Abstract
Increased synthesis of arginine vasopressin (AVP) plays a critical role in fluid retention and hyponatremia in patients with heart failure. The AVP receptor antagonists constitute a new class of agents that are promising in the management of hyponatremia and congestion. Three of these agents—conviaptan, tolvaptan, and lixivaptan—have been studied in clinical settings. All are effective in inducing aquaresis (ie, electrolyte-free water excretion) and normalizing serum sodium concentration. They are well tolerated without causing electrolyte disorders, hypotension, or renal impairment. Conivaptan has been approved by the US Food and Drug Administration for short-term intravenous treatment of euvolemic hyponatremia of variable etiology but has not been adequately studied in heart failure. The addition of tolvaptan to standard therapy in hospitalized patients with heart failure has led to symptomatic improvement and decreased body weight, but there is no long-term clinical benefit. Early data on lixivaptan in heart failure suggest a dose-dependent aquaresis effect, and larger studies are under way.
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References and Recommended Reading
Rosamond W, Flegal K, Friday G, et al.: Heart disease and stroke statistics—2007 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 2007, 115:e69–e171.
Gheorghiade M, Zannad F, Sopko G, et al.: Acute heart failure syndromes: current state and framework for future research. Circulation 2005, 112:3958–3968.
Gheorghiade M, Filippatos G, De Luca L, Burnett J: Congestion in acute heart failure syndromes: an essential target of evaluation and treatment. Am J Med 2006, 119(12 Suppl. 1):S3–S10.
Gheorghiade M, Rossi JS, Cotts W, et al.: Characterization and prognostic value of persistent hyponatremia in patients with severe heart failure in the ESCAPE Trial. Arch Intern Med 2007, 167:1998–2005.
Gheorghiade M, Abraham WT, Albert NM, et al.: Relationship between admission serum sodium concentration and clinical outcomes in patients hospitalized for heart failure: an analysis from the OPTIMIZE-HF registry. Eur Heart J 2007, 28:980–988.
Verbalis JG, Goldsmith SR, Greenberg A, et al.: Hyponatremia treatment guidelines 2007: expert panel recommendations. Am J Med 2007, 120(11 Suppl 1):S1–S21.
Lee WH, Packer M: Prognostic importance of serum sodium concentration and its modification by converting-enzyme inhibition in patients with severe chronic heart failure. Circulation 1986, 73:257–267.
Klein L, O’Connor CM, Leimberger JD, et al.: Lower serum sodium is associated with increased short-term mortality in hospitalized patients with worsening heart failure: results from the OPTIME-CHF study. Circulation 2005, 111:2454–2460.
De Luca L, Klein L, Udelson JE, et al.: Hyponatremia in patients with heart failure. Am J Cardiol 2005, 96:19L–23L.
Chin MH, Goldman L: Correlates of major complications or death in patients admitted to the hospital with congestive heart failure. Arch Intern Med 1996, 156:1814–1820.
Felker GM, Leimberger JD, Califf RM, et al.: Risk stratification after hospitalization for decompensated heart failure. J Card Fail 2004, 10:460–466.
Rich MW, Beckham V, Wittenberg C, et al.: A multidisciplinary intervention to prevent the readmission of elderly patients with congestive heart failure. N Engl J Med 1995, 333:1190–1195.
Cawley MJ: Hyponatremia: current treatment strategies and the role of vasopressin antagonists. Ann Pharmacother 2007, 41:840–850.
Ali F, Raufi MA, Washington B, Ghali JK: Conivaptan: a dual receptor vasopressin v1a/v2 antagonist. Cardiovasc Drug Rev 2007, 25:261–279.
Lee CR, Watkins ML, Patterson JH, et al.: Vasopressin: a new target for the treatment of heart failure. Am Heart J 2003, 146:9–18.
Costello-Boerrigter LC, Smith WB, Boerrigter G, et al.: Vasopressin-2-receptor antagonism augments water excretion without changes in renal hemodynamics or sodium and potassium excretion in human heart failure. Am J Physiol Renal Physiol 2006, 290:F273–F278.
US Food and Drug Administration: Patient information sheet: conivaptan (marketed as Vaprisol). Available at http://www.fda.gov/CDER/drug/InfoSheets/patient/conivaptanPIS.htm. Accessed April 9, 2008.
Wada K, Matsukawa U, Fujimori A, et al.: A novel vasopressin dual V1A/V2 receptor antagonist, conivaptan hydrochloride, improves hyponatremia in rats with syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Biol Pharm Bull 2007, 30:91–95.
Wada K, Tahara A, Arai Y, et al.: Effect of the vasopressin receptor antagonist conivaptan in rats with heart failure following myocardial infarction. Eur J Pharmacol 2002, 450:169–177.
Wada K, Fujimori A, Matsukawa U, et al.: Intravenous administration of conivaptan hydrochloride improves cardiac hemodynamics in rats with myocardial infarction-induced congestive heart failure. Eur J Pharmacol 2005, 507:145–151.
Yatsu T, Tomura Y, Tahara A, et al.: Cardiovascular and renal effects of conivaptan hydrochloride (YM087), a vasopressin V1A and V2 receptor antagonist, in dogs with pacing-induced congestive heart failure. Eur J Pharmacol 1999, 376:239–246.
Yatsu T, Kusayama T, Tomura Y, et al.: Effect of conivaptan, a combined vasopressin V(1a) and V(2) receptor antagonist, on vasopressin-induced cardiac and haemodynamic changes in anaesthetised dogs. Pharmacol Res 2002, 46:375–381.
Verbalis JG, Zeltser D, Smith N, et al.: Assessment of the efficacy and safety of intravenous conivaptan in patients with euvolemic hyponatremia: subgroup analysis of a randomized, controlled study. Clin Endocrinol 2007 Nov 22 (Epub ahead of print).
Zeltser D, Rosansky S, van Rensburg H, et al.: Assessment of the efficacy and safety of intravenous conivaptan in euvolemic and hypervolemic hyponatremia. Am J Nephrol 2007, 27:447–457.
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, 91:2145–2152.
Udelson JE, Smith WB, Hendrix GH, et al.: Acute hemodynamic effects of conivaptan, a dual V(1A) and V(2) vasopressin receptor antagonist, in patients with advanced heart failure. Circulation 2001, 104:2417–2423.
Kondo K, Ogawa H, Yamashita H, et al.: 7-Chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzoyl-amino)benzoyl]-2,3,4,5-tetrahydro-1H-1-benzazepine (OPC-41061): a potent, orally active nonpeptide arginine vasopressin V2 receptor antagonist. Bioorg Med Chem 1999, 7:1743–1754.
Yamamura Y, Nakamura S, Itoh S, et al.: OPC-41061, a highly potent human vasopressin V2-receptor antagonist: pharmacological profile and aquaretic effect by single and multiple oral dosing in rats. J Pharmacol Exp Ther 1998, 287:860–867.
Gheorghiade M, Gottlieb SS, Udelson JE, et al.: Vasopressin v(2) receptor blockade with tolvaptan versus fluid restriction in the treatment of hyponatremia. Am J Cardiol 2006, 97:1064–1067.
Schrier RW, Gross P, Gheorghiade M, et al.: Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia. N Engl J Med 2006, 355:2099–2112.
Gheorghiade M, Niazi I, Ouyang J, et al.: Vasopressin V2-receptor blockade with tolvaptan in patients with chronic heart failure: results from a double-blind, randomized trial. Circulation 2003, 107:2690–2696.
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, 291:1963–1971.
Rossi J, Bayram M, Udelson JE, et al.: Improvement in hyponatremia during hospitalization for worsening heart failure is associated with improved outcomes: insights from the Acute and Chronic Therapeutic Impact of a Vasopressin Antagonist in Chronic Heart Failure (ACTIV in CHF) trial. Acute Card Care 2007, 9:82–86.
Gheorghiade M, Konstam MA, Burnett JC Jr, 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, 297:1332–1343.
Konstam MA, Gheorghiade M, Burnett JC Jr, et al.: Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the EVEREST Outcome Trial. JAMA 2007, 297:1319–1331.
Gheorghiade M, Orlandi C, Burnett JC, et al.: Rationale and design of the multicenter, randomized, double-blind, placebo-controlled study to evaluate the Efficacy of Vasopressin antagonism in Heart Failure: Outcome Study with Tolvaptan (EVEREST). J Card Fail 2005, 11:260–269.
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, 49:2151–2159.
Mehra MR, Rockman HA, Greenberg BH: Highlights of the 2007 Scientific Meeting of the Heart Failure Society of America. J Am Coll Cardiol 2008; 51:320–327.
Martinez-Castelao A: Lixivaptan (American Home Products). Curr Opin Investig Drugs 2001, 2:525–530.
Gerbes AL, Gülberg V, Ginès P, et al.: Therapy of hyponatremia in cirrhosis with a vasopressin receptor antagonist: a randomized double-blind multicenter trial. Gastroenterology 2003, 124:933–939.
Martin PY, Abraham WT, Lieming X, et al.: Selective V2-receptor vasopressin antagonism decreases urinary aquaporin-2 excretion in patients with chronic heart failure. J Am Soc Nephrol 1999, 10:2165–2170.
Wong F, Blei AT, Blendis LM, Thuluvath PJ: A vasopressin receptor antagonist (VPA-985) improves serum sodium concentration in patients with hyponatremia: a multicenter, randomized, placebo-controlled trial. Hepatology 2003, 37:182–191.
Abraham WT, Shamshirsaz AA, McFann K, et al.: Aquaretic effect of lixivaptan, an oral, non-peptide, selective V2 receptor vasopressin antagonist, in New York Heart Association functional class II and III chronic heart failure patients. J Am Coll Cardiol 2006, 47:1615–1621.
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Farmakis, D., Filippatos, G., Kremastinos, D.T. et al. Vasopressin and vasopressin antagonists in heart failure and hyponatremia. Curr Heart Fail Rep 5, 91–96 (2008). https://doi.org/10.1007/s11897-008-0015-z
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DOI: https://doi.org/10.1007/s11897-008-0015-z