Pharmacological approach to managing portal hypertension
The goal of treatment for portal hypertension varies depending on the different stages and substages of cirrhosis, and hence, pharmacological therapies for managing portal hypertension should be considered in the context of other complications of cirrhosis, according to a presentation at the recent APASL 2017 held in Shanghai, China recently.
“Most studies have focused on treating/preventing variceal haemorrhage, but it is now recognized that the objective of treatment should also be to prevent other complications of cirrhosis and death,” said Professor Guadalupe Garcia-Tsao, president of the AASLD* and director of the Clinical and Translational Core at Yale Liver Center, Yale School of Medicine in New Haven, Connecticut, US.
Cirrhosis is the most common cause of portal hypertension, which can lead to the formation of gastroesophageal varices and variceal haemorrhage, according to Garcia-Tsao, who explained that cirrhosis complications such as variceal haemorrhage, ascites, and encephalopathy are some of the defining features of decompensation.
In the earlier disease stage, the objective of managing compensated patients without clinically significant portal hypertension (CSPH) is to prevent CSPH, she said.
“For patients with compensated cirrhosis and CSPH but without varices, the main objective of treatment should no longer be to prevent varices, but to prevent clinical decompensation,” said Garcia-Tsao, citing recommendations from the latest AASLD practice guidance. [Hepatology 2017;65:310-335]
Recent data from a double-blind placebo-controlled trial showed that that decompensation rate was lower in the nonselective β-blocker (NSBB) arm compared with the placebo arm (16 percent vs 17 percent; p=0.11), although the difference was not statistically different. Nonetheless, ascite development rate was significantly lower in the NSBB arm than placebo controls (9 percent vs 20 percent; p=0.037). [Villanueva, AASLD 2016]
Additionally, statins were also associated with a decreased risk of decompensation (hazard ratio [HR], 0.55; p<0.001) and death (HR, 0.56; p<0.001) in HCV patients with compensated cirrhosis. [Gastroenterology 2016;150:430-440]
On the other hand, in patients with CSPH and varices, the goal is to prevent variceal haemorrhage and/or other decompensating events, said Garcia-Tsao.
According to the latest AASLD guidance, patients with medium or large varices that have not bled are recommended the following treatment: carvedilol, NSBB such as propanolol or nadolol, or endoscopic variceal ligation (EVL). [Hepatology 2017;65:310-335] The guidance also recommends that patients treated with NSBB or carvedilol do not require monitoring with serial endoscopies. However, transjugular intrahepatic portosystemic shunt (TIPS) or a combination therapy of NSBB and EVL is not recommended for these patients. [Hepatology 2017;65:310-335]
“If variceal haemorrhage occurs in the absence of other decompensating events, endpoint of treatment is prevention of rebleeding or other complications,” said Garcia-Tsao. [J Hepatol 2015;63:743-752]
Citing guidance from AASLD, the first-line therapy to prevent recurrent variceal haemorrhage in all patients regardless of ascites presence is a combination therapy of NSBB (propanolol or nadolol) plus EVL, with NSBB being the key component of combination therapy. Additionally, carvedilol is not recommended as a secondary prophylaxis in this setting. [Hepatology 2017;65:310-335]
“In patients who had bled from varices, the addition of simvastatin to standard therapy improves survival without reducing the rate of other complications of cirrhosis,” said Garcia-Tsao, citing a recent double-blind trial which showed significantly decreased mortality rate in patients with Child-Pugh class A or B cirrhosis who received simvastatin add-on vs placebo (HR for death, 0.39; p=0.03) [Gastroenterology 2016;150:1160-1170]
“If variceal haemorrhage occurs in addition to other complications, [the] endpoint of therapies is prevention of death,” she added. [J Hepatol 2015;63:743-52]
NSBB should be used cautiously in patients with cirrhosis and ascites at a maximal dose of 80 mg: propanolol BID and nadolol QD, as recommended by the AASLD guidance. [Hepatology 2017;65:310-335] If these patients develop systolic blood pressure of <90 mmHg, hyponatremia or acute kidney injury, the drug dose should be reduced or discontinued, and carvedilol should be avoided in these patients, cautioned Garcia-Tsao.