Author + information
- Received August 8, 2019
- Revision received September 18, 2019
- Accepted September 23, 2019
- Published online January 8, 2020.
- Zachary L. Cox, PharmDa,b,∗ (, )
- Rebecca Hung, MDc,
- Daniel J. Lenihan, MDd and
- Jeffrey M. Testani, MD, MTRe
- aDepartment of Pharmacy Practice, Lipscomb University College of Pharmacy, Nashville, Tennessee
- bDepartment of Pharmacy, Vanderbilt University Medical Center, Nashville, Tennessee
- cDivision of Cardiology, Vanderbilt University Medical Center, Nashville, Tennessee
- dCardiovascular Division, Washington University School of Medicine, St. Louis, Missouri
- eDivision of Internal Medicine, Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven, Connecticut
- ↵∗Address for correspondence:
Dr. Zachary L. Cox, PharmD, One University Park Drive, Burton Health Science Center, Nashville, Tennessee 37204.
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)
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.
- Received August 8, 2019.
- Revision received September 18, 2019.
- Accepted September 23, 2019.
- 2019 American College of Cardiology Foundation
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