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.


Aims: To evaluate whether the addition of hydrochlorothiazide (HCTZ) to intravenous furosemide is a safe and effective strategy for improving diuretic response in acute heart failure (AHF).

Methods and results: A prospective, double-blind, placebo-controlled trial, including patients with AHF randomized to receive HCTZ or placebo in addition to an intravenous furosemide regimen. The coprimary endpoints were changes in body weight and patient-reported dyspnoea 72 h after randomization. Secondary outcomes included metrics of diuretic response and mortality/rehospitalizations at 30 and 90 days. Safety outcomes (changes in renal function and/or electrolytes) were also assessed. Two hundred and thirty patients (48 women, 83 years) were randomized. Patients assigned to HCTZ were more likely to lose weight at 72 h than those assigned to placebo [2.3 vs. 1.5 kg; adjusted estimated difference (notionally 95 confidence interval) 1.14 (1.84 to 0.42); P 0.002], but there were no significant differences in patient-reported dyspnoea (area under the curve for visual analogue scale: 960 vs. 720; P 0.497). These results were similar 96 h after randomization. Patients allocated to HCTZ showed greater 24 h diuresis (1775 vs. 1400 mL; P 0.05) and weight loss for each 40 mg of furosemide (at 72 and at 96 h) (P 0.001). Patients assigned to HCTZ more frequently presented impaired renal function (increase in creatinine 26.5 moL/L or decrease in eGFR 50; 46.5 vs. 17.2; P 0.001), but hypokalaemia and hypokalaemia were similar between groups. There were no differences in mortality or rehospitalizations.

Conclusion: The addition of HCTZ to loop diuretic therapy improved diuretic response in patients with AHF.

Trial registration: NCT01647932.

Keywords: Diuretics; Furosemide; Heart failure; Hydrochlorothiazide; Thiazides.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Diuretics / adverse effects
  • Diuretics / therapeutic use
  • Dyspnea
  • Female
  • Furosemide / therapeutic use
  • Heart Failure*
  • Humans
  • Hydrochlorothiazide / therapeutic use
  • Hypokalemia* / chemically induced
  • Hypokalemia* / complications
  • Prospective Studies
  • Sodium Chloride Symporter Inhibitors / therapeutic use


  • Furosemide
  • Sodium Chloride Symporter Inhibitors
  • Diuretics
  • Hydrochlorothiazide

Associated data

  • EudraCT/2013-001852-36