Clinical trial NCT01647932: Safety and Efficacy of the Combination of Loop With Thiazide-type Diuretics in Patients With Decompensated Heart Failure
Official title: 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).
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Heart Failure
Keywords: Heart Failure
Diuretics
Diuretic resistance
Lead sponsor: Spanish Society of Internal Medicine
Sponsor class: OTHER
First posted: 2012-07-24
Enrollment: 232
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Changes in body weight
timeFrame: Bodyweight will be measured every 24 hours (during hospitalisation) from the date of inclusion / randomisation until the date of discharge.
measure: Patient-reported dyspnea
timeFrame: Patient-reported dyspnea is assessed every 24 hours (during hospitalisation) from the date of inclusion / randomisation until the date of discharge.
Secondary outcomes:
measure: Diuresis
timeFrame: 24-hour diuresis will be quantified every 24 hours (during hospitalisation) from the 1st day until the 4th day of hospitalisation.
measure: Worsening renal function
timeFrame: Renal function will be determined every 24 hours (during hospitalisation) from the date of inclusion / randomisation until the date of discharge.
measure: Changes in electrolyte levels (sodium and potassium)
timeFrame: Electrolyte levels (sodium and potassium) will be determined every 24 hours (during hospitalisation) from the date of inclusion / randomisation until the date of discharge.
measure: Metrics of diuretic response
timeFrame: weight loss and net fluid loss per mg of furosemide
measure: Mortality (all-cause and heart failure)
timeFrame: Mortality (all-cause and heart failure) at 30 and 90days post-discharge
measure: Rehospitalization (all-cause and heart failure)
timeFrame: Rehospitalization (all-cause and heart failure) at 30 and 90days post-discharge
Other outcomes:
Locations:
city: Olot
country: Spain
facility: Internal Medicine Service, Hospital d'Olot (Girona)
state: Girona
Study officials:
affiliation: Heart Failure Study Group, Spanish Society of Internal Medicine
name: Joan Carles Trullas, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.