A 56 year old male with alcoholic cirrhosis has been abstinent for 3 months and is being followed for increasing ascites. He was initially treated with diuretics with good control of his ascites. Recently, despite an 88 mmol sodium diet, fluid restriction of 1200 cc daily and increasing doses of diuretics, his ascites has worsened leading to monthly large volume paracenteses. He currently is receiving spironolactone 200 mg and furosemide 120 mg daily. When last seen a week earlier his creatinine was 1.6 mg/dL, potassium 3.9 mmol/L, sodium 128 mmol/L, total bilirubin 3.4 mg/dl, albumin 2.6 g/dL and INR 1.8 (MELD score 22, Child-Pugh score 11-class C). He now presents to the emergency room because of increasing abdominal girth and difficulty breathing. In the emergency room his laboratory tests are unchanged except his serum sodium is now 122 mmol/L. The patient is admitted because of his refractory ascites and worsening hyponatremia.
How does the development of hyponatremia affect his prognosis?
What is the role of the new vasopressin V2receptor antagonist, tolvaptan, in his management both as an inpatient and outpatient?
Would maintaining his serum sodium at near normal levels affect his prognosis?
AQP, aquaporin; AVP, arginine vasopressin; cAMP, cyclic adenosine monophosphate; MELD, model for endstage liver disease; PKA, protein kinase A.
2. The problem
Disorders of water metabolism are common in patients with cirrhosis. Most commonly there is a reduced ability to excrete solute-free water by the kidney leading to hyponatremia. The primary reason for this inability to excrete solute-free water in the patient with cirrhosis is an increase in levels of arginine vasopressin (AVP). The nonosmotic secretion of AVP in these patients is thought to be due to arterial splanchnic vasodilation and arterial underfilling leading to activation of baroreceptors that regulate the release of AVP.1, 2 Hyponatremia is common in the patient with cirrhosis and the severity of hyponatremia is a marker of more advanced disease. In one large series, the prevalence of hyponatremia (serum Na <135 mmol/L) was high in inpatients (57%) and outpatients (40%). Twenty one percent of patients with cirrhosis had a serum sodium level of ≤ 130 mmol/L. Patients with hyponatremia had worse ascites that was more difficult to treat, and were more likely to suffer from hepatic encephalopathy and hepatorenal syndrome. Patients with a serum Na ≤130 mmol/L, despite the presence of more ascites, were more likely to be off diuretics compared to those with higher serum Na levels, suggesting diuretics had been stopped in the former because of the hyponatremia.3 The development of hyponatremia is also a marker of an increased risk of death in cirrhosis independent of the MELD score.4, 5 Lastly, patients with hyponatremia undergoing liver transplantation appear to be at increased risk of neurologic injuries, renal failure and infections in the immediate post-transplant period.6 Hence, hyponatremia is common in cirrhosis, is associated with more severe complications of portal hypertension, complicates the management of the ascites, and its development indicates a poor prognosis for the patient.
Hyponatremia is difficult to treat. The approach used for most patients is fluid restriction. This is a difficult treatment for both the patients and the physician and is of limited effectiveness even in an inpatient environment. For example, in one report serum sodium failed to rise over 7 days of fluid restriction, (1.5 L daily) in patients hospitalized and receiving diuretics.7 Even if the serum sodium rises the rate of increase is usually slow and if the hyponatremia is severe, <125 mmol/L, a prolonged hospitalization may be required. Also during this period diuretics are frequently held leading to worsening ascites. More rapid correction can be achieved with the infusion of hypertonic saline. However, this will worsen the fluid retention and puts the patient at risk for development of hypernatremia and osmotic demyelination. A number of other agents including demeclocycline, urea, and kappa-opioids have been used to correct hyponatremia in cirrhosis but complications of therapy have lead to their abandonment.8 The development of a new class of drugs that block the effects of AVP on the renal tubule has lead to hope that a new and effective therapy is now available for the patient with cirrhosis and hyponatremia.
3. Vasopressin V2-receptor antagonists
The effect of AVP on water homeostasis is mediated via its effect on water transport by the principle cells in the collecting duct. AVP binds to the V2 receptor on the basolateral membrane of the principle cells leading to activation of the Gs-coupled adenylyl cyclase system and an increase in levels of cyclic adenosine monophosphate (cAMP). Protein kinase A (PKA) is stimulated by cAMP leading to phosphorylation of preformed aquaporin-2 (AQP2) which is then translocated to the apical membrane making the cells more water permeable (Fig 1A).9 An increase in AVP, as is seen in cirrhosis, causes more AQP2 to move to the apical membrane making the cells more permeable to water. This decreases solute-free water clearance leading to the development of hyponatremia (Fig. 1B). Drugs such as tolvaptan by binding to the V2 receptor block the effect of AVP resulting in an increase in solute-free water clearance and correction of the hyponatremia (Fig. 1C). In addition, this group of drugs causes a mild natriuresis, increases urine output, and causes more rapid weight loss compared to patients not receiving the drug.10, 11
Tolvaptan (Samsca, Otsuka America Pharmaceutical, Inc, Tokyo, Japan) was recently approved by the FDA for the treatment of hyponatremia in patients with cirrhosis. This approval was based on two randomized controlled trials comparing placebo to tolvaptan in patients with hyponatremia.11 The majority of the patients in the studies suffered from congestive heart failure; there were only 63 patients with cirrhosis who received tolvaptan. Patients with a Child-Pugh score of >10 or sodium >120 mmol/L were excluded. Patients were treated for up to 30 days and during the first 4 days the dose of tolvaptan could be increased depending upon the response to treatment. Serum sodium rose quickly in those receiving tolvaptan and was ≥135 mmol/L by day 20. Discontinuation of the treatment was associated with a fall in serum sodium. No mention is made of the use of diuretics in this group of patients.11
The adverse events seen with tolvaptan are shown in Table 1. There was no mention of the adverse events in patients with congestive heart failure versus cirrhosis except for the increase risk of gastro-intestinal bleeding in patients with cirrhosis receiving tolvaptan. This issue was discussed during the FDA review of tolvaptan and the increased risk of bleeding may be due to the effect of tolvaptan on vitamin K dependent clotting factors and platelet function.12 No difference in survival was seen with tolvaptan vs. placebo but the patients were treated for a maximum of only 30 days. However in a longer study of up to one year the use of another vasopressin V2 antagonist, satavaptan, in combination with diuretics was associated with an increase in mortality compared to placebo leading to withdrawal of the drug by the pharmaceutical company Sanofi-Aventis. Somewhat more variceal bleeding was observed in those receiving satavaptan but other adverse events occurred at the same frequency in treated vs. control groups. The reason for an increase in death rate in those receiving satavaptan appeared to be due to a more frequent fatal outcome with a particular adverse event.13
Table 1. Adverse Reactions (>2% More Than Placebo) from Controlled Trials
Tolvaptan 15mg/day-60mg/day N = 223 %
Placebo N = 220 %
Data taken from Table 1 in package insert and FDA website.
GI bleeding 63 treated versus 57 controls
4. Monitoring for drug-related adverse events
The adverse event most feared in the use of these drugs is a too rapid rise in serum sodium (>12 mmol/L/24 hours) leading to hypernatremia, osmotic demyelination and CNS injury. In the long term study with satavaptan, 9.5% of patients had a serum sodium of >145 mmol/L.13 Therefore, the FDA has included a black box warning that institution of therapy should occur in an inpatient setting with close monitoring of serum sodium. Also, as patients with cirrhosis may be at risk for more side effects, slower rates of increase are recommended by the FDA. Patients with cirrhosis tolerate hyponatremia with minimal neurologic sequelae and therefore use of tolvaptan should be limited to those with serum sodiums of <125 mmol/L. Daily or every other day serum sodium levels should be determined while patients are receiving tolvaptan. Also, tolvaptan causes a diuresis, which if excessive, could lead to renal insufficiency. The use of diuretics in combination with tolvaptan has not been studied, but when diuretics were used with satavaptan, there was better control of the ascites without a significant decrease in renal dysfunction.13 Monitoring of renal function should be performed when patients receive tolvaptan, especially in concert with diuretics, until more experience is gained with the use of this drug in patients with cirrhosis. The one side effect of major concern is the increased risk of variceal bleeding, and perhaps gastro-intestinal tract bleeding in general. There is no way to monitor for this risk but patients with known high risk varices or a past history of variceal or gastrointestinal tract bleeding probably should not receive tolvaptan.
5. Areas of uncertainty
Tolvaptan has been used in fewer than 100 patients with cirrhosis and hyponatremia, and most of the safety data the FDA relied upon is from patients with congestive heart failure.12 Therefore, it remains unclear how safe this drug is in patients with cirrhosis. In addition, a similar drug when used for up to a year in patients with cirrhosis, ascites and hyponatremia was associated with an increased risk of dying. A similar association has not been seen with tolvaptan but the drug was only given for 30 days so the long term risks and benefits with tolvaptan are unknown. We also lack information on how tolvaptan works when given in concert with diuretics. As these V2 receptor antagonists cause a diuresis it is possible that patients may develop renal insufficiency when the drug is given with diuretics. Lastly, patients with Child-Pugh scores of greater than 10 were excluded in the tolvaptan trials. The more severe forms of hyponatremia (Na <125 mmol/L) are seen in patients with more advanced liver disease, and hence the safety and efficacy of tolvaptan in this group of patients with cirrhosis is unknown as well. About 30% of patients in the satavaptan trial had Child-Pugh scores of >10.13 As this study showed an increased risk of mortality, the concern about giving V2 receptor antagonists to patients with advanced liver disease appears warranted. Clearly we need more studies of tolvaptan in patients with cirrhosis in order to better define how to use this drug.
The use of tolvaptan should be limited to the inpatient setting to correct severe (Na <125 mmol/L) hyponatremia in the patient with cirrhosis. The current recommendation for initial use of tolvaptan is to increase the dose gradually from 15mg a day to 60 mg a day. The dose increase is targeted to achieve a serum sodium level of 135 mmol/L, with the rise in serum sodium being no greater than 12 mmol/L/day, but this recommendation should not be applied to patients with cirrhosis. There are two reasons: firstly, there may be enhanced toxicity of the drug in patients with cirrhosis, and secondly, patients with cirrhosis tolerate hyponatremia quite well and rapid correction is unnecessary. The goal for the inpatient should be a gradual rise (6-10 mmol/L/day) in serum sodium to >130 mmol/L allowing for reinstitution of diuretic therapy and discharge of the patient.
How to use this drug in the outpatient setting and in combination with diuretics is unknown. Concerns about overly vigorous diuresis leading to renal insufficiency and lack of data on long term safely are the major reasons tolvaptan should not be considered for outpatient usage. If it is used for outpatients, the length of time the patient receives the drug should be brief (a few days) and careful monitoring of serum sodium and renal function should be performed.
It is disappointing that more studies were not performed in the patient with cirrhosis to help the practitioner better use this drug for the management of a common complication of cirrhosis. Although there is no evidence that correcting the serum sodium influences the patient's prognosis, it is clear that hyponatremia when severe leads to hospitalization, discontinuation of diuretics and fluid restriction, all of which are undesirable outcomes. Further studies combining tolvaptan with diuretics, extending the period of treatment and using different end-points such as hospitalizations for hyponatremia, need for more or less diuretics to control the ascites, and need for paracentesis, would better define how to use this important new class of drugs in the patient with cirrhosis and ascites.
Tolvaptan is marketed by Otsuka America Pharmaceutical, Inc as Samsca. The price for a 30 day supply of either the 15mg or the 30mg strength tablet taken once a day is approximately $ 10,000.