Loop Diuretic Dosage in Patients With Acute Heart Failure and Renal Failure: Conventional Versus Carbohydrate Antigen 125-guided Therapy (IMPROVE-HF)

Study Overview
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Brief Summary
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Worsening renal function (WRF) is a frequent finding in patients with decompensated acute heart failure (AHF) and it is associated to increased length of hospitalization and higher morbidity and mortality. Traditionally, WRF in AHF setting has been attributed to low cardiac output, but recent evidence also suggests venous congestion play a crucial role. Loop diuretics are the mainstay treatment of AHF, but their use traditionally has been associated to WRF, but also renal function improvement in patients with unequivocal signs of congestion. Nevertheless, traditional symptoms or signs of patients with AHF have shown a limited accuracy to neither identify nor quantify the degree of venous congestion. Recent authors have reported that plasma levels of antigen carbohydrate 125 (CA125) are closely related to the degree of venous congestion. The investigators hypothesize that CA125 may have a role for identifying the hyperhydrated (High CA125) patients that need high loop diuretic doses, and those with normal CA125 values needing low loop diuretic doses. In this randomized study (1:1) the investigators seek to evaluate whether a CA125 loop diuretic guided management therapy is superior to a standard strategy. The primary endpoint is the magnitude of changes of renal function at 24 and 72 hours after initiation of intravenous diuretic in an acute worsening of heart failure

Official Title
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Loop Diuretic Dosage in Patients With Acute Heart Failure and Renal Failure: Conventional Versus Carbohydrate Antigen 125-guided Therapy (IMPROVE-HF)

Conditions
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Heart Failure

Intervention / Treatment
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* Drug: CA125 guided strategy
* Drug: CA125 guided strategy
* Drug: Conventional Strategy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with the diagnosis of acute heart failure (AHF) and the concurrence of the following conditions: Presence of symptoms (dyspnea at rest or minimal exertion) and signs attributable to congestion (signs of congestion on chest radiography, or presence of peripheral edema or ascites, or jugular venous distension at 45 degrees or presence of crackles on auscultation). Elevated natriuretic peptide (NT-proBNP> 1000 pg/ml or BNP> 100 mg/dl). Creatinine ≥1,4 mg/dl on admission, provided that the estimated glomerular filtration rate less than 60 ml / min / m2. Intent to be treated with loop diuretics intravenously. Exclusion Criteria: Life expectancy less than 6 months of life due to other comorbid conditions. Cardiogenic shock. Diagnosis of acute coronary syndrome in the previous 30 days. Pregnancy at the time of inclusion. Restrictive or Obstructive pulmonary disease or severe degree. Chronic renal insufficiency in stage V (estimated glomerular filtration rate <15 ml / min / m2) or patient previously included in known dialysis program. Participation in another clinical trial randomized at the time of inclusion. Temperature ≥38 ° C or diagnosis of pneumonia.

Ages Eligible for Study
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Minimum Age: 18 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: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CA125 guided strategy<br>In this group loop diuretic (Furosemide) dosage will be guided by Carbohydrate Antigen 125 (CA125) plasma levels | Drug: CA125 guided strategy<br>* Initial dose of intravenous furosemide ≤80 mg / day regardless of prior dose of loop diuretics who were receiving.<br>* Other names: Loop diuretic (Furosemide) dosage in CA125 ≤35 U/ml patients;Drug: CA125 guided strategy<br>* Initial dose of intravenous furosemide ≥120 mg/day or 2.5 times the dose the patient was taking at home.<br>* Other names: Loop diuretic dosage (Furosemide) in CA125 >35 U/ml patients;|
| Active Comparator: Conventional strategy<br>Standard treatment strategy Therapy is based on established european guidelines | Drug: Conventional Strategy<br>* The dosage of loop diuretics is done according to the presence of symptoms and signs of systemic congestion and current recommendations<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in renal function (GFR) | Glomerular filtration rate (GFR) estimated by MDRD. Prespecified interim analysis of primary outcome will be made by protocol when first 100 patients are included. | 24 and 72 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Improvement in signs and symptoms of heart failure (NYHA) | Evaluation of dyspnea (changes in the functional class of the New York Heart Association -NYHA) | 24 and 72 hours | 
| Improvement in signs and symptoms of heart failure (VAS) | Evaluation of signs of systemic congestion, and patient global assessment (by visual analogue scale -VAS-) | 24 and 72 hours | 
| Changes in plasma levels of natriuretic peptide (NT-proBNP) |  | 72 hours | 
| Changes in plasma levels of high sensitive troponin |  | 72 hours | 
| Time required to change intravenous diuretics to oral administration. |  | Through study completion (30-day follow-up) | 
| Composite of all-cause mortality plus acute heart failure related rehospitalization | Number of events in each group during 30-day follow-up | 30 days | 
| Change in renal function (creatinin) | Serum levels of creatinine | 24 h, 72 h and 30 days | 
| Change in renal function (urea) | Serum levels of urea | 24 h, 72 h and 30 days | 
| Change in renal function (cystatin C) | Serum levels of Cystatin C | 24 h, 72 h and 30 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Heart Failure, Renal Failure, Biomarker guided-therapy, Loop diuretics, Carbohydrate antigen 125