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Review
. 2024 Apr;21(2):115-130.
doi: 10.1007/s11897-024-00644-2. Epub 2024 Feb 1.

Diuretic Treatment in Patients with Heart Failure: Current Evidence and Future Directions-Part II: Combination Therapy

Cuthbert J J  1   2 , Cleland J G F  3 , Clark A L  4
Affiliations
Review

Diuretic Treatment in Patients with Heart Failure: Current Evidence and Future Directions-Part II: Combination Therapy

Cuthbert J J et al. Curr Heart Fail Rep. 2024 Apr.

Abstract

Purpose of review: Fluid retention or congestion is a major cause of symptoms, poor quality of life, and adverse outcome in patients with heart failure (HF). Despite advances in disease-modifying therapy, the mainstay of treatment for congestion-loop diuretics-has remained largely unchanged for 50 years. In these two articles (part I: loop diuretics and part II: combination therapy), we will review the history of diuretic treatment and current trial evidence for different diuretic strategies and explore potential future directions of research.

Recent findings: We will assess recent trials, including DOSE, TRANSFORM, ADVOR, CLOROTIC, OSPREY-AHF, and PUSH-AHF, and assess how these may influence current practice and future research. There are few data on which to base diuretic therapy in clinical practice. The most robust evidence is for high-dose loop diuretic treatment over low-dose treatment for patients admitted to hospital with HF, yet this is not reflected in guidelines. There is an urgent need for more and better research on different diuretic strategies in patients with HF.

Keywords: Acetazolamide; Combination therapy; Decompensated HF; Digoxin; Diuretic treatment; Loop diuretic; Oral salt; Sodium-glucose co-transporter 2 inhibitors; Steroid; Thiazide; Tolvaptan.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Mechanism of action of different diuretic agents. Abbreviations: CA, carbonic anhydrase; ACZ, acetazolamide; SGLT2I, sodium glucose co-transporter 2 inhibitor; THZ, thiazide; AVP, arginine vasopressin
Fig. 2
Fig. 2
Conflicting and competing mechanisms of corticosteroid benefits and harm in patients with HF. ANP, atrial natriuretic peptide; NPR-A, natriuretic peptide receptor-A; AVP, arginine vasopressin; ACTH, adrenocorticotropic hormone
Fig. 3
Fig. 3
Cumulative urine output in RCTs of combination diuretic therapy. Urine output was reported at 24 h in the CLOROTIC and SMAC-HF trials and was used to estimate urine output at 48 and 72 h; urine output was reported at 72 h in the DOSE and TACTICS trials and used to estimate urine output at 24 and 48 h. Urine output from the ADVOR, EMPA-RESPONSE-AHF, EMPAG-HF, OSPREY, and Liu et al. trials was estimated from the figures. Data collection on urine output stopped after 48 h in the ADVOR trial; 72 h urine output is estimated from values at 24 and 48 h. Abbreviations: plbo, placebo; HCTZ, hydrochlorothiazide; ACZ, acetazolamide; Empa, empagliflozin; NaCl, slow sodium; Tolv, tolvaptan; Pred, prednisolone; HSS, hypertonic saline solution
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References

    1. Yeoh SE, Osmanska J, Petrie MC, et al. Dapagliflozin vs. metolazone in heart failure resistant to loop diuretics. Eur Heart J. 2023;44(31):2966–2977. doi: 10.1093/eurheartj/ehad341. - DOI - PMC - PubMed
    1. Doggrell SA. Tolvaptan (Otsuka) Curr Opin Investig Drugs. 2004;5(9):977–983. - PubMed
    1. Gheorghiade M, Konstam MA, Burnett JC Jr, Grinfeld L, Maggioni AP, Swedberg K, Udelson JE, Zannad F, Cook T, Ouyang J, Zimmer C, Orlandi C. Efficacy of vasopressin antagonism in heart failure outcome study with tolvaptan (EVEREST) investigators. Short-term clinical effects of tolvaptan, an oral vasopressin antagonist, in patients hospitalized for heart failure: the EVEREST Clinical Status Trials. JAMA. 2007;297(12):1332–43. - PubMed
    1. Felker GM, Mentz RJ, Cole RT, Adams KF, Egnaczyk GF, Fiuzat M, Patel CB, Echols M, Khouri MG, Tauras JM, Gupta D, Monds P, Roberts R, O'Connor CM. Efficacy and safety of tolvaptan in patients hospitalized with acute heart failure. J Am Coll Cardiol. 2017;69(11):1399–1406. doi: 10.1016/j.jacc.2016.09.004. - DOI - PubMed
    1. Cox ZL, Hung R, Lenihan DJ, Testani JM. Diuretic strategies for loop diuretic resistance in acute heart failure: the 3T trial. JACC Heart Fail. 2020;8(3):157–168. doi: 10.1016/j.jchf.2019.09.012. - DOI - PMC - PubMed
Papers of particular interest, published recently, have been highlighted as: • Of importance
    1. Shoaib A, Mamas MA, Ahmad QS, et al. Characteristics and outcome of acute heart failure patients according to the severity of peripheral oedema. Int J Cardiol. 2019;285:40–46. doi: 10.1016/j.ijcard.2019.03.020. - DOI - PubMed
    1. Shoaib A, Waleed M, Khan S, et al. Breathlessness at rest is not the dominant presentation of patients admitted with heart failure. Eur J Heart Fail. 2014;16(12):1283–1291. doi: 10.1002/ejhf.153. - DOI - PubMed
    1. Stokes W. A new effective diuretic - Lasix. Br Med J. 1964;2(5414):910–914. doi: 10.1136/bmj.2.5414.910. - DOI - PMC - PubMed
    1. Trullàs JC, Casado J, Morales-Rull JL, Formiga F, Conde-Martel A, Quirós R, Epelde F, González-Franco Á, Manzano L, Montero-Pérez-Barquero M. Prevalence and outcome of diuretic resistance in heart failure. Intern Emerg Med. 2019;14(4):529–537. doi: 10.1007/s11739-018-02019-7. - DOI - PubMed
    1. Neuberg GW, Miller AB, O'Connor CM, Belkin RN, Carson PE, Cropp AB, Frid DJ, Nye RG, Pressler ML, Wertheimer JH, Packer M. PRAISE Investigators. Prospective randomized amlodipine survival evaluation. Diuretic resistance predicts mortality in patients with advanced heart failure. Am Heart J. 2002;144(1):31–8. doi: 10.1067/mhj.2002.123144. - DOI - PubMed

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