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

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

Study Overview

• Status: Completed
• Conditions: Heart Failure
• Intervention / Treatment: Drug: CA125 guided strategy; Drug: CA125 guided strategy; Drug: Conventional Strategy

• Study Type: Interventional
• Enrollment (Actual): 170
• Phase: Phase 4

Contacts and Locations

Study Locations

• Spain
  • Valencia, Spain, 46010
    • Hospital Clínico Universitario de Valencia

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Patients with the diagnosis of acute heart failure (AHF) and the concurrence of the following conditions:

1. 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).
2. Elevated natriuretic peptide (NT-proBNP> 1000 pg/ml or BNP> 100 mg/dl).
3. Creatinine ≥1,4 mg/dl on admission, provided that the estimated glomerular filtration rate less than 60 ml / min / m2.
4. Intent to be treated with loop diuretics intravenously.

Exclusion Criteria:

1. Life expectancy less than 6 months of life due to other comorbid conditions.
2. Cardiogenic shock.
3. Diagnosis of acute coronary syndrome in the previous 30 days.
4. Pregnancy at the time of inclusion.
5. Restrictive or Obstructive pulmonary disease or severe degree.
6. Chronic renal insufficiency in stage V (estimated glomerular filtration rate <15 ml / min / m2) or patient previously included in known dialysis program.
7. Participation in another clinical trial randomized at the time of inclusion.
8. Temperature ≥38 ° C or diagnosis of pneumonia.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: SINGLE

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Fundación para la Investigación del Hospital Clínico de Valencia
• Investigators: Principal Investigator: Julio Nuñez, MD, PhD, Fundación para la Investigación del Hospital Clínico de Valencia

Publications and helpful links

General Publications

• de la Espriella R, Nunez E, Llacer P, Garcia-Blas S, Ventura S, Nunez JM, Sanchez R, Facila L, Vaquer JM, Bodi V, Santas E, Minana G, Mollar A, Nunez G, Chorro FJ, Gorriz JL, Sanchis J, Bayes-Genis A, Nunez J. Early urinary sodium trajectory and risk of adverse outcomes in acute heart failure and renal dysfunction. Rev Esp Cardiol (Engl Ed). 2021 Jul;74(7):616-623. doi: 10.1016/j.rec.2020.06.004. Epub 2020 Jul 2. English, Spanish.

Study record dates

Study Major Dates

• Study Start (ACTUAL): January 1, 2015
• Primary Completion (ACTUAL): January 30, 2017
• Study Completion (ACTUAL): January 30, 2017

Study Registration Dates

• First Submitted: December 14, 2015
• First Submitted That Met QC Criteria: December 28, 2015
• First Posted (ESTIMATE): December 31, 2015

Study Record Updates

• Last Update Posted (ACTUAL): February 13, 2018
• Last Update Submitted That Met QC Criteria: February 11, 2018
• Last Verified: February 1, 2018

More Information

Terms related to this study

• Keywords: Heart Failure; Renal Failure; Loop diuretics; Biomarker guided-therapy; Carbohydrate antigen 125
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Kidney Diseases; Urologic Diseases; Heart Failure; Renal Insufficiency; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Natriuretic Agents; Membrane Transport Modulators; Furosemide; Diuretics; Sodium Potassium Chloride Symporter Inhibitors
• Other Study ID Numbers: 2014-001433-83