Vasopressin Receptor Antagonists for the Treatment of Hyponatremia
in patients with hyponatremia and CHF or cirrhosis is problematic secondary to the poor inherent prognosis of these conditions. It is still of importance to acknowledge that the majority of patients in SALTWATER had improved serum sodium concentrations and less need for fluid restriction. This was accomplished safely and without the risk of too rapid correction of the serum sodium concentration. It is also difficult to judge if hyponatremia is the only metric that should guide the use of vaptans in chronic hyponatremia. To date there is no evidence to suggest improved survival or improved symptoms associated with treated hyponatremia.40
Tolvaptan has also been studied as a treatment for decompensated CHF irrespective of serum sodium. The rationale for this approach was to assess the potential benefit of pharmacological blockade of ADH, a hormone that is significantly and persistently elevated in patients with CHF. A small clinical trial had previously shown that tolvaptan significantly increases urinary output and decreases body weight without causing electrolyte disturbances or worsening renal function.41
tolvaptan was associated with a significant improvement in the combined endpoint of self-reported global clinical status and fluid loss, but the difference was driven entirely by a 0.7 kg difference in weight loss between the two groups during the index hospitalization. In the long-term arm, with a median follow-up period of 9.9 months, tolvaptan was not associated with improved survival, improved CHF management, or decreased need for re-hospitalization. This study does not address treatment of hyponatremia even in patients with CHF, but does provide some assurance, in a large-scale, carefully adjudicated trial, that tolvaptan is safe.34,42
Conclusion and Recommendation
The Efficacy of vasopressin antagonism in heart failure outcome study with tolvaptan (EVEREST) trial was designed to prove the hypothesis that tolvaptan would improve symptoms and survival in patients admitted to the hospital with acute decompensated CHF. A total of 4,133 patients hospitalized with heart failure were randomized to receive tolvaptan 30 mg orally once a day (n=2072) or placebo (n=2,061). Hyponatremia was not an inclusion criterion, and only 7.7 % of the study participants had hyponatremia as defined by serum sodium levels below 134 mmol/l. In the short-term arm,
1. Upadhyay A, Jaber BL, Madias NE, Incidence and prevalence of hyponatremia, Am J Med, 2006;119:S30–5.
2. 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;73:257–67.
3. Wald R, Jaber BL, Price LL, et al., Impact of hospital-associated hyponatremia on selected outcomes, Arch Intern Med, 2010;170:294–302.
4. Waikar SS, Mount DB, Curhan GC, Mortality after hospitalization with mild, moderate, and severe hyponatremia, Am J Med, 2009;122:857–65.
5. Gill G, Huda B, Boyd A, et al., Characteristics and mortality of severe hyponatraemia—a hospital-based study, Clin Endocrinol, 2006;65:246–9.
6. Baran D, Hutchinson TA, The outcome of hyponatremia in a general hospital population, Clin Nephrol, 1984;22:72–6.
7. Whelan B, Bennett K, O’Riordan D, et al., Serum sodium as a risk factor for in-hospital mortality in acute unselected general medical patients, QJM, 2009;102:17582.
8. Hoorn EJ, Zietse R, Hyponatremia and mortality: how innocent is the bystander?, Clin J Am Soc Nephrol, 2011;6:951–3.
9. Chawla A, Sterns RH, Nigwekar SU, et al., Mortality and serum sodium: do patients die from or with hyponatremia?, Clin J Am Soc Nephrol, 2011;6:960–5.
10. Adrogue HJ, Madias NE, Hyponatremia, N Engl J Med, 2000;342:1581–9.
11. Schrier RW, Pathogenesis of sodium and water retention in high-output and low-output cardiac failure, nephrotic syndrome, cirrhosis, and pregnancy (1), N Engl J Med, 1988;319:1065–72.
12. Schrier RW, Pathogenesis of sodium and water retention in high-output and low-output cardiac failure, nephrotic syndrome, cirrhosis, and pregnancy (2), N Engl J Med, 1988;319:1127–34.
13. Rao R, Zhang MZ, Zhao M, et al., Lithium treatment inhibits renal GSK-3 activity and promotes cyclooxygenase 2-dependent polyuria, Am J Physiol Renal Physiol, 2005;288:F642–9.
14. Cherrill DA, Stote RM, Birge JR, et al., Demeclocycline treatment in the syndrome of inappropriate antidiuretic hormone secretion, Ann Intern Med, 1975;83:654–6.
15. Zietse R, van der Lubbe N, Hoorn EJ, Current and future treatment options in SIADH, NDT Plus, 2009;2:iii12–19.
16. Serros ER, Lowe AG, Kirschenbaum MA, Effect of prostaglandin inhibition on demeclocycline administration in conscious rats,
The use of VRAs is indicated for patients with euvolemic and hypervolemic hyponatremia. Patients with hypovolemic hyponatremia should be treated with normal saline and the use of vaptans is contraindicated in this setting. Vaptans have not been studied in acute symptomatic hyponatremia and hypertonic saline should be used instead. Vaptans reproducibly raise the serum sodium concentration in patients with hyponatremia and decrease the need for conventional therapy including water restriction. Vaptans are safe regarding the rate of correction of hyponatremia. In all published trials using vaptans including more than 2,000 patients who received tolvaptan with CHF, not a single patient developed osmotic demyelination. To date, it has not been established whether the use of vaptans improves mortality and morbidity associated with hyponatremia. Nevertheless, vaptans represent an important addition to the current armamentarium available to correct hyponatremia. n
Prostaglandins Med, 1980;5:175–82.
17. Curtis NJ, van Heyningen C, Turner JJ, Irreversible nephrotoxicity from demeclocycline in the treatment of hyponatremia, Age Ageing, 2002;31:151–2.
18. Zietse R, Zoutendijk R, Hoorn EJ, Fluid, electrolyte and acid-base disorders associated with antibiotic therapy, Nat Rev Nephrol, 2009;5:193–202.
19. Sterns RH, Cappuccio JD, Silver SM, et al., Neurologic sequelae after treatment of severe hyponatremia: a multicenter perspective, J Am Soc Nephrol, 1994;4:1522–30.
20. Verbalis JG, Goldsmith SR, Greenberg A, et al., Hyponatremia treatment guidelines 2007: expert panel recommendations, Am J Med, 2007;120:S1–21.
21. Klein L, O’Connor CM, Gattis WA, et al., Pharmacologic therapy for patients with chronic heart failure and reduced systolic function: review of trials and practical considerations, Am J Cardiol, 2003;91:18F–40F.
22. Schrier RW, Berl T, Anderson RJ, Osmotic and nonosmotic control of vasopressin release, Am J Physiol, 1979;236:F321–32.
23. Thibonnier M, Conarty DM, Preston JA, et al., Molecular pharmacology of human vasopressin receptors, Adv Exp Med Biol, 1998;449:251–76.
24. Birnbaumer M, Vasopressin receptors, Trends Endocrinol Metab, 2000;11:406_10.
25. Kinter LB, Dytko G, Ashton D, et al., Discovery and therapeutic utility of vasopressin antagonists in rats, J Cardiovasc Pharmacol, 1986;8(Suppl. 7):S36–43.
26. Yamamura Y, Ogawa H, Chihara T, et al., OPC-21268, an orally effective, nonpeptide vasopressin V1 receptor antagonist, Science, 1991;252:572–4.
27. Saito T, Ishikawa S, Abe K, et al., Acute aquaresis by the nonpeptide arginine vasopressin (AVP) antagonist OPC-31260 improves hyponatremia in patients with syndrome of inappropriate secretion of antidiuretic hormone (SIADH), J Clin Endocrinol Metab, 1997;82:1054–7.
28. Yatsu T, Tomura Y, Tahara A, et al., [Pharmacology of conivaptan hydrochloride (YM087), a novel vasopressin V1A/V2 receptor antagonist]. Nihon Yakurigaku Zasshi, 1999;114(Suppl. 1):113P–17P.
29. Decaux G, Long-term treatment of patients with inappropriate secretion of antidiuretic hormone by the vasopressin receptor antagonist conivaptan, urea, or furosemide, Am J Med, 2001;110:582–4.
30. 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;91:2145–52.
31. 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;27:447–57.
32. 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;287:860–7.
33. Berl T, Quittnat-Pelletier F, Verbalis JG, et al., Oral tolvaptan is safe and effective in chronic hyponatremia, J Am Soc Nephrol, 2010;21:705–12.
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;297:1332–43.
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;297:1319–31.
36. Schrier RW, Gross P, Gheorghiade M, et al., Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia, N Engl J Med, 2006;355:2099112.
37. Shea AM, Hammill BG, Curtis LH, et al., Medical costs of abnormal serum sodium levels, J Am Soc Nephrol, 2008;19:764–70.
38. Terzian C, Frye EB, Piotrowski ZH, Admission hyponatremia in the elderly: factors influencing prognosis, J Gen Intern Med, 1994;9:89–91.
39. Renneboog B, Musch W, Vandemergel X, et al., Mild chronic hyponatremia is associated with falls, unsteadiness, and attention deficits, Am J Med, 2006;119:71.e1–8.
40. Greenberg A, Lehrich RW, Treatment of chronic hyponatremia: now we know how, but do we know when or if?, J Am Soc Nephrol, 2010;21:552–5.
41. 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 (ACTIV in CHF), JAMA, 2004;291:1963–71.
42. 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;11:260–9.
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