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

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).

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.

Study Overview

• Status: Completed
• Conditions: Heart Failure
• Intervention / Treatment: Drug: hydrochlorothiazide; Drug: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 232
• Phase: Phase 3

Contacts and Locations

Study Locations

• Spain
  • Girona
    • Olot, Girona, Spain, 17800
      • Internal Medicine Service, Hospital d'Olot (Girona)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Spanish Society of Internal Medicine
• Investigators: Principal Investigator: Joan Carles Trullas, MD, PhD, Heart Failure Study Group, Spanish Society of Internal Medicine

Publications and helpful links

General Publications

• Jentzer JC, DeWald TA, Hernandez AF. Combination of loop diuretics with thiazide-type diuretics in heart failure. J Am Coll Cardiol. 2010 Nov 2;56(19):1527-34. doi: 10.1016/j.jacc.2010.06.034.
• ter Maaten JM, Valente MA, Damman K, Hillege HL, Navis G, Voors AA. Diuretic response in acute heart failure-pathophysiology, evaluation, and therapy. Nat Rev Cardiol. 2015 Mar;12(3):184-92. doi: 10.1038/nrcardio.2014.215. Epub 2015 Jan 6.
• Trullas JC, Morales-Rull JL, Casado J, Freitas Ramirez A, Manzano L, Formiga F; CLOROTIC investigators. Rationale and Design of the "Safety and Efficacy of the Combination of Loop with Thiazide-type Diuretics in Patients with Decompensated Heart Failure (CLOROTIC) Trial:" A Double-Blind, Randomized, Placebo-Controlled Study to Determine the Effect of Combined Diuretic Therapy (Loop Diuretics With Thiazide-Type Diuretics) Among Patients With Decompensated Heart Failure. J Card Fail. 2016 Jul;22(7):529-36. doi: 10.1016/j.cardfail.2015.11.003. Epub 2015 Nov 11.
• Trullas JC, Morales-Rull JL, Formiga F. [Diuretic therapy in acute heart failure]. Med Clin (Barc). 2014 Mar;142 Suppl 1:36-41. doi: 10.1016/S0025-7753(14)70081-8. Spanish.
• Trullas JC, Casado J, Morales-Rull JL, Formiga F, Conde-Martel A, Quiros R, Epelde F, Gonzalez-Franco A, Manzano L, Montero-Perez-Barquero M. Prevalence and outcome of diuretic resistance in heart failure. Intern Emerg Med. 2019 Jun;14(4):529-537. doi: 10.1007/s11739-018-02019-7. Epub 2019 Jan 4.

Study record dates

Study Major Dates

• Study Start: October 1, 2014
• Primary Completion (Actual): December 15, 2019
• Study Completion (Actual): December 15, 2019

Study Registration Dates

• First Submitted: June 28, 2012
• First Submitted That Met QC Criteria: July 19, 2012
• First Posted (Estimate): July 24, 2012

Study Record Updates

• Last Update Posted (Actual): October 4, 2022
• Last Update Submitted That Met QC Criteria: September 30, 2022
• Last Verified: September 1, 2022

More Information

Terms related to this study

• Keywords: Heart Failure; Diuretics; Diuretic resistance
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Natriuretic Agents; Membrane Transport Modulators; Diuretics; Sodium Chloride Symporter Inhibitors; Hydrochlorothiazide
• Other Study ID Numbers: SEMI-IC-CLOR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No