Aquaretics Use in Acute Decompensated Heart Failure (ADHF) Patients: A Literature Review

Norman Sukmadi, Kevin Surya, Arif Sejati


This is a literature review of the use of aquaretic in patients with acute decompensated heart failure (ADHF), including the physiologic function of vasopressin and its mechanism of action in heart failure patients, and aquaretic drugs with their respective risks and benefits.
Vasopressin is one of several hormones that can cause hyponatremia and worsen congestion in ADHF patients. Aquaretics are a class of drugs that have an antagonistic effect on vasopressin receptors, especially V2R. Aquaretics use in ADHF patients can provide relief for congestive symptoms with no serious adverse effects. In-depth additional understanding regarding aquaretics may be useful for clinical judgments in treating ADHF patients.


Acute Decompensated Heart Failure; Aquaretics


Savarese G, Lund LH. Global public health burden of heart failure. Card Fail Rev. 2017;3(1):7–11.

Heart Disease and Stroke Statistics—2020 Update: A Report From the American Heart Association. Circulation [Internet]. [cited 2020 Jun 21]. Available from:

Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The task force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2016;37(27):2129–200.

Dariush M, Benjamin EJ, Go Alan S, et al. Executive summary: Heart disease and stroke statistics—2016 update. Circulation. 2016;133(4):447–54.

Farmakis D, Parissis J, Filippatos G. Acute heart failure: epidemiology, classification, and pathophysiology [Internet]. Vol. 1. Oxford University Press; 2015 [cited 2020 Jun 21]. Available from:

Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: A report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. J Am Coll Cardiol. 2013;62(16):e147–239.

John FJ, Marvin KA, James UE. Arginine vasopressin antagonists for the treatment of heart failure and hyponatremia. Circulation. 2008;118(4):410–21.

Narayen G, Mandal SN. Vasopressin receptor antagonists and their role in clinical medicine. Indian J Endocrinol Metab. 2012;16(2):183–91.

Cuzzo B, Padala SA, Lappin SL. Vasopressin (Antidiuretic Hormone, ADH). In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 [cited 2020 Jun 27]. Available from:

Holmes CL, Landry DW, Granton JT. Science review: Vasopressin and the cardiovascular system part 1 – receptor physiology. Crit Care. 2003;7(6):427–34.

Thibonnier M, Coles P, Thibonnier A, Shoham M. The basic and clinical pharmacology of nonpeptide vasopressin receptor antagonists. Annu Rev Pharmacol Toxicol. 2001;41(1):175–202.

Ranieri M, Di Mise A, Tamma G, Valenti G. Vasopressin–aquaporin-2 pathway: recent advances in understanding water balance disorders. F1000 Research [Internet]. 2019 Feb 4 [cited 2020 Jun 27];8. Available from:

Park E-J, Kwon T-H. A Minireview on vasopressin-regulated aquaporin-2 in kidney collecting duct cells. Electrolytes Blood Press. 2015;13(1):1–6.

Thibonnier M, Preston JA, Dulin N, Wilkins PL, Berti-Mattera LN, Mattera R. The human V3 pituitary vasopressin receptor: Ligand binding profile and density-dependent signaling pathways. Endocrinology. 1997;138(10):4109–22.

David LE, Hani SN, Steven GR, et al. Association of arginine vasopressin levels with outcomes and the effect of V2 blockade in patients hospitalized for heart failure with reduced ejection fraction. Circ Heart Fail. 2013;6(1):47–52.

Ghali JK, Tam SW. The critical link of hypervolemia and hyponatremia in heart failure and the potential role of arginine vasopressin antagonists. J Card Fail. 2010;16(5):419–31.

Izumi Y, Miura K, Iwao H. Therapeutic potential of vasopressin-receptor antagonists in heart failure. J Pharmacol Sci. 2014;124(1):1–6.

Corona G, Giuliani C, Parenti G, et al. Moderate hyponatremia is associated with increased risk of mortality: Evidence from a Meta-Analysis. PLOS ONE. 2013;8(12):e80451.

Bolignano D, Coppolino G, Criseo M, Campo S, Romeo A, Buemi M. Aquaretic agents: what’s beyond the treatment of hyponatremia? Curr Pharm Des. 2007;13(8):865–71.

Decaux G, Soupart A, Vassart G. Non-peptide arginine-vasopressin antagonists: the vaptans. Lancet. 2008;371(9624):1624–32.

Ali F, Raufi MA, Washington B, Ghali JK. Conivaptan: A dual receptor vasopressin V1a/V2 antagonist. Cardiovasc Drug Rev. 2007;25(3):261–79.

Ghali JK, Orlandi C, Abraham WT. The efficacy and safety of lixivaptan in outpatients with heart failure and volume overload: results of a multicentre, randomized, double-blind, placebo-controlled, parallel-group study. Eur J Heart Fail. 2012;14(6):642–51.

Palladio Biosciences. A 52-week, phase 3, double-blind, placebo-controlled, randomized study of the efficacy and safety of Lixivaptan in subjects with autosomal dominant polycystic kidney disease (ADPKD) [Internet].; 2020 May [cited 2020 Jul 1]. Report No.: NCT04064346. Available from:

Aronson D, Verbalis JG, Mueller M, Krum H. Short- and long-term treatment of dilutional hyponatraemia with satavaptan, a selective arginine vasopressin V2-receptor antagonist: the DILIPO study. Eur J Heart Fail. 2011;13(3):327–36.

Yi J-H, Shin H-J, Kim H-J. V2 receptor antagonist; Tolvaptan. Electrolytes Blood Press E BP. 2011;9(2):50–4.

Palmer BF. The role of V2 receptor antagonists in the treatment of hyponatremia. Electrolytes Blood Press E BP. 2013;11(1):1–8.

Jermyn R, Rajper N, Estrada C, Patel S, Weisfelner Bloom M, Wadhwa NK. Triple diuretics and aquaretic strategy for acute decompensated heart failure due to volume overload. Case Rep Cardiol [Internet]. 2013 [cited 2020 Jun 27];2013. Available from:

Gheorghiade M, Gattis WA, O’Connor CM, et al. Effects of tolvaptan, a vasopressin antagonist, in patients hospitalized with worsening heart failure: A randomized controlled trial. JAMA. 2004;291(16):1963–71.

Luo X, Jin Q, Wu Y. Tolvaptan add‐on therapy in patients with acute heart failure: A systematic review and meta‐analysis. Pharmacol Res Perspect. 2020;8(3):e00614.

Ma G, Ma X, Wang G, Teng W, Hui X. Effects of tolvaptan add-on therapy in patients with acute heart failure: meta-analysis on randomised controlled trials. BMJ Open [Internet]. 2019 May 1 [cited 2020 Jul 4];9(4). Available from:

Felker GM, Mentz RJ, Cole RT, et al. Efficacy and safety of tolvaptan in patients hospitalized with acute heart failure. J Am Coll Cardiol. 2017;69(11):1399–406.

Konstam MA, Kiernan M, Chandler A, et al. Short-term effects of tolvaptan in patients with acute heart failure and volume overload. J Am Coll Cardiol. 2017;69(11):1409–19.

Ng TMH, Grazette LP, Fong MW, et al. Tolvaptan vs. furosemide‐based diuretic regimens in patients hospitalized for heart failure with hyponatremia (AQUA‐AHF). ESC Heart Fail. 2020;7(4):1927–34.

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):157–68.

Kimura K, Momose T, Hasegawa T, et al. Early administration of tolvaptan preserves renal function in elderly patients with acute decompensated heart failure. J Cardiol. 2016;67(5):399–405.

Yamamoto T, Miura S, Shirai K, Urata H. Renoprotective benefit of tolvaptan in acute decompensated heart failure patients with loop diuretic-resistant status. J Clin Med Res. 2019;11(1):49–55.

Kin H, Matsumura K, Yamamoto Y, et al. Renoprotective effect of tolvaptan in patients with new‐onset acute heart failure. ESC Heart Fail. 2020;7(4):1764–70.

Wang C, Xiong B, Cai L. Effects of Tolvaptan in patients with acute heart failure: a systematic review and meta-analysis. BMC Cardiovasc Disord [Internet]. 2017 Jun 20 [cited 2020 Jun 21];17. Available from:

Gheorghiade M, Konstam MA, Burnett JC, et al. 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.

Konstam MA, Gheorghiade M, Burnett JC, et al. Effects of oral tolvaptan in patients hospitalized for worsening heart failure: The EVEREST outcome trial. JAMA. 2007;297(12):1319–31.

Wang L, Zhang Q, Liu M, et al. Tolvaptan in reversing worsening acute heart failure: A systematic review and meta-analysis. J Int Med Res. 2019;47(11):5414–25.

Nakao Y, Saito M, Yamaguchi O. Effect of tolvaptan on long-term prognosis in Japanese patients with heart failure: a systematic review and meta-analysis. Eur Heart J [Internet]. 2020 Nov 1 [cited 2021 Aug 3];41(Supplement_2). Available from:

Udelson JE, McGrew FA, Flores E, et al. Multicenter, randomized, double-blind, placebo-controlled study on the effect of oral tolvaptan on left ventricular dilation and function in patients with heart failure and systolic dysfunction. J Am Coll Cardiol. 2007;49(22):2151–9.

Dasta JF, Sundar S, Chase S, Lingohr-Smith M, Lin J. Economic impact of tolvaptan treatment vs. fluid restriction based on real-world data among hospitalized patients with heart failure and hyponatremia. Hosp Pract 1995. 2018;46(4):197–202.

SAMSCA® (tolvaptan) Dose & Administration [Internet]. [cited 2020 Aug 3]. Available from:

Wu M-Y, Chen T-T, Chen Y-C, et al. Effects and safety of oral tolvaptan in patients with congestive heart failure: A systematic review and network meta-analysis. PLoS ONE [Internet]. 2017 Sep 12 [cited 2020 Jul 2];12(9). Available from:

Aditya S, Rattan A. Vaptans: A new option in the management of hyponatremia. Int J Appl Basic Med Res. 2012;2(2):77–83.

Ghali JK, Koren MJ, Taylor JR, et al. Efficacy and safety of oral conivaptan: A V1A/V2 vasopressin receptor antagonist, assessed in a randomized, placebo-controlled trial in patients with euvolemic or hypervolemic hyponatremia. J Clin Endocrinol Metab. 2006;91(6):2145–52.

Fukunami M, Matsuzaki M, Hori M, Izumi T, for the Tolvaptan Investigators. Efficacy and safety of tolvaptan in heart failure patients with sustained volume overload despite the use of conventional diuretics: A phase III open-label study. Cardiovasc Drugs Ther. 2011;25(1):47–56.

Kinugawa K, Sato N, Inomata T, Shimakawa T, Iwatake N, Mizuguchi K. Efficacy and safety of tolvaptan in heart failure patients with volume overload. Circ J Off J Jpn Circ Soc. 2014;78(4):844–52.

Khan MY, Rawala MS, Siddiqui M, Abid W, Aslam A. Tolvaptan-induced liver injury: Who is at risk? A case report and literature review. Cureus [Internet]. [cited 2020 Jul 5];11(6). Available from:

Torres VE, Chapman AB, Devuyst O, et al. Tolvaptan in patients with autosomal dominant polycystic kidney disease. N Engl J Med. 2012;367(25):2407–18.

Fujioka K, Mizuno S, Ichise T, et al. Impact of renal function on mid-term outcomes in heart failure patients treated with tolvaptan. Ther Adv Cardiovasc Dis. 2019;13:1753944718819064.

Bowman BT, Rosner MH. Lixivaptan – an evidence-based review of its clinical potential in the treatment of hyponatremia. Core Evid. 2013;8:47.

Full Text: PDF


  • There are currently no refbacks.

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.