REWORD-HF REverse WOrsening Renal Function in Decompensated Heart Failure

Study Overview
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Brief Summary
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The purpose of this study is to determine whether in patients with acute decompensated congestive heart failure and the cardiorenal syndrome, i.e. a state in which therapy directed to improve symptoms is limited by further worsening renal function, fluid removal by ultrafiltration is superior to different pharmacological approaches in acutely relieving congestion and preventing further deterioration in renal function and whether it results in longer admission-free survival 90 days after enrolment

Detailed Description
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Acute decompensated congestive heart failure (ADCHF), the most common single cause of hospitalization over 65 years, results in 4-8% in-hospital mortality and 30-38% incidence of readmissions within 3 months after discharge. While fluid accumulation remains the main factor causing hospitalization, impaired cardiac output in ADHF causes renal arterial underfilling and increased venous pressure, reducing the glomerular filtration rate and causing acute kidney injury. Aggressive therapy is required to alleviate volume overload during hospital admission and achievement of a dry weight is capital in preventing rehospitalisation. Currently diuretics are considered the standard of care for volume overload in ADHF, yet any patients, especially those with advanced HF become soon resistant to standard doses of loop diuretics, so escalating doses and the association of thiazides are often required to achieve effective diuresis, an approach that will progressively worsen renal function, causing the cardiorenal syndrome. When diuretic resistance develops and symptoms persists, mechanical fluid removal via ultrafiltration should be considered. Ultrafiltration is an alternative method of sodium and water removal, that filters plasma water directly across a semipermeable membrane in response to a transmembrane pressure gradient, resulting in an ultrafiltrate that is isoosmotic compared with plasma water, In view of the limits of traditional therapies for the treatment of congestion and concomitant progressive renal dysfunction in ADHF patients, there is a compelling need for additional studies to individuate the better method for fluid removal in volume-overloaded patients and guide management decisions to reduce associated morbidity. The main objectives of the present project are to evaluate whether in patients with acute decompensated congestive heart failure and the cardiorenal syndrome, i.e. a state in which therapy directed to improve CHF symptoms is limited by further worsening renal function, fluid removal by ultrafiltration is superior to different pharmacological approaches in acutely relieving congestion and preventing further deterioration in renal function and whether it results in longer admission-free survival 90 days after enrolment

Official Title
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Impact of Different Therapeutic Approaches in Patients With Cardiorenal Syndrome in the Setting of Acute Decompensated Congestive Heart Failure (ADCHF)

Conditions
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Acute Decompensated Heart Failure

Intervention / Treatment
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* Drug: Furosemide or Furosemide and Dopamine
* Device: Ultrafiltration


Participation Criteria
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Eligibility Criteria
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Inclusion criteria On admission (screening) Informed consent Age 18-80 years NYHA class III - IV Signs of pulmonary (pulmonary rales, and interstitial oedema or pleural effusion on chest Xray) and/or systemic congestion (pitting ankle oedema and enlarged liver or ascites and neck vein distension ≥ 7 cm) and weight gain ≥ 2 kg during the previous week Glomerular filtration rate ≥ 30 ml/min BNP increased >400 pg/ml (diagnostic cut-off for ADCHF), as confirmatory diagnostic test) 24 hours after admission (randomization) Persistent signs of pulmonary (pulmonary rales, interstitial oedema or pleural effusion on chest Xray) and/or systemic congestion (ankle oedema, enlarged liver or ascites, neck vein distension ≥ 7 cm) Serum creatinine or urine output criteria indicative of modified RIFLE (AKI: risk) class at least 1 (increase x 1.5 in serum creatinine or decrease > 25% in GFR or urine output < 0.5 ml/Kg/h for more than 6 hours) 29-30 during diuretic infusion Exclusion criteria Chronic kidney disease stage 4-5 (GFR < 30 ml/min) Acute coronary syndromes Systolic blood pressure <90 mm Hg/need for intravenous inotropes Hematocrit > 45% Unattainable venous access Contraindications to anticoagulation by heparin Systemic infection Heart transplant

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Infusional drug treatment<br>Diuretics or diuretics plus fixed low dose dopamine infusion | Drug: Furosemide or Furosemide and Dopamine<br>* Patients randomized to pharmacological treatment receive either intravenous diuretics at escalating doses up to 20 mg/h or intravenous diuretics up to 20 mg/h and dopamine infusion at a constant rate of 3 mcg/Kg/m.<br>|
| Experimental: Ultrafiltration<br>Device: Ultrafiltration appliance Sessions of 8 h UF are conducted on 2 subsequent days in the first 48 hours after randomization; a third session is performed on day 3 in case of persistent congestion | Device: Ultrafiltration<br>* All loop diuretics will be discontinued. Rate of fluid removal will be based on the extent of fluid overload as assessed by increase in body weight vs the patient's known dry weight less than 3 kg 200 ml/h more than 3 kg and less than 5 kg 300 mlh more than 5 kg 500 mlh Criteria for achievement of target UF goals are removal of > 50% and <70% of fluid excess based on the estimated increase in body weight Diuretic infusion is allowed provided that a minimum of 3 hours after the end of the UF session have elapsed, at a maximum cumulative dose of 100 mg furosemide, till start of the next UF session The use of inotropic agents is prohibited<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in a composite clinical-lab score | Changes in a score derived by summing up changes in dyspnea, weight loss, glomerular filtration rate (GFR), brain natriuretic peptide (BNP) | Baseline and 96 h after randomization,precisely:48 h after end of the last UF session in the intervention arm;24 h after end of 72 h infusional drug treatment in the control arm | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in the dyspnea Likert scale |  | Measured at day 4, at day 10, at day 90 vs baseline | 
| Changes in modified RIFLE (AKIN) stage |  | Measured at day 4 vs baseline | 
| Length of stay during index admission |  | Measured at average day 10 | 
| Occurrence of major adverse events | All cause mortality, hospital readmission and unscheduled office and emergency department visits for ADCHF | Measured at day 90 | 
| Days spent alive and out of hospital (DAOH) within 90 days | Sum of days spent alive and out of hospital | Measured at day 90 | 
| BNP changes | Changes in BNP at specified times VS baseline | Measured at day 0, at day 4, at 10 and day 90 | 
| Changes in neutrophil gelatinase associated lipocalin (NGAL) | Changes in NGAL at specified times VS screening | Measured at day -1, at day 0 and day 4 | 
| Changes in Cystatin C (CysC) | Changes in Cystatin C (CysC) at specified times VS baseline | Measured at day 0, day 4, day 10 and day 90 | 
| Treatment-related adverse events | Bleeding, thrombosis, clotting, infection | Measured at day 4 | 
| Adverse changes in blood pressure, heart rate and rhythm | Hypotension (< 90 mmHg), tachycardia (> 110 bpm) arrhythmias | Measured at day 4 | 
| Adverse changes in lab parameters | Hyper-Azotemia (>180 mg/dl), hyper-kaliemia (6.5 mEq/l), hemoconcentration (hematocrit >45%) | Measured at day 4 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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1 Acute Decompensated Heart Failure, 2 Cardiorenal Syndrome, 3 Ultrafiltration, 4 Dopamine