy in the treatment of acute decompensated heart failure (ADHF) complicated by cardiorenal syndrome Bart et al. (N Eng J Med 367:2296–2304, 1). The study found that ultrafiltration was inferior to pharmacological therapy, resulting in a significant increase in serum creatinine and serious adverse events while producing no significant difference in weight loss. The CARRESS trial calls into question the viability of ultrafiltration as a preferable treatment strategy in ADHF patients with cardiorenal syndrome.     

Evolving Treatment Strategies for Management of Cardiorenal Syndrome

The treatment of acute decompensated heart failure in the presence of progressive renal dysfunction is a commonly encountered dilemma in clinical practice. Also known as cardiorenal syndrome, this complex disease state has forced researchers and clinicians to develop new treatment strategies to relieve the symptomatic congestion of heart failure while preserving renal function. Loop diuretics remain the standard of pharmacologic treatment of acute heart failure, but their effects on renal function have been called into question. The DOSE trial set out to determine optimal diuretic dosing strategies but no clear regimen was firmly established. Initial studies with vasopressin antagonists showed promise in their ability to increase urine output, provide short-term symptom relief, and correct hyponatremia while maintaining renal function. Unfortunately, the EVEREST trial did not demonstrate any benefit on long-term clinical outcomes. Adenosine antagonists also appeared to be an emerging therapeutic option, but the recently completed PROTECT trial failed to establish their role in the treatment of cardiorenal syndrome. Both nesiritide and low-dose dopamine have endured years of trials with mixed results. Most recently, findings from the ASCEND-HF trial showed that nesiritide was safe with no adverse effects on renal function or mortality and was associated with a modest improvement in dyspnea. The ongoing ROSE study, sponsored by the National Institutes of Health Heart Failure Research Network, will attempt to confirm the safety and efficacy profiles of low-dose nesiritide and dopamine, as well as clarify their roles within acute heart failure management. Despite its inherent complexities, ultrafiltration has demonstrated potential benefit in several clinical outcomes compared to traditional pharmacotherapy. The results of the CARRESS-HF trial will reveal how the use of ultrafiltration specifically applies to patients with cardiorenal syndrome. The most exciting aspects about our evolving understanding of the cardiorenal system are the innovative treatments that have emerged as a result. The creation of chimeric natriuretic peptides, targeted intra-renal pharmacotherapy, the novel use of phosphodiesterase inhibitors, and combination treatment strategies demonstrate that despite our varied success in treating cardiorenal syndrome in the past, there are highly encouraging translational therapies rapidly developing in the pipeline.     

Role of Adenosine Antagonism in the Cardiorenal Syndrome

Acute decompensated heart failure (ADHF), generally related to signs and symptoms of volume overload, is one the most common reasons for hospitalization in the United States. Recently, it has been observed that the majority of patients with ADHF have baseline renal dysfunction. Moreover, heart failure (HF) treatment is limited by worsening renal function despite persistent volume overload. This connection between HF and renal dysfunction has been termed the cardiorenal syndrome and has made treatment of patients with stable and unstable HF challenging. Selective adenosine A1 receptor antagonists are novel pharmacologic agents that are currently under development to treat volume overload in HF while protecting or possibly improving renal function. In this article, we review the cardiorenal syndrome, the role of adenosine in renal function, and emerging data regarding the safety and efficacy of adenosine A1 receptor antagonists in patients with advanced HF.     

Dialyse- und Ultrafiltrationsverfahren bei kardiorenalem Syndrom

Renal failure is common in patients with severe heart failure and this complex pathophysiological interaction is classified as cardiorenal syndrome. In these patients hydropic decompensation is the main reason for hospitalization. In patients with refractory heart failure characterized by diuretic resistance and congestion due to volume overload, ultrafiltration has to be considered. In cases of acute decompensated heart failure with deterioration of renal function, extracorporeal ultrafiltration is the preferred treatment modality. On the other hand, patients suffering from chronic decompensated heart failure, particularly patients with ascites, will profit from the treatment-specific advantages of peritoneal ultrafiltration. A prerequisite for an optimized care of patients with cardiorenal syndrome is the close collaboration between intensive care physicians, cardiologists and nephrologists.     

The cardiorenal syndrome: lessons from the ADHERE database and treatment options

Significant renal dysfunction is common in patients hospitalized for heart failure and carries a grim prognosis. Patients with heart failure who have or develop renal dysfunction while being treated for heart failure are said to have the cardiorenal syndrome. The Acute Decompensated Heart Failure National Registry (ADHERE) database, which enrolled nonselected patients admitted to the hospital for acute decompensated heart failure (ADHF), was used to determine the causes for this renal dysfunction and whether treatment can optimize outcomes. Results show that the average patient admitted for ADHF is older than those typically enrolled in clinical trials and has at least moderate kidney damage, with significantly impaired glomerular filtration rates. Renal dysfunction in patients with heart failure is complex and often multifactorial in origin, but the syndrome may be reversible in some patients. Reduction of angiotensin II levels with angiotensin-converting enzyme (ACE) inhibitors may prevent glomerular hyperfiltration and ultimately preserve renal function; however, patients who are volume-depleted may be especially sensitive to ACE inhibitor-induced efferent arteriolar dilation, so ACE inhibitor therapy in patients with renal dysfunction should be initiated when the patient is volume replete. In conclusion, impaired renal function is common in heart failure patients and may be a key cause of the cascade involving fluid retention, decompensation, and eventual hospital admission. Future pharmacologic research should focus on therapies aimed at maintaining or improving renal function in heart failure patients to reduce the high mortality associated with the cardiorenal syndrome.     

The Cardiorenal Syndrome: Lessons from the ADHERE Database and Treatment Options

Significant renal dysfunction is common in patients hospitalized for heart failure and carries a grim prognosis. Patients with heart failure who have or develop renal dysfunction while being treated for heart failure are said to have the cardiorenal syndrome. The Acute Decompensated Heart Failure National Registry (ADHERE®) database, which enrolled nonselected patients admitted to the hospital for acute decompensated heart failure (ADHF), was used to determine the causes for this renal dysfunction and whether treatment can optimize outcomes. Results show that the average patient admitted for ADHF is older than those typically enrolled in clinical trials and has at least moderate kidney damage, with significantly impaired glomerular filtration rates. Renal dysfunction in patients with heart failure is complex and often multifactorial in origin, but the syndrome may be reversible in some patients. Reduction of angiotensin II levels with angiotensin-converting enzyme (ACE) inhibitors may prevent glomerular hyperfiltration and ultimately preserve renal function; however, patients who are volume-depleted may be especially sensitive to ACE inhibitor–induced efferent arteriolar dilation, so ACE inhibitor therapy in patients with renal dysfunction should be initiated when the patient is volume replete. In conclusion, impaired renal function is common in heart failure patients and may be a key cause of the cascade involving fluid retention, decompensation, and eventual hospital admission. Future pharmacologic research should focus on therapies aimed at maintaining or improving renal function in heart failure patients to reduce the high mortality associated with the cardiorenal syndrome.Supported by an unrestricted educational grant from Scios Inc.     

Decompensated Heart Failure and Renal Failure: What Is the Current Evidence?

Purpose of Review

Acute decompensated heart failure (ADHF) is one of the biggest challenges in the management of chronic heart failure. Despite several advances in medical and device therapy, high readmission and mortality rates continue to be a burden on healthcare systems worldwide. The aim of the current review is to provide an overview on current as well as future approaches in cardiorenal interactions in patients with ADHF.

Recent Findings

One of the strongest predictors of adverse outcomes in ADHF is renal dysfunction, referred to as cardiorenal syndromes (CRS) or cardiorenal interactions. Patients with ADHF frequently develop worsening of renal function (WRF) and/or acute kidney injury (AKI). Recent studies brought new information about biomarkers in diagnosing and predicting prognosis of CRS. Among others, dry weight at hospital discharge is considered a surrogate marker of successful treatment in ADHF patients with/without renal dysfunction.

Summary

The etiology of WRF appears to be an important factor for determining risk related to WRF as well as clinical management. The hypertonic saline used as adjunctive therapy for intravenous loop diuretics and/or induction of aquaresis (e.g., using tolvaptan) may be promising and efficient approaches in the future.

     

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.     

Contemporary in-hospital management strategies for acute decompensated heart failure

Acute decompensated heart failure (ADHF) is a common syndrome with diverse etiologies and precipitating factors, which is associated with significant morbidity and mortality. Tremendous resources are used in treating this syndrome, with few prospectively designed clinical trials to guide therapy. Patients suffering from ADHF are at increased risk for readmission to the hospital as well as an increased risk of death. Prompt identification and management of these patients can lead to shorter length of hospital stay, lower likelihood of readmission, and, perhaps, lower mortality. Initial treatment should target the relief of congestive symptoms. Intravenous loop diuretics are the mainstay of therapy, whereas ultrafiltration has emerged as a viable option in patients refractory to conventional treatment with diuretics. The safety and efficacy of nesiritide have been clarified in a recent large randomized trial, reassuring a favorable safety profile, but with modest improvement in short-term clinical outcomes. Thus, the preferred intravenous vasoactive medication has yet to be determined in large clinical trials, and positive inotropic agents should be reserved for patients with hemodynamic collapse. This article reviews the in-hospital assessment and management of ADHF.     

Congestive Renal Failure: The Pathophysiology and Treatment of Renal Venous Hypertension

Longstanding experimental evidence supports the role of renal venous hypertension in causing kidney dysfunction and “congestive renal failure.” A focus has been heart failure, in which the cardiorenal syndrome may partly be due to high venous pressure, rather than traditional mechanisms involving low cardiac output. Analogous diseases are intra-abdominal hypertension and renal vein thrombosis. Proposed pathophysiologic mechanisms include reduced transglomerular pressure, elevated renal interstitial pressure, myogenic and neural reflexes, baroreceptor stimulation, activation of sympathetic nervous and renin angiotensin aldosterone systems, and enhanced proinflammatory pathways. Most clinical trials have addressed the underlying condition rather than venous hypertension per se. Interpreting the effects of therapeutic interventions on renal venous congestion are therefore problematic because of such confounders as changes in left ventricular function, cardiac output, and blood pressure. Nevertheless, there is preliminary evidence from small studies of intense medical therapy or extracorporeal ultrafiltration for heart failure that there can be changes to central venous pressure that correlate inversely with renal function, independently from the cardiac index. Larger more rigorous trials are needed to definitively establish under what circumstances conventional pharmacologic or ultrafiltration goals might best be directed toward central venous pressures rather than left ventricular or cardiac output parameters.     

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.     

Cardiorenal syndrome: A literature review

The incidence of cardiorenal syndrome is increasing; however, its pathophysiology and effective management are still not well understood. For many years, diuretics have been the mainstay of treatment for cardiorenal syndrome, although a significant proportion of patients develop resistance to diuretics and even deteriorate while on diuretics. Trials on different ways to counteract diuretic resistance and newer treatment modalities, such as nesiritide, arginine vasopressin receptor antagonists, adenosine receptor antagonists and ultrafiltration, have shown promising results.     

Renal dysfunction in acute congestive heart failure: a common problem for cardiologists and nephrologists

The term acute heart failure (AHF) refers to a clinical syndrome with typical symptoms and signs, in which a structural or functional heart abnormality leads to defective oxygen delivery. The term cardiorenal syndrome has been proposed to outline the strict interplay between cardiac and renal function. In the setting of acute cardiac decompensation, acute kidney injury (AKI) is generally referred to as cardiorenal syndrome type 1. In this review, we summarize the fundamental pathophysiological aspects of both AHF and AHF-related AKI. We also review the latest therapeutic options, including both pharmacological ones, such as loop diuretics, potassium-sparing diuretics and vaptans, and non-pharmacological ones, such as ultrafiltration, and their impact on patients’ outcome. We discuss the pathophysiology of diuretic resistance, a common occurrence in these patients, reviewing the available strategies to treat it and highlighting how a close collaboration between cardiologists and nephrologists is frequently crucial for the management of this complication. Finally, we discuss three new promising non-pharmacological tools for the prevention of AHF recurrence, including two methods that exploit sympathetic denervation and one technique that acts by increasing vagal tone.     

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.     

The progressive cardiorenal syndrome in heart failure: Mechanisms and therapeutic insights

The cardiorenal syndrome refers to the interdependence of cardiocirculatory aberrations and renal dysfunction that signify a worsening in heart failure outcome. Biochemically, it appears covertly as an abnormality in renal function and when progressive, is manifested by symptom exacerbation and worsening renal impairment during application of therapy to ameliorate such symptoms. The pathways leading to these distinct impairments involve not only hemodynamic deterioration but also neurohormonal, inflammatory, and intrinsic renal mechanisms that produce this syndrome. Traditional therapy with diuretics typically worsens the cardiorenal syndrome, and vasodilator or inotropic therapy has not been shown to help either. New therapeutic avenues involving vasopressin antagonists, adenosine antagonists, and ultrafiltration are being investigated. In the absence of underlying primary renal parenchymal disease, mechanical ventricular assist devices or cardiac transplantation achieve reversal of the progressive cardiorenal syndrome, indicating the sentinel role of interrupting the cardiocirculatory aberrations that accompany this clinical manifestation.     

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.     

Congestion as a Therapeutic Target in Acute Heart Failure Syndromes

This review begins by discussing the importance of clinical congestion as the dominant presenting manifestation of acute heart failure syndromes (AHFS). The pathophysiology of the cardiorenal syndrome is reviewed, including its relationship to the use of current therapy, that is, loop diuretics. The review then summarizes results from recent clinical trials evaluating therapy for AHFS, with a focus on those studies investigating ultrafiltration and vasopressin antagonists, and also, but more briefly, vasodilators and inotropic agents. Possible reasons for the success and failure of various therapeutic strategies directed at the congested state are discussed. The review concludes with recommendations for possible new strategies and specific investigations designed to benefit from the lessons learned from both the recent successful trials and the more numerous failures.     

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.