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Vasopressin and vasopressin antagonists in heart failure and hyponatremia

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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

  1. 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.

    Article  PubMed  Google Scholar 

  2. Gheorghiade M, Zannad F, Sopko G, et al.: Acute heart failure syndromes: current state and framework for future research. Circulation 2005, 112:3958–3968.

    Article  PubMed  Google Scholar 

  3. 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.

    Article  PubMed  Google Scholar 

  4. 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.

    Article  PubMed  Google Scholar 

  5. 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.

    Article  PubMed  CAS  Google Scholar 

  6. 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.

    Article  PubMed  CAS  Google Scholar 

  7. 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.

    PubMed  CAS  Google Scholar 

  8. 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.

    Article  PubMed  CAS  Google Scholar 

  9. De Luca L, Klein L, Udelson JE, et al.: Hyponatremia in patients with heart failure. Am J Cardiol 2005, 96:19L–23L.

    PubMed  Google Scholar 

  10. 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.

    Article  PubMed  CAS  Google Scholar 

  11. Felker GM, Leimberger JD, Califf RM, et al.: Risk stratification after hospitalization for decompensated heart failure. J Card Fail 2004, 10:460–466.

    Article  PubMed  Google Scholar 

  12. 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.

    Article  PubMed  CAS  Google Scholar 

  13. Cawley MJ: Hyponatremia: current treatment strategies and the role of vasopressin antagonists. Ann Pharmacother 2007, 41:840–850.

    Article  PubMed  CAS  Google Scholar 

  14. Ali F, Raufi MA, Washington B, Ghali JK: Conivaptan: a dual receptor vasopressin v1a/v2 antagonist. Cardiovasc Drug Rev 2007, 25:261–279.

    Article  PubMed  CAS  Google Scholar 

  15. 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.

    Article  PubMed  CAS  Google Scholar 

  16. 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.

    Article  PubMed  CAS  Google Scholar 

  17. 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.

  18. 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.

    Article  PubMed  CAS  Google Scholar 

  19. 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.

    Article  PubMed  CAS  Google Scholar 

  20. 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.

    Article  PubMed  CAS  Google Scholar 

  21. 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.

    Article  PubMed  CAS  Google Scholar 

  22. 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.

    Article  PubMed  CAS  Google Scholar 

  23. 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).

  24. 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.

    Article  PubMed  CAS  Google Scholar 

  25. 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.

    Article  PubMed  CAS  Google Scholar 

  26. 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.

    Article  PubMed  CAS  Google Scholar 

  27. 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.

    Article  PubMed  CAS  Google Scholar 

  28. 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.

    PubMed  CAS  Google Scholar 

  29. 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.

    Article  PubMed  CAS  Google Scholar 

  30. 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.

    Article  PubMed  CAS  Google Scholar 

  31. 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.

    Article  PubMed  CAS  Google Scholar 

  32. 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.

    Article  PubMed  CAS  Google Scholar 

  33. 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.

    Article  PubMed  Google Scholar 

  34. 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.

    Article  PubMed  CAS  Google Scholar 

  35. 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.

    Article  PubMed  CAS  Google Scholar 

  36. 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.

    Article  PubMed  CAS  Google Scholar 

  37. 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.

    Article  PubMed  CAS  Google Scholar 

  38. 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.

    Article  PubMed  Google Scholar 

  39. Martinez-Castelao A: Lixivaptan (American Home Products). Curr Opin Investig Drugs 2001, 2:525–530.

    PubMed  CAS  Google Scholar 

  40. 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.

    Article  PubMed  CAS  Google Scholar 

  41. 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.

    PubMed  CAS  Google Scholar 

  42. 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.

    Article  PubMed  CAS  Google Scholar 

  43. 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.

    Article  PubMed  CAS  Google Scholar 

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Correspondence to Gerasimos Filippatos.

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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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