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.     

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.     

The Effects of Adenosine A1 Receptor Antagonism in Patients With Acute Decompensated Heart Failure and Worsening Renal Function: The REACH UP Study

BackgroundWorsening renal function (WRF) portends a poor prognosis, and recent deterioration in creatinine might identify patients with elevated intrarenal adenosine in whom adenosine A₁ antagonism may improve renal hemodynamics and function. The purpose of this pilot study was to assess whether rolofylline, an adenosine A₁ antagonist (A₁RA), would facilitate diuresis while maintaining renal function in patients with acutely decompensated heart failure (ADHF) and recent WRF.Methods and ResultsSeventy-six patients with ADHF, volume overload, and recent renal deterioration received rolofylline (30 mg, n = 36) or placebo (n = 40) for 3 days. Rolofylline did not demonstrate a beneficial effect on the primary end points of worsening heart failure or renal function after admission or death or readmission within 30 days. Similar proportions of patients receiving rolofylline (33%) and placebo (30%) were treatment failures within 30 days. However, persistent renal impairment (through Day 14) tended to be less common with rolofylline (6%) than placebo (18%). At Day 14, 11 patients receiving placebo and 13 patients receiving rolofylline had a decrease in creatinine ≥0.3 mg/dL. There were fewer heart failure readmissions with rolofylline (n = 2) than with placebo (n = 7) through Day 60.ConclusionsThe Placebo-Controlled Study of the Effects of KW-3902 Injectable Emulsion on Heart Failure Signs and Symptoms, Diuresis, Renal Function, and Clinical Outcomes in Subjects Hospitalized with Worsening Renal Function and Heart Failure Requiring Intravenous Therapy (ie, REACH UP) study did not demonstrate any clear benefit of rolofylline in patients with ADHF and worsening renal function. However, beneficial trends raise the possibility that A₁RAs might prevent renal dysfunction in these high risk patients. To test this hypothesis, further larger studies need to evaluate the effects of adenosine A₁ antagonists in patients with progressive renal dysfunction in the face of active heart failure therapy.     

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.     

Cardiorenal Syndrome and the Role of Ultrafiltration in Heart Failure

Acute decompensated heart failure (ADHF) with associated volume overload is the most common cause of hospitalization in heart failure patients. When accompanied by worsening renal function, it is described as a cardiorenal syndrome and is a therapeutic challenge. Initial treatment commonly encompasses intravenous diuretics however, suboptimal results and high rehospitalization rates have led experts to search for alternative therapeutic strategies. Recent technological advances in extracorporeal therapies have made ultrafiltration a feasible option for treatment of hypervolemia in ADHF. Recent large randomized trials have compared the efficacy and safety of ultrafiltration with diuretics. Additionally, the benefits of novel pharmacologic approaches, including combining hypertonic saline with diuretics, have recently been studied. The aim of this review is to discuss the developments in both pharmacologic and extracorporeal methods for treating hypervolemia in ADHF and acute cardiorenal syndrome.     

Rationale and design of the multicenter, randomized, double-blind, placebo-controlled study to evaluate the Efficacy of Vasopressin antagonism in Heart Failure: Outcome Study with Tolvaptan (EVEREST)

BACKGROUND: Hospitalizations for worsening heart failure due to fluid overload (congestion) are common. Agents that treat congestion without causing electrolyte abnormalities or worsening renal function are needed. Tolvaptan is an oral vasopressin (V 2 ) antagonist that decreases body weight and increases urine volume without inducing renal dysfunction or hypokalemia. The Efficacy of Vasopressin antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) trial is evaluating mortality, morbidity, and patient-assessed global clinical status in patients treated with tolvaptan compared with standard care. METHODS AND RESULTS: Patients are eligible for inclusion if they have a reduced left ventricular ejection fraction and are hospitalized for worsening heart failure with evidence of systemic congestion. Patients are randomized 1:1 to tolvaptan 30 mg/day or matching placebo for a minimum of 60 days. Time to all-cause mortality and time to cardiovascular mortality or heart failure hospitalization are the coprimary end points. Patient-assessed global clinical status and quality of life are also evaluated. EVEREST will be continued until 1065 deaths occur. As of April 18, 2005, 2260 patients have been enrolled. CONCLUSION: Tolvaptan has been shown to reduce body weight in patients with worsening heart failure without inducing renal dysfunction or causing hypokalemia. The results of EVEREST will determine whether these effects translate into improved clinical outcomes.     

Managing acute renal failure in patients with acute decompensated heart failure: The cardiorenal syndrome

In patients with acute decompensated heart failure, worsening renal function during conventional decongestive therapy (cardiorenal syndrome) affects prognosis and the initiation of therapies with known benefit in chronic heart failure. Potential strategies for decongestion in patients who develop cardiorenal syndrome include invasive hemodynamic monitoring to guide therapy, use of continuous diuretic infusions, ultrafiltration, or novel therapy with adenosine or vasopressin receptor antagonists. Clinical trials by the National Heart, Lung, and Blood Institute’s Heart Failure Network are currently underway to validate such therapies in patients with acute decompensated heart failure with worsening renal function and to establish novel biomarkers for the early identification of patients who develop 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.     

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.     

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.     

Higher Diuretic Requirements in Acute Heart Failure With Admission Hyponatraemia Versus Normonatraemia

BackgroundDiuretic requirements in patients with acute decompensated heart failure (ADHF) and hyponatraemia versus normonatraemia on admission has not been previously explored.MethodsThe Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) trial dataset was utilised to examine the characteristics and diuretic requirements of patients with ADHF with hyponatraemia or normonatraemia on admission.ResultsPatients with ADHF and admission hyponatraemia (n = 103, average Na 130.2 meq/L) had a higher degree of congestion evident in higher frequency of jugular venous distension (JVD) >12 cmH₂O (p = 0.007), 2+ lower extremity oedema (p = 0.001), and higher right atrial pressure (p = 0.007), compared with normonatraemic patients (n = 327, average Na 138.6 meq/L). Despite a similar baseline furosemide dose in both groups (median 200 mg), the hyponatraemia group received higher in-hospital furosemide (280 vs. 200 mg, in both groups, respectively, p < 0.001) which represented a higher percentage of furosemide utilisation relative to baseline, compared with the normonatraemia group (33% vs 0%, in both groups respectively, p = 0.007). With in-hospital diuresis, the Na level of hyponatraemic subjects started significantly increasing at discharge and up to 6 months after randomisation—all relative to baseline. Hyponatraemic patients had significantly lower systolic blood pressure (SBP) longitudinally at multiple time points compared with normonataremic patients, but it did not further decrease despite the higher furosemide dose in the former group.ConclusionPatients with ADHF and hyponatraemia on admission had a higher degree of congestion and required higher doses of furosemide, compared with normonatraemic subjects. The lower Na and SBP in this instance should not lead to withholding or minimising diuretic dosage which should rather be dictated by volume status.     

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.     

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.     

Clinical Effectiveness of Tolvaptan in Patients with Acute Decompensated Heart Failure and Renal Failure: Design and Rationale of the AQUAMARINE Study

Purpose

Over half of all admitted acute decompensated heart failure (ADHF) patients have renal failure. Although diuretics represent the mainstay of treatment strategy even in this population, there are unmet needs for safer and more effective treatment. Tolvaptan is a vasopressin-2 receptor antagonist, and we hypothesized that adding tolvaptan to standard diuretic therapy would be more effective in ADHF patients with renal function impairment.

Methods

The Answering question on tolvaptan’s efficacy for patients with acute decompensated heart failure and renal failure (AQUAMARINE) is a multicenter, randomized controlled clinical trial, which will enroll 220 patients from 17 hospitals in Japan. ADHF patients whose estimated glomerular filtration rate is above 15 and below 60 mL/min/1.72 m² will be randomly assigned within 6 h after admission to usual care with furosemide or tolvaptan add-on therapy. Primary endpoint is achieved urine output within 48 h. Secondary endpoints include dyspnea relief measured by 7-points Likert scale, incidence of worsening renal function, dose of furosemide used within 48 h, and changes of brain natriuretic peptide.

Conclusion

This study is the first multicenter study in Japan to evaluate clinical effectiveness of tolvaptan add-on therapy in ADHF patients with renal failure. The results of this study address the treatment strategy of this high-risk population (UMIN Clinical Trial Registry Number: UMIN000007109).     

Early ultrafiltration in patients with decompensated heart failure and diuretic resistance.

OBJECTIVES: We sought to determine if ultrafiltration before intravenous (IV) diuretics in patients with decompensated heart failure and diuretic resistance results in euvolemia and early discharge without hypotension or worsening renal function. BACKGROUND: Heart failure patients with renal insufficiency and diuretic resistance have increased hospital mortality and length of stay. Peripheral veno-venous ultrafiltration may re-establish euvolemia and diuretic responsiveness. METHODS: Ultrafiltration was initiated within 4.7 +/- 3.5 h of hospitalization and before IV diuretics in 20 heart failure patients with volume overload and diuretic resistance (age 74.5 +/- 8.2 years; 75% ischemic disease; ejection fraction 31 +/- 15%) and continued until euvolemia. Re-evaluation was each hospital day, at 30 days, and at 90 days. RESULTS: A total of 8,654 +/- 4,205 ml were removed with ultrafiltration. Twelve patients (60%) were discharged in < or =3 days. One patient was readmitted in 30 days. Weight (p = 0.006), Minnesota Living with Heart Failure scores (p = 0.003), and Global Assessment (p = 0.00003) improved after ultrafiltration and at 30 and 90 days. Median B-type natriuretic peptide levels decreased after ultrafiltration (from 1,230 pg/ml to 788 pg/ml) and at 30 days (815 pg/ml) (p = 0.035). Blood pressure, renal function, and medications were unchanged. CONCLUSIONS: In heart failure patients with volume overload and diuretic resistance, ultrafiltration before IV diuretics effectively and safely decreases length of stay and readmissions. Clinical benefits persist at three months.     

Change in intrathoracic impedance measures during acute decompensated heart failure admission: results from the Diagnostic Data for Discharge in Heart Failure Patients (3D-HF) Pilot Study

BackgroundDespite the high number of admissions for acute decompensated heart failure (ADHF), there are no specific criteria for discharge readiness. A number of patients have implantable devices that might provide data to assist in determining readiness for discharge.Methods and ResultsThe 3D-HF (Diagnostic Data for Discharge in Heart Failure Patients) study was a prospective observational pilot study enrolling HF patients with Optivol-capable cardiac devices within 48 hours of a hospital admission characterized by worsening HF symptoms. The primary end point was the difference in times from admission to 50% improvement in impedance and to when patient was medically ready for discharge. The nonparametric sign test was used to determine if the difference was significant. A total of 20 subjects were enrolled over a 24-month period. The median ADHF length of stay was 7 days. Of the 20 subjects, 18 achieved the intrathoracic impedance improvement threshold before discharge. The time to reach the threshold for improvement was 2.5 days (interquartile range 2.0–6.0). The difference between days to 50% impedance and days to provider’s discharge decision was 3.0 (P = .0072).ConclusionsIntrathoracic impedance changes were evident over a short duration in the majority of patients admitted for ADHF and may be a potential criterion for discharge readiness.     

Overview of acutely decompensated congestive heart failure (ADHF): a report from the ADHERE registry

Acute decompensated heart failure (ADHF) has emerged as a major public health problem, and HF has become the leading cause of hospitalization in persons over 65 years of age. It is estimated that there are 6.5 million hospital days attributed to ADHF each year. Patients hospitalized with ADHF face a substantial risk of readmission, as high as 50% by 6 months after discharge. Despite the large number of patients hospitalized and this substantial risk, data on these patients have been limited and there has been little effort to improve the quality of care for patients hospitalized with ADHF. The Acute Decompensated Heart Failure National Registry (ADHERE) was designed to bridge this gap in knowledge and care by prospectively studying the characteristics, management, and outcomes of a broad spectrum of patients hospitalized with ADHF. Participating community and university hospitals identified patients with a primary or secondary discharge diagnosis of HF and collected medical history, management, treatments, and health outcomes via secure Web browser technology. As of October 2004, more than 160,000 patients from 281 hospitals have been enrolled. These patients differ substantially from those typically enrolled in randomized clinical trials. Initial data from the ADHERE registry have provided important insights into the clinical characteristics, patterns of care, and outcomes of patients with ADHF. ADHERE has documented significant delays in diagnosis and initiation of ADHF therapies as well as a substantial under-use of evidenced-based, guideline-recommended chronic HF therapies at hospital discharge. As such, there are substantial opportunities to improve the quality of care for ADHF patients in the nation's hospitals.