Investigating a Tailored Diuretic Algorithm in Acute Heart Failure Patients

Study Overview
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Brief Summary
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Acutely decompensated heart failure (ADHF) is highly prevalent and has a high (financial) burden on the health care system. Treatment often consists of the administration of IV decongestive agents. Adequate dosing is difficult due to varying diuretic resistance and inadequate parameters to evaluate the response. Urine sodium is a promising biomarker to evaluate the diuretic response. It is hypothesized that a tailored, urine sodium guided diuretic algorithm will result in faster and more complete decongestion and therefore lead to better survival (in terms of mortality and heart failure events) while being non-inferior in terms of safety (mainly regression of kidney function).

Detailed Description
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Rationale: Acutely decompensated heart failure is a highly prevalent diagnosis with a high burden on resources and a high risk of mortality and re-hospitalization. The prescription of diuretics to relieve congestion has been the cornerstone of treatment for years, but evidence about diuretic response and adequate dosing is still lacking. Inadequate diuretic response (and insufficient decongestion) has a negative influence on outcome but is often not timely addressed. Urinary sodium (Ur-Na) is a promising biomarker in the prediction of diuretic response to the prescribed dose. It is hypothesized that an Ur-Na based, intensified algorithm can help tailor diuretics in an individual way, but sufficient evidence to support its implementation is lacking. Objective: Investigate if a tailored diuretic algorithm based on Ur-Na has a positive effect on a primary endpoint of reduction in a combined endpoint of death, heart failure events and change in the Kansas City questionnaire total symptom score (KCCQ-TSS) versus standard clinical care in patients hospitalized with AHF, without imposing safety concerns (e.g. worsening renal function). Study design: Prospective, Single-Blinded, Randomized, Blinded-endpoint trial Study population: Patients admitted with acutely decompensated heart failure (diagnosed according to the 2021 ESC (European Society of Cardiology) guidelines) who are 18 year or older. Intervention: Arm I: Tailored, Ur-Na based, intensified diuretic strategy; Arm II: Usual care Main study parameters/endpoints: Hierarchical composite endpoint of all-cause death, heart failure events and a 4-point or greater difference in Kansas City questionnaire total symptom score (KCCQ-TSS); assessed using a win-ratio approach.

Official Title
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TAILOR-AHF: Randomized Trial Investigating a Tailored Diuretic Algorithm in Acute Heart Failure Patients

Conditions
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Heart Failure Acute

Intervention / Treatment
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* Other: Urine sodium guided diuretic algorithm
* Other: Usual care


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age > 18 years; HF (HFrEF, HFmrEF or HFpEF) diagnosed according to the 2021 HF Guidelines of the European Society of Cardiology [5]; Presentation with AHF meaning at least one symptom (dyspnea, orthopnea, or edema) and one sign (rales, peripheral edema, ascites, or pulmonary vascular congestion on chest radiography) of AHF; An elevated NT-proBNP >300pg/ml; Requiring the need for iv diuretics. Exclusion Criteria: Terminal renal insufficiency defined as: dialysis patients or eGFR (estimated glomerular filtration rate) < 10 mL/min/1.73 m2; Patients included in other investigational studies regarding heart failure. Presentation with cardiogenic shock or respiratory insufficiency or another reason requiring admission to the intensive care unit upon admission (IC transfer later in the hospitalization is not an exclusion).

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tailored, Urine sodium guided, intensified diuretic strategy<br> | Other: Urine sodium guided diuretic algorithm<br>* Loop diuretics are administered intravenously as soon as possible after diagnosis of ADHF and continued 3dd until recompensation. Spot urine sodium is measured 2 hours after administration of the first in-hospital IV diuretic dose and repeated until the target of 100mmol/L is reached in the first 72 hours of admission (after which, UrNa will be measured once daily). When target is not met, the next dosage of loop diuretic is doubled (max 3dd 250mg furosemide) and thereafter, other diuretics (thiazide, MRA) are added. Acetazolamide in the first 72 hours is advised as background therapy in both treatment arms.<br>|
| Active Comparator: Usual care<br> | Other: Usual care<br>* Treatment with IV loop diuretics left to the discretion of the treating physician. Acetazolamide in the first 72 hours is advised as background therapy in both treatment arms.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hierarchical composite of all-cause mortality, heart failure events and delta quality of life at 90 days follow-up. | The primary endpoint is a hierarchical composite calculated using a win-ratio approach of: i) Mortality (all-cause) at 90 days after hospitalization; ii) Heart failure events at 90 days after hospitalization (1. a >2 times increase in oral loop diuretic dose, 2. the need for iv administration of loop diuretics, 3. an emergency department visit or hospitalization for HF), wherein a single event or hospitalization will be sufficient to reach the combined endpoint; iii) Delta in quality of life measured using the Kansas City Cardiomyopathy Questionnaire total symptom score (KCCQ-TSS) from baseline to 90 days after hospitalization | 90 days after inclusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Delta NT-pro BNP | Delta NT-proBNP from admission to discharge and 90-days follow up | From admission to discharge and 90 days after hospitalisation | 
| Successful decongestion | Number of participants with successful decongestion (defined as a clinical congestion score of 2 or less and NYHA I-II) | Day 3 after inclusion | 
| Change in clinical congestion score | Change in clinical congestion score from admission to discharge | From date of randomization until date of hospital discharge (regarding initial hospitalisation at time of randomisation, assessed up to 90 days), | 
| Quality of life (Kansas City Cardiomyopathy Questionnaire) | Quality of life assessed using the Kansas City Cardiomyopathy Questionnaire | 90 days after inclusion | 
| Adverse (safety) events | All-cause readmissions at 90-days, all-cause and cardiovascular mortality at 90-days, (symptomatic) hypotension, hypokalemia, urinary tract infection, phlebitis, atrial fibrillation, fall/trauma and decompensated HF | 90 days after inclusion | 
| All-cause mortality and heart failure readmissions | All-cause mortality and heart failure readmissions at 14 days follow up | 14 days after inclusion | 
| Chronic dialysis | Occurence of the need for chronic dialysis at 90-days follow up | 90 days after inclusion | 
| Days alive outside the hospital | Days alive outside the hospital at 90-days follow up | 90 days after inclusion | 
| Time to first heart failure hospitalization and number of heart failure hospitalizations | Time to first heart failure hospitalization and number of heart failure hospitalizations | 90 days after inclusion | 
| Number of outpatient visits | Number of outpatient visits in the first 90 days | 90 days after inclusion | 
| Number of worsening heart failure events | Number of worsening heart failure events at 90 days: i) a >2 times increase in oral loop diuretic dose, ii) the need for iv administration of loop diuretics, iii) an emergency department visit or hospitalization for HF | 90 days after inclusion | 
| Delta weight | Delta weight (in kilograms) from admission to discharge | From date of randomization until date of hospital discharge (regarding initial hospitalisation at time of randomisation, assessed up to 90 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Decongestion, Heart failure, Natriuresis, Urinary Sodium