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

Feb 07, 2023
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Author/Summarized by Author:
Dharam J. Kumbhani, MD, SM, FACC; Neil Keshvani, MD
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC
Trial Sponsor:
Heart Failure Working Group of the Spanish Society of Internal Medicine
Date Published:
12/30/2022
Date Updated:
02/07/2023
Original Posted Date:
12/22/2022
References

Contribution To Literature:

Among patients with acute decompensated HF in the CLOROTIC trial, addition of HCTZ to loop diuretic therapy resulted in improved diuretic response as compared with placebo but with a greater risk of impaired renal function and hypokalemia.

Description:

The goal of the trial was to compare changes in body weight and patient-reported dyspnea among patients with acute decompensated heart failure (HF) receiving intravenous (IV) loop diuretics with hydrochlorothiazide (HCTZ) versus placebo.

Study Design

The CLOROTIC trial was a multicenter, randomized, double-blind, placebo-controlled trial of patients hospitalized with acute decompensated HF. Patients were randomized in 1:1 fashion to receive HCTZ (n = 114) or placebo (n = 116) for 5 days supplied as oral tablets. All patients were also on furosemide. Dose of HCTZ: estimated glomerular filtration rate (eGFR) >50 mL/min: 25 mg daily; 20–50 mL/min: 50 mg daily; and <20 mL/min: 100 mg daily. Up-titration or down-titration of study medication was not permitted, and its dose could only be adjusted based on changes in GFR during the treatment period. Patients could not be discharged during the 5-day randomized treatment period for close monitoring of adverse effects. The study was halted in October 2019 due to slow enrollment.

  • Total screened: 6,914
  • Total randomized participants: 230
  • Mean patient age: 83 years
  • Percentage female: 48%

Inclusion criteria:

  • Age >18 years
  • Chronic HF (no criteria for etiology of HF or ejection fraction [EF])
  • Hospitalization within previous 24 hours for acute decompensated HF
  • Treatment with oral loop diuretic ≥1 month prior to hospitalization
  • IV furosemide dose between 80 mg and 240 mg daily

Exclusion criteria:

  • Clinical instability (acute coronary syndrome, cardiogenic shock, or intensive care unit admission)
  • Treatment with inotropic agents
  • Treatment with any thiazide diuretic during the month before admission
  • Requirement of renal replacement therapy
  • Potassium ≤2.5 or sodium ≤125 at randomization

Other salient features/characteristics:

  • New York Heart Association class III (51%) or IV (10%)
  • 60% with history of HF hospitalization in the previous 12 months
  • Median eGFR: 43 mL/min/1.73 m2
  • Median N-terminal pro-B-type natriuretic peptide (NT-proBNP): 4672 pg/mL
  • Mean EF: 55%; 65.3% of participants had EF >50%
  • Mean systolic blood pressure: 125 mm Hg
  • Mean oral furosemide dose: 80 mg/day

Principal Findings:

The co-primary outcome, adjusted changes in body weight from baseline to 72 hours of randomization, for HCTZ versus placebo, was: -2.3 kg vs. -1.5 kg (p = 0.002).

The co-primary outcome, change in patient-reported dyspnea from baseline to 72 hours of randomization using the visual analogue scale, for HCTZ versus placebo, was mean area under the curve (AUC) at 72 hours: 960 vs. 720 (p = 0.50).

Key secondary outcomes for HCTZ vs. placebo:

  • Change in weight at 96 hours: -2.5 kg vs. -1.5 kg (p < 0.001)
  • 24-hour diuresis quantification: 1775 mL vs. 1400 mL (p = 0.05)
  • Hospital length of stay: 7.0 vs. 7.0 (p = 0.17)
  • All-cause mortality at 30 days: 9.6% vs. 6.0% (p = 0.44)
  • All-cause rehospitalization at 30 days: 23.7% vs. 16.4% (p = 0.22)
  • Impaired renal function: 46.5% vs. 17.2% (p < 0.001)
  • Increase in creatinine >26.5 μmol/L: 46.5% vs. 17.2% (p < 0.001)
  • Potassium levels ≤3.5 mmoL/L: 44.7% vs. 19.0% (p < 0.001)

Interpretation:

The results of this trial show that, among patients with acute decompensated HF, treatment with HCTZ in addition to IV loop diuretics led to increased diuretic response without change in patient-reported dyspnea. Patients assigned to HCTZ were more likely to lose weight at both 72 and 96 hours compared to those receiving placebo therapy. A large percentage of patients enrolled had existing renal dysfunction at baseline, with high doses of HCTZ prescribed for patients with more advanced chronic kidney disease per the trial protocol. Treatment with HCTZ led to increases in creatinine, hypokalemia, and impaired renal function as compared with placebo without differences in all-cause mortality or all-cause rehospitalization at 30 days and 90 days. However, the study was ended prematurely for slow enrollment; thus, it is difficult to make firm conclusions regarding clinical safety. Additionally, renal function was not assessed in follow-up visits, so it is unknown whether the observed increases in creatinine and worsened renal function in the HCTZ arms were transient and associated with improved diuretic response while hospitalized or if the worsened renal function persisted after treatment with HCTZ.

These results suggest a potential role for thiazide diuretics on top of loop diuretics among patients hospitalized with acute HF. The results of this trial come on the heels of the ADVOR trial, which assessed the efficacy of IV acetazolamide in addition to IV loop diuretics, which led to greater decongestion compared to placebo among patients with acute decompensated HF. Together, these trials suggest that add-on diuretic therapy may result in greater decongestion among patients with acute HF already on loop diuretics. A lack of adequate long-term safety assessment with regard to renal function in the current trial leaves some doubt as to the overall safety of using thiazides.

References:

Highlighted text has been updated as of February 7, 2023.

Trullàs JC, Morales-Rull JL, Caso J, et al. Combining loop with thiazide diuretics for decompensated heart failure: the CLOROTIC trial. Eur Heart J 2023;44:411-21.

Editorial: Zakeri R, Wilson DG, Mohammed SF. Time to revisit combination loop and thiazide diuretic therapy for patients with acute heart failure. Eur Heart J 2023;44:422-4.

Clinical Topics: Geriatric Cardiology, Heart Failure and Cardiomyopathies, Statins, Acute Heart Failure, Heart Failure and Cardiac Biomarkers

Keywords: Body Weight, Creatinine, Diuresis, Diuretics, Dyspnea, Furosemide, Geriatrics, Glomerular Filtration Rate, Heart Failure, Hydrochlorothiazide, Hypokalemia, Length of Stay, Natriuretic Peptide, Brain, Renal Insufficiency, Sodium Potassium Chloride Symporter Inhibitors, Stroke Volume, Thiazides


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