Safety and Efficacy of the Combination of Loop With Thiazide-type Diuretics in Patients With Decompensated Heart Failure

Study Overview
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Brief Summary
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The purpose of this study is to determine whether a combined diuretic therapy (loop diuretics with thiazide-type diuretics) is more effective (in terms of improving fluid overload symptoms) among patients with decompensated heart failure in comparison with loop diuretic alone.

Detailed Description
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Volume overload is an important clinical target in heart failure management, typically addressed using loop diuretics. An important and challenging subset of heart failure patients exhibit fluid overload despite significant doses of loop diuretics. One approach to overcome loop diuretic resistance is the addition of a thiazide-type diuretic to produce diuretic synergy via sequential nephron blockade, first described more than 40 years ago. Although potentially able to induce diuresis in patients otherwise resistant to high doses of loop diuretics, this strategy has not been subjected to large-scale clinical trials to establish safety and clinical efficacy. Combination diuretic therapy using any of several thiazide-type diuretics can more than double daily urine sodium excretion to induce weight loss and edema resolution. To our knowledge there are no clinical trials designed to prove the efficacy and safety of combined diuretic therapy (a commonly used therapy) among patients with decompensated heart failure.

Official Title
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Safety and Efficacy of the Combination of Loop Diuretics With Thiazide-type Diuretics in Patients With Decompensated Heart Failure: a Double-blind, Randomized, Placebo-controlled Trial (CLOROTIC Trial).

Conditions
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Heart Failure

Intervention / Treatment
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* Drug: hydrochlorothiazide
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: History of chronic heart failure Admission for acute decompensated heart failure There is no prespecified inclusion criterion with respect to heart failure etiology and/or ejection fraction Receipt of an oral loop diuretic for at least 1 month before hospitalization, at a dose between 80 mg and 240 mg daily in the case of furosemide and an equivalent dose in the case of a different loop diuretic (20 mg of torasemide or 1 mg of bumetanide was considered to be equivalent to 40 mg of furosemide) Exclusion Criteria: Other etiologies of fluid overload different from heart failure Hyponatremia: any symptomatic sodium value or a sodium level below 125mmol/l Unstable patients: acute coronary syndrome, cardiogenic shock or ICU admission. Patients requiring inotropic agents or renal replacement therapies Life expectancy < 6 months Prior treatment with thiazide-type diuretics Aldosterone antagonists are permitted if the patient had been taking them on a long-term basis (at least 30 days before randomisation) Pregnancy or breastfeeding period Active alcoholism and/or other substance abuse

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Loop plus thiazide-type diuretic<br>Loop diuretic plus hydrochlorothiazide | Drug: hydrochlorothiazide<br>* hydrochlorothiazide according to clearance of creatinine; >50ml/min 25mg daily, 20-50ml/min 50mg daily amd <20ml/min 100mg daily.<br>|
| Placebo Comparator: Loop diuretic plus placebo<br>Loop diuretic plus placebo | Drug: Placebo<br>* Placebo according to clearance of creatinine; >50ml/min 1/2 pill daily, 20-50ml/min 1 pill daily amd <20ml/min 2 pills daily.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in body weight | Bodyweight will be measured every 24 hours (during hospitalisation) from the date of inclusion / randomisation until the date of discharge. Changes in body weight measurements: the mean of weight lost every 24 hours and the total weight lost from baseline to the 5th day of hospitalisation. Participants will be followed for the duration of hospital stay, an expected average of 9 days. | Bodyweight will be measured every 24 hours (during hospitalisation) from the date of inclusion / randomisation until the date of discharge. | 
| Patient-reported dyspnea | Patient-reported dyspnea is assessed every 24 hours (during hospitalisation) from the date of inclusion / randomisation until the date of discharge. Patient-reported dyspnea is assessed with the use of a visual-analogue scale (VAS) and the Linker 7 point scale. Changes in patient-reported dyspnea: changes in the dyspnea scales from baseline to the 5th day of hospitalisation. | Patient-reported dyspnea is assessed every 24 hours (during hospitalisation) from the date of inclusion / randomisation until the date of discharge. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Diuresis |  | 24-hour diuresis will be quantified every 24 hours (during hospitalisation) from the 1st day until the 4th day of hospitalisation. | 
| Worsening renal function | Renal function will be determined every 24 hours (during hospitalisation) from the date of inclusion / randomisation until the date of discharge. Renal function is assessed with the serum creatinine level. Worsening renal function is defined as an increase in the serum creatinine level of more than 0.3 mg/dl at any time during hospitalisation Participants will be followed for the duration of hospital stay, an expected average of 9 days. | Renal function will be determined every 24 hours (during hospitalisation) from the date of inclusion / randomisation until the date of discharge. | 
| Changes in electrolyte levels (sodium and potassium) | Electrolyte levels (sodium and potassium) will be determined every 24 hours (during hospitalisation) from the date of inclusion / randomisation until the date of discharge. Electrolyte levels are assessed with the serum sodium and potassium levels. Participants will be followed for the duration of hospital stay, an expected average of 9 days. | Electrolyte levels (sodium and potassium) will be determined every 24 hours (during hospitalisation) from the date of inclusion / randomisation until the date of discharge. | 
| Metrics of diuretic response | weight loss and net fluid loss per mg of furosemide | weight loss and net fluid loss per mg of furosemide | 
| Mortality (all-cause and heart failure) | Mortality (all-cause and heart failure) at 30 and 90days post-discharge | Mortality (all-cause and heart failure) at 30 and 90days post-discharge | 
| Rehospitalization (all-cause and heart failure) | Rehospitalization (all-cause and heart failure) at 30 and 90days post-discharge | Rehospitalization (all-cause and heart failure) at 30 and 90days post-discharge | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Heart Failure, Diuretics, Diuretic resistance