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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Loop plus thiazide-type diuretic | Active Comparator | Loop diuretic plus hydrochlorothiazide |
|
| Loop diuretic plus placebo | Placebo Comparator | Loop diuretic plus placebo |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| hydrochlorothiazide | Drug | hydrochlorothiazide according to clearance of creatinine; >50ml/min 25mg daily, 20-50ml/min 50mg daily amd <20ml/min 100mg daily. |
|
| 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. |
| 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. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Joan Carles Trullas, MD, PhD | Heart Failure Study Group, Spanish Society of Internal Medicine | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Internal Medicine Service, Hospital d'Olot (Girona) | Olot | Girona | 17800 | Spain |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 21029871 | Background | 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. | |
| 25560378 | Background | 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. |
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| ID | Term |
|---|---|
| D006333 | Heart Failure |
| ID | Term |
|---|---|
| D006331 | Heart Diseases |
| D002318 | Cardiovascular Diseases |
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| ID | Term |
|---|---|
| D006852 | Hydrochlorothiazide |
| ID | Term |
|---|---|
| D002740 | Chlorothiazide |
| D001581 | Benzothiadiazines |
| D013449 | Sulfonamides |
| D013450 | Sulfones |
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| Placebo | Drug | Placebo according to clearance of creatinine; >50ml/min 1/2 pill daily, 20-50ml/min 1 pill daily amd <20ml/min 2 pills daily. |
|
| 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 |
| 26576715 | Background | 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. |
| 24930082 | Background | 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. |
| 30610440 | Background | 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. |
| 42155809 | Derived | Garcia-Escriva D, Perez-Silvestre J, Nunez J, Casado J, Morales-Rull JL, Sanchez-Marteles M, Conde-Martel A, Llacer P, Salamanca-Bautista P, Plasin MA, Cerqueiro JM, Gil P, Manzano L, Formiga F, Trullas JC; CLOROTIC trial investigators. Serum chloride and the response to hydrochlorothiazide in patients with acute heart failure: a post-hoc analysis from the CLOROTIC trial. Rev Esp Cardiol (Engl Ed). 2026 May 18:S1885-5857(26)00104-0. doi: 10.1016/j.rec.2026.04.006. Online ahead of print. English, Spanish. |
| 41871344 | Derived | McCallum W, Tighiouart H, Tuttle M, Oka T, Kaur T, Casado J, Morales-Rull JL, Formiga F, Manzano L, Testani JM, Sarnak MJ, Trullas JC. Acute declines in kidney function with thiazide plus loop diuretics vs loop diuretics alone in acute decompensated heart failure. Nephrol Dial Transplant. 2026 Mar 23:gfag070. doi: 10.1093/ndt/gfag070. Online ahead of print. |
| 40590131 | Derived | Conde-Martel A, Hernandez-Meneses M, Morales-Rull JL, Casado J, Carrera-Izquierdo M, Leon M, Sanchez-Marteles M, Davila-Ramos MF, Hernandez-Carballo C, Llacer P, Moreno-Garcia MC, Salamanca-Bautista P, Formiga F, Manzano L, Trullas JC. Hypokalemia During Decongestion With Loop Diuretics and Hydrochlorothiazide, a Post Hoc Analysis of the CLOROTIC Trial. Circ Heart Fail. 2025 Sep;18(9):e012914. doi: 10.1161/CIRCHEARTFAILURE.125.012914. Epub 2025 Jul 1. |
| 38215973 | Derived | Conde-Martel A, Trullas JC, Morales-Rull JL, Casado J, Carrera-Izquierdo M, Sanchez-Marteles M, Llacer P, Salamanca-Bautista P, Manzano L, Formiga F. Sex differences in clinical characteristics and outcomes in the CLOROTIC (combining loop with thiazide diuretics for decompensated heart failure) trial. Rev Clin Esp (Barc). 2024 Feb;224(2):67-76. doi: 10.1016/j.rceng.2023.11.003. Epub 2024 Jan 11. |
| 37540036 | Derived | Trullas JC, Morales-Rull JL, Casado J, Carrera-Izquierdo M, Sanchez-Marteles M, Conde-Martel A, Davila-Ramos MF, Llacer P, Salamanca-Bautista P, Chivite D, Jordana-Comajuncosa R, Villalonga M, Paez-Rubio MI, Manzano L, Formiga F. Combining loop and thiazide diuretics for acute heart failure across the estimated glomerular filtration rate spectrum: A post-hoc analysis of the CLOROTIC trial. Eur J Heart Fail. 2023 Oct;25(10):1784-1793. doi: 10.1002/ejhf.2988. Epub 2023 Aug 16. |
| 36423214 | Derived | Trullas JC, Morales-Rull JL, Casado J, Carrera-Izquierdo M, Sanchez-Marteles M, Conde-Martel A, Davila-Ramos MF, Llacer P, Salamanca-Bautista P, Perez-Silvestre J, Plasin MA, Cerqueiro JM, Gil P, Formiga F, Manzano L; CLOROTIC trial investigators. Combining loop with thiazide diuretics for decompensated heart failure: the CLOROTIC trial. Eur Heart J. 2023 Feb 1;44(5):411-421. doi: 10.1093/eurheartj/ehac689. |
| D013457 |
| Sulfur Compounds |
| D009930 | Organic Chemicals |
| D049971 | Thiazides |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |