Vasopressin Receptor Antagonists

 

Goals:

1. Understand that hyponatremia is common and has serious effects
2. Understand the current treatment of hyponatremia and its limitations
3. Understand that vasopressin receptor antagonists can treat hyponatremia
4. Understand that vasopressin receptor antagonists may hold promise for CHF

 

Hyponatremia

• Is the most common electrolyte imbalance we face
• Incidence varies, but one large chart review of 120,137 patients showed

• 7.2% outpatients and 28.2% inpatients had sodium <136mmol/L.

• 0.03% outpatients and 0.49% inpatients had sodium <116mmol/L

• Serious and life threatening effects are well known and generally occur <125mmol/L
• Renneboog et al. showed in a case control study of 122 ED patients with sodium of 115-132mmol/L (avg 125) that falls occur much more frequently in patients with asymptomatic hyponatremia than controls (21.3% vs. 5.3%)

• A subset (16) of the hyponatremic patients performed worse on gait and attention testing before correction of sodium levels

• Compared to EtOH level of 0.06%

Current Treatment

• For hypo-osmotic hyponatremia, mainstay is water restriction

• Hypertonic saline with or without loop diuretics can also be used acutely, but is dangerous.

• Demeclocycline is also used (450-1200mg/day divided doses)

• Causes renal insuffiency

• Expensive (~$750 for 30 day supply)

• Osmotic demyelination (central pontine myelinolysis) is consequence of correcting levels too fast (>12mmol/L/24h)

 

Vasopressin Receptor Antagonists in Hyponatremia

• V_1A receptors are in vascular smooth muscle and mediate vasoconstriction and positive inotropy

• May also play a role in cardiac remodeling

• V₂ receptors are in the renal collecting duct and mediates free water resorbtion by upregulating aquaporin channels

               

Conivaptan

• Non-peptide antagonist at V1A/V2

• Causes increased, dilute urine production in rats (and humans)

• Two placebo controlled, double blind trials evaluating its use for hyponatremia (Verbalis and Ghali)

• Both confirmed marked serum sodium increases in treatment groups that occurred rapidly (within 24h) and persisted through the study period (4 days and 5 days)

• Results were reversible

• Thirst was a very common SE, but despite increased water intake (dramatic in a few cases) the treatment groups were net negative in water balance and had large increases in water clearance

• Approved for sale as VaprisolÒ for IV infusion for not more than 4 days in treatment of acute SIADH

• Serious interaction at p450 CYP3A4 (statins, CCB’s, digoxin, amiodarone, warfarin, among others)

• 2 case reports of rhabdomyolysis with statins

 

Tolvaptan

• Oral V2 specific antagonist

• Two parallel trials (SALT 1&2 – Schrier et al.) investigated its impact on hyponatremia

• Treatment groups had significant increases in sodium for 30 days

• Effect was dose dependant

• Major SE’s were thirst, dehydration

 

Lixivaptan and Satavaptan

• Also currently in development

 

Vasopressin in CHF

• Strong evidence that elevated AVP levels play a role in CHF

• CHF patients with hyponatremia (even mild) have increased mortality

• Two placebo controlled trials looking at tolvaptan in CHF, both acute and chronic

• Gheorghiade 2003 and Gheorghiade 2004

• In both studies patients receiving tolvaptan lost more weight and cleared more water

• In the second study, there was a significant mortality benefit at 60 days in patients with severe CHF who received tolvaptan, although the study was not designed/powered to look at this

• Efficacy of Vasopressin antagonism in hEart failuRE: outcome Study with Tolvaptan (EVEREST) trial currently underway to assess outcomes in CHF. Should be published in next couple months

• May be most beneficial in the subset of CHF patients that are hyponatremic

• Currently no good evidence that vasopressin blockade is beneficial in CHF

 

References

• Decaux,G. Is asymptomatic hyponatremia really asymptomatic? Am J Med. 119(7) s1:S79-S82

• Ghali JK, Koren MJ, Taylor JR, Brooks-Asplund E, Kaisheng F, Long WA, Smith N. 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.

• Gheorghiade, M; Niazi I; Ouyang J et al. for the Tolvaptan Investigators. Vasopressin V2-receptor blockade with tolvaptan in patients with chronic heart failure. Circulation 2003; 107:2690-2696

• Gerbes AL, Gülberg V, Ginès P. Therapy of hyponatremia in cirrhosis with a vasopressin receptor antagonist: a randomized double-blind multicenter trial. Gastroenterology 2003;124:933-939.

• Goldsmith SR, Francis GS, Cowley AW, Levine TB, Cohn JN. Increased plasma arginine vasopressin levels in patients with congestive heart failure. J Am Coll Cardiol. 1983;1:1385-1390

• Goldsmith SR. Efficacy and safety of conivaptan in acute decompensated heart failure; a dose-ranging pilot study. J Card Fail. 2006;12(6) Suppl: S72.

• Gross P, Decaux G, Gerbes AL. Double blind, placebo-controlled study of the activity and tolerance of two doses of VPA-985 in patients with hyponatremia. J Am Soc Nephrol 1999;10:121A. (abstr)

• Lee DS; Austin PC; Rouleau JL; Liu PP; Naimark D;  Tu JV  Predicting Mortality Among Patients Hospitalized for Heart Failure: Derivation and Validation of a Clinical Model JAMA 290: 2581-2587

• 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(2): 257-267

• Quittnat F; Gross P. Vaptans and the treatment of water-retaining disorders. Semin. Nephrol. 2006 May;26(3):234-43.

• Schrier RW; Gross P; Gheorghiade, M; Berl T; Verbalis J; et al. Tolvaptan, a Selective Oral Vasopressin V2-Receptor Antagonist, for Hyponatremia. N Eng J Med. 355(20) 2099-2112.

• Soupart A, Gross P, Legros JJ. Successful long-term treatment of hyponatremia in syndrome of inappropriate antidiuretic hormone secretion in with SR 121 463 B, an orally active, nonpeptide, vasopressin V-2 receptor antagonist. J Am Soc Nephrol 2004;15:563A. (abstr)

• http://www.utdol.com/utd/content/topic.do?topicKey=fldlytes/29369&type=A&selectedTitle=4~102 “Treatment of hyponatremia” UpToDate Online

• Verbalis JG, Bisaha JG, Smith N. Novel vasopressin V1a and V2 antagonist (conivaptan) increases serum sodium concentration and effective water clearance in patients with hyponatremia. Circulation. 2004;110(Suppl 3):723. [Abstract].