Vaptans and Cirrhosis: The Greatest Thing Since Sliced Bread?

How safe and effective are the vaptans in cirrhotic patients with ascites?

There has been substantial press attesting to the efficacy and safety of the “vaptans.” These agents are vasopressin receptor antagonists that block so-called “V₂” receptors in the collecting ducts, thereby decreasing reabsorption of water. One cohort with troublesome volume overload and hyponatremia (that is too much water for an expanded total body volume) consists of patients with cirrhosis and ascites. Vaptans are commonly administered to these patients. Do they work and are they safe?

A LOOK AT THE SAFETY AND EFFICACY DATA

A recent meta-analysis addressed the safety and efficacy of vaptans in cirrhotic persons with ascites.¹ Twelve trials with a total of 2266 patients were included. Eight of these trials were double-blinded; all were randomized.

The agents do increase serum sodium concentration and decrease ascites volume. But, vaptans provided no benefit in regard to mortality (RR=1.06, 95% CI=0.90-126), variceal bleeding, hepatic encephalopathy, spontaneous bacterial peritonitis, hepatorenal syndrome, or renal failure. They did decrease weight and time to first paracentesis, minor endpoints at best. Vaptans also increased the number of adverse events, serious adverse events, and patient withdrawals from active treatment. In defense of vaptans, however, there were no differences between vaptan versus placebo entrants in dangerous, rapid rises in serum sodium concentration, serum creatinine, or serum potassium.

When the FDA approved tolvaptan in 2009 for hypervolemic and euvolemic hyponatremia, a special caution was added regarding administration in persons with cirrhosis.¹ Interestingly enough, the caveat was directed at tolvaptan’s depletion of vitamin K–dependent clotting factors and potential to inhibit platelet aggregation. One trial utilized in the meta-analysis revealed more gastrointestinal bleeding, hematomas, and ecchymoses in patients who were treated with tolvaptan.¹

A FEW MORE CAVEATS

Looking at other recent publications that have addressed the issue (by a PubMed search), a number of other caveats were uncovered. Do not use vaptans in the setting of hypovolemic hyponatremia.² Effects may vary substantially from patient to patient, so vaptans may be less useful in cases of acute, severe, symptomatic hyponatremia.² Old standbys such as water restriction and hypertonic saline may be safer. In the setting of syndrome of inappropriate antidiuretic hormone secretion (SIADH), another review commented, “Further trials are needed to determine the optimal dosing, proper monitoring, and adequate precautions for the use of vaptans in this patient population (SIADH).”³ Another said, “The optimal vaptan regimen to treat SIADH is currently not established . . . we are hesitant to consider vaptans a treatment of choice for the inappropriate hyponatremias.”⁴ Finally, another reference warns that conivaptan (both a V_1a and V₂ receptor blocker) can cause splanchnic vasodilatation in cirrhotic persons, a condition to be avoided.⁵

Vaptans have the potential to be remarkable agents for treating hyponatremia. However, early experience suggests caution in their use and humility in claims regarding their benefits in cirrhosis.