Carvedilol for Portal Hypertension in Patients With Cirrhosis

Abstract

A 48-year-old male with hepatitis C-related cirrhosis is found on endoscopy to have large esophageal varices with red signs. He has never previously had variceal bleeding, and there is no evidence of hepatic encephalopathy. He does have mild ascites. Comorbidity includes diabetes which has been present for many years and is well-controlled on a stable dose of insulin. He has no cardiopulmonary disease. The hemoglobin is 12.4 g/dL, white blood cell count is 6800/mm 3 , and platelets are 112 Â 10 9 /L. Serum bilirubin is 1.8 mg/ dL, creatinine is 1.2 mg/dL, international normalized ratio is 1.3, and the serum albumin is 3.5 g/dL. The electrocardiogram and chest x-ray are normal. The ultrasound examination does not show portal vein thrombosis or hepatocellular carcinoma.What is the role of carvedilol in the prevention of variceal bleeding in this patient? How will the dose of carvedilol be adjusted and how is the patient to be monitored for adverse drug events? When would carvedilol be preferred over nadolol or propranolol? Would the approach be different if the patient was of Child-Pugh class C cirrhosis? The ProblemPortal hypertension is an almost unavoidable complication of cirrhosis, and provides the driving force for most of its complications, such as esophageal and gastric varices, variceal bleeding, portal hypertensive gastropathy, ascites, spontaneous bacterial peritonitis, hepatorenal syndrome, thrombopenia, leukopenia and anemia, and portal-systemic encephalopathy.1 Recent studies have shown that for these complications to develop, the portacaval pressure gradient-evaluated clinically by the hepatic venous pressure gradient (HVPG)-should increase above 10 mm Hg and should be above 12 mm Hg for variceal bleeding. 2,3The prevalence of varices is about 40% in asymptomatic compensated patients.2 Development of varices follows an incidence of approximately 6% per year. The incidence is nearly double in patients with a baseline HVPG >10 mm Hg, who therefore represent a high-risk group.2 These patients are also at higher risk of developing decompensation (ascites, bleeding, jaundice, encephalopathy) and hepatocellular carcinoma. 4,5 Because of this, there is a great interest in strategies to revert portal hypertension, since these would prevent portal hypertension-related complications, clinical decompensation, and death. The benefit of reduction of HVPG has actually been proven for patients exhibiting a ''good hemodynamic response'' to nonselective beta-adrenergic blockers; i.e., those who exhibit a decrease in HVPG > 20% of baseline or to values below 12 mm Hg during continued therapy, 6,7 or who show a decrease in HVPG >10% of baseline 20 minutes after an intravenous infusion of propranolol. 8,9 Besides the increased intravascular pressure, the risk of bleeding from varices is further influenced by other factors, such as the diameter of the varices and the thickness of the variceal wall.10 These factors are interrelated by Laplace's law in the concept of wall tension (t), according to which: t ¼ variceal tran...

Pathophysiology of Portal Hypertension and Its Clinical Links

“…In addition, through its α1 adrenoceptor blocking effect, carvedilol decreases the hepatic vascular tone and hepatic resistance, resulting in a further decrease in portal pressure. 62 Carvedilol showed a greater portal hypotensive effect than propranolol in randomized controlled hemodynamic studies. 63,64 However, the vasodilating activity of carvedilol may enhance arterial hypotension and sodium retention, a risk which is especially relevant in patients with advanced, decompensated cirrhosis.…”

“…62 This results in reduced portal blood inflow and in a fall in portal pressure. In addition, through its α1 adrenoceptor blocking effect, carvedilol decreases the hepatic vascular tone and hepatic resistance, resulting in a further decrease in portal pressure.…”

Appropriate Use of Beta Blockers in Cirrhosis

“…Long-acting propranolol is now available and may increase compliance by once-a-day dosing. Carvedilol is a beta blocker with additional alpha-1 antagonist activity and has been studied in patients with cirrhosis and portal hypertension, but its use has not yet become mainstream [15]. Carvedilol was initially developed for the treatment of heart failure and arterial hypertension and through its non-selective beta-blocking mechanism causes a decrease in heart rate and cardiac output as well as splanchnic vasoconstriction.…”

Hipertensión portal: recomendaciones para su evaluación y tratamiento

“…Estos incluyen el propranolol, el nadolol, que son los fárma-cos más empleados, y más recientemente el carvedilol, que se diferencia de los anteriores por tener además actividad vasodilatadora por ser anti-alfa-adrenérgico y aumentar la liberación de óxido nítrico 118 . El timolol es un BBNS, pero solo se ha utilizado en un estudio.…”