Elsevier

JACC: Heart Failure

Volume 8, Issue 3, March 2020, Pages 157-168
JACC: Heart Failure

Mini-Focus Issue: MRAs and Diuretics
Clinical Research
Diuretic Strategies for Loop Diuretic Resistance in Acute Heart Failure: The 3T Trial

https://doi.org/10.1016/j.jchf.2019.09.012Get rights and content
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Abstract

Objectives

This study compared combination diuretic strategies in acute heart failure (AHF) complicated by diuretic resistance (DR).

Background

Combination diuretic regimens to overcome loop DR are commonly used but with limited evidence.

Methods

This study was a randomized, double-blinded trial in 60 patients hospitalized with AHF and intravenous (IV) loop DR. Patients were randomized to oral metolazone, IV chlorothiazide, or tolvaptan therapy. All patients received concomitant high-dose IV infusions of furosemide. The primary outcome was 48-h weight loss.

Results

The cohort exhibited DR prior to enrollment, producing 1,188 ± 476 ml of urine in 12 h during high-dose loop diuretic therapy (IV furosemide: 612 ± 439 mg/day). All 3 interventions significantly improved diuretic efficacy (p < 0.001). Compared to metolazone (4.6 ± 2.7 kg), neither IV chlorothiazide (5.8 ± 2.7 kg; 1.2 kg [95% confidence interval (CI)]: −2.9 to 0.6; p = 0.292) nor tolvaptan (4.1 ± 3.3 kg; 0.5 kg [95% CI: −1.5 to 2.4; p = 0.456) resulted in more weight loss at 48 h. Median (interquartile range [IQR]) cumulative urine output increased significantly and did not differ among those receiving metolazone (7.78 [IQR: 6.59 to 10.10] l) and chlorothiazide (8.77 [IQR: 7.37 to 10.86] l; p = 0.245) or tolvaptan (9.70 [IQR: 6.36 to 13.81] l; p = 0.160). Serum sodium decreased less with tolvaptan than with metolazone (+4 ± 5 vs. −1 ± 3 mEq/l; p = 0.001), but 48-h spot urine sodium was lower with tolvaptan (58 ± 25 mmol/l) than with metolazone (104 ± 16 mmol/l; p = 0.002) and with chlorothiazide (117 ± 14 mmol/l; p < 0.001).

Conclusions

In this moderately sized DR trial, weight loss was excellent with the addition of metolazone, IV chlorothiazide, or tolvaptan to loop diuretics, without a detectable between-group difference. (Comparison of Oral or Intravenous Thiazides vs. tolvaptan in Diuretic Resistant Decompensated Heart Failure [3T]; NCT02606253)

Key Words

acute heart failure
diuretic resistance
diuretics
heart failure
thiazide
tolvaptan

Abbreviations and Acronyms

AHF
acute heart failure
DR
diuretic resistance
eGFR
estimated glomerular filtration rate
FE
furosemide equivalent
FENa
fractional excretion of sodium
HFrEF
heart failure with reduced ejection fraction
HFpEF
heart failure with preserved ejection fraction
IQR
interquartile range
IV
intravenous
LVEF
left ventricular ejection fraction
SCr
serum creatinine

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Supported by a grant from Otsuka Pharmaceuticals, Cures Within Reach, and by Clinical Translational Science Award award UL1 TR002243 from the National Center for Advancing Translational Sciences. Study contents are the sole responsibility of the authors and do not necessarily represent official views of the U.S. National Institutes of Health or the National Center for Advancing Translational Sciences. Dr. Cox has received research support from Otsuka Pharmaceuticals. Dr. Testani has received grants and personal fees from Sequana Medical, Bristol-Myers Squibb, 3ive Labs, Bayer, Boehringer Ingelheim, MagentaMed, Otsuka, Renalguard, Sanofi, FIRE1, Abbott, and W.L. Gore; and has received personal fees from AstraZeneca, Novartis, Cardionomic, and Bayer. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.