Combining loop with thiazide diuretics for decompensated heart failure: the CLOROTIC trial

Abstract

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 μmoL/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.

Critical Analysis of the Effects of SGLT2 Inhibitors on Renal Tubular Sodium, Water and Chloride Homeostasis and Their Role in Influencing Heart Failure Outcomes

“…Yet, assuming that the effect of SGLT2 inhibitor on volume homeostasis occur and are durable, it is difficult to know if treatmentmediated changes in the volume set point (if any) contribute to the effect of these drugs to reduce the risk of major heart failure events. Short-or long-term use of many conventional natriuretic and aquaretic drugs has not reduced cardiovascular death or hospitalizations for heart failure, 136,[138][139][140]157 demonstrating that immediate changes in urinary sodium or water excretion do not yield long-term clinical benefits. It is possible that the effects of SGLT2 inhibitors on sodium avidity may differ from other agents, but the volume effect of these drugs is small.…”

“…Although intensive short-term diuresis to achieve hemoconcentration in hospitalized patients is associated with lower cardiac filling pressures, 153 early decongestion has not been associated with improved outcomes in observational studies or clinical trials. 138–141,154,155 More intensive treatment with intravenous loop diuretics yields a greater short-term diuresis, but does not reduce heart failure events at 60 days. 138 The addition of hydrochlorothiazide to a loop diuretic yields a modest diuretic effect, but no effect on death or rehospitalization at 90 days.…”

The year in cardiovascular medicine 2022: the top 10 papers in heart failure and cardiomyopathies

“…The Safety and Efficacy of the Combination of Loop with Thiazide-type Diuretics in Patients with Decompensated Heart Failure (CLOROTIC trial; NCT01647932) 7 evaluated if addition of hydrochlorothiazide (HCT) to intravenous furosemide is a safe and effective strategy for improving diuretic response in patients with AHF. In total, 230 patients (48 women, 83 years) were randomized to HCT or placebo; those on HCT lost more weight at 72 h [2.3 vs. 1.5 kg; 1.14 (95 CI 1.84 to 0.42); P 0.002], but there were no significant differences in patient-reported dyspnoea.…”

Cardiorenal Syndrome in the Hospital

“…The efficacy of using hydrochlorothiazide with a loop diuretic was examined in the Safety and Efficacy of the Combination of Loop with Thiazide-type Diuretics in Patients with Decompensated Heart Failure (CLOROTIC) trial, which randomized 230 patients admitted for acute decompensated heart failure to either thiazide plus loop or loop diuretic alone. 53 It showed greater weight loss in the combined arm, but with higher rates of a rise in serum creatinine >0.3 mg/dl. A number of observational studies have shown thiazide diuretics to be efficacious in acute decompensated heart failure, even at low GFR.…”