Zachary L Cox1, Rebecca Hung2, Daniel J Lenihan3, Jeffrey M Testani4. 1. Department of Pharmacy Practice, Lipscomb University College of Pharmacy, Nashville Tennessee; Department of Pharmacy, Vanderbilt University Medical Center, Nashville Tennessee. Electronic address: Zachary.l.cox@vumc.org. 2. Division of Cardiology, Vanderbilt University Medical Center, Nashville Tennessee. 3. Cardiovascular Division, Washington University School of Medicine, St. Louis, Missouri. 4. Division of Internal Medicine, Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven, Connecticut.
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).
RCT Entities:
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).
Authors: Clyde W Yancy; Mariell Jessup; Biykem Bozkurt; Javed Butler; Donald E Casey; Mark H Drazner; Gregg C Fonarow; Stephen A Geraci; Tamara Horwich; James L Januzzi; Maryl R Johnson; Edward K Kasper; Wayne C Levy; Frederick A Masoudi; Patrick E McBride; John J V McMurray; Judith E Mitchell; Pamela N Peterson; Barbara Riegel; Flora Sam; Lynne W Stevenson; W H Wilson Tang; Emily J Tsai; Bruce L Wilkoff Journal: J Am Coll Cardiol Date: 2013-06-05 Impact factor: 24.094
Authors: Ovidiu Chioncel; Alexandre Mebazaa; Aldo P Maggioni; Veli-Pekka Harjola; Giuseppe Rosano; Cecile Laroche; Massimo F Piepoli; Maria G Crespo-Leiro; Mitja Lainscak; Piotr Ponikowski; Gerasimos Filippatos; Frank Ruschitzka; Petar Seferovic; Andrew J S Coats; Lars H Lund Journal: Eur J Heart Fail Date: 2019-05-24 Impact factor: 15.534
Authors: Marvin A Konstam; Michael Kiernan; Arthur Chandler; Ravi Dhingra; Freny Vaghaiwalla Mody; Howard Eisen; W Herbert Haught; Lynne Wagoner; Divya Gupta; Richard Patten; Paul Gordon; Kenneth Korr; Russell Fileccia; Susan J Pressler; Douglas Gregory; Patricia Wedge; Douglas Dowling; Matthew Romeling; Jeremy M Konstam; Joseph M Massaro; James E Udelson Journal: J Am Coll Cardiol Date: 2017-03-21 Impact factor: 24.094
Authors: G Michael Felker; Robert J Mentz; Robert T Cole; Kirkwood F Adams; Gregory F Egnaczyk; Mona Fiuzat; Chetan B Patel; Melvin Echols; Michel G Khouri; James M Tauras; Divya Gupta; Pamela Monds; Rhonda Roberts; Christopher M O'Connor Journal: J Am Coll Cardiol Date: 2016-09-18 Impact factor: 24.094
Authors: Michael S Kiernan; Susanna R Stevens; W H Wilson Tang; Javed Butler; Kevin J Anstrom; Edo Y Birati; Justin L Grodin; Divya Gupta; Kenneth B Margulies; Shane LaRue; Victor G Dávila-Román; Adrian F Hernandez; Lisa de Las Fuentes Journal: J Card Fail Date: 2018-03-01 Impact factor: 5.712
Authors: Piotr Ponikowski; Adriaan A Voors; Stefan D Anker; Héctor Bueno; John G F Cleland; Andrew J S Coats; Volkmar Falk; José Ramón González-Juanatey; Veli-Pekka Harjola; Ewa A Jankowska; Mariell Jessup; Cecilia Linde; Petros Nihoyannopoulos; John T Parissis; Burkert Pieske; Jillian P Riley; Giuseppe M C Rosano; Luis M Ruilope; Frank Ruschitzka; Frans H Rutten; Peter van der Meer Journal: Eur Heart J Date: 2016-05-20 Impact factor: 29.983
Authors: Meredith A Brisco-Bacik; Jozine M Ter Maaten; Steven R Houser; Natasha A Vedage; Veena Rao; Tariq Ahmad; F Perry Wilson; Jeffrey M Testani Journal: J Am Heart Assoc Date: 2018-09-18 Impact factor: 5.501
Authors: Saif Ali; Sharon Jung; Shuktika Nandkeolyar; Liset Stoletniy; Antoine Sakr; Frederik H Verbrugge; Anthony Hilliard; Dmitry Abramov Journal: Am J Cardiovasc Drugs Date: 2021-03-12 Impact factor: 3.571
Authors: Zachary L Cox; James Fleming; Juan Ivey-Miranda; Matthew Griffin; Devin Mahoney; Keyanna Jackson; Daniel Z Hodson; Daniel Thomas; Nicole Gomez; Veena S Rao; Jeffrey M Testani Journal: ESC Heart Fail Date: 2020-09-06