The Changing Landscape of Beta Blockers in Cirrhosis

FEBRUARY 12, 2017
Patients with cirrhosis are often subject to manifestations of disease progression including hepatic encephalopathy, spontaneous bacterial peritonitis, and esophageal varices leading to varicieal hemorrhage. Approximately 50% of patients with cirrhosis have esophageal varices, and of those patients, one-third will have a bleeding episode.1 As a result, upon diagnosis of cirrhosis, an esophagogastroduodenoscopy (EGD), the gold standard in diagnosis, should be performed to assess for presence and classification of varices; the classification then facilitates choice of therapy for primary prophylaxis of varicieal hemorrhage.
Non-selective beta blockers such as nadolol and propranolol are the agents of choice in both primary and secondary prevention of varicieal hemorrhage.1,2  Carvedilol has also been used successfully in this patient population. They exert their action by antagonism of beta-2 receptors resulting in splanchnic vasoconstriction causing reduced portal blood flow. This leads to a reduction of portal pressures.2 As a result, studies have shown use of non-selective beta-blockers in patients with medium to large varices lowers hemorrhage rates by over 50% and increases survival.1
Recent studies, however, have shifted previous practice and a new hypothesis has emerged in the use of beta blockers in patients for primary prophylaxis.2-6 Previous practice was to utilize beta blockers upon diagnosis of medium to large varices and to continue therapy unless patients had adverse effects or were unable to tolerate therapy due to bradycardia or hypotension due to their beneficial effects. Currently, the window hypothesis now postulates that beta blockers in this patient population result in increased survival rates only within a clinical window and use outside that window leads to increased morbidity and mortality.
The clinical window that benefits patients is the second stage of disease progression in cirrhotic patients.2 Patients in stage 1, or early cirrhosis, often do not have medium or large varices and the utilization of beta-blockers in these patients does not prevent the formation of varices or varicieal bleeding. The risk benefit in this stage weighs more to risk of adverse effects of beta blocker use.
Patients in stage 2, or decompensated cirrhosis, is where beta blockers are indicated for prophylaxis of both primary and secondary varicieal hemorrhage.2 At this stage, patients are exhibiting increases in sympathetic nervous sympathetic system (SNS) and renin-angiotensin-aldosterone system (RAAS) activity in response to decreasing arterial blood pressure and increased risk of gut bacterial translocation and death. In conjunction, cardiac reserve, although intact, is beginning to decline.
The clinical window closes when patients enter stage 3 or end-stage cirrhosis.2 Stage 3 is characterized by maximum RAAS and SNS stimulation, a critically impaired cardiac reserve, and gut bacterial translocation and death. Beta blocker utilization in this stage leads to further negative effects on cardiac reserve. As a result, it is recommended that beta blockers be discontinued in patients with cirrhosis with evidence of refractory ascites, systolic blood pressure <90 mm Hg, mean arterial pressure ≤82 mm Hg, serum sodium level <120 mEq/L, acute kidney injury, hepatorenal syndrome, spontaneous bacterial peritonitis, sepsis, severe alcoholic hepatitis, poor follow-up or non-adherence to beta blocker therapy.2,7 One of the more controversial aspects of the window closing is with systolic blood pressure. The Baveno VI guidelines on portal hypertension recommend discontinuing prophylactic therapy when the systolic blood pressure is less than 90 mm Hg.7 However, mean arterial pressure (MAP) may be a better overall marker of perfusion with research showing a MAP of 82 or greater leads to improved survival.8 As a result, some clinicians have stated that beta blockers should be discontinued when the systolic blood pressure drops below 100 mm Hg as it would be difficult to maintain a MAP above 82 with a systolic BP of less than 90 mm Hg.2
Although there is a new landscape of beta blocker use in cirrhosis, there are still patients who benefit from therapy. In patients who continue to be beta blocker candidates, therapy should be titrated to heart rate goals of 55-60 beats per minute as rest. Hepatic venous pressure gradient can be monitored to guide therapy, however, it is invasive and not routinely performed at most medical centers.2 Most importantly, vigilant discontinuation of therapy when patients reach end-stage cirrhosis status to avoid further morbidity and mortality caused by beta blockers is now a crucial intervention and pharmacists can have significant impact in patient care recommending this course of action.
1.       Garcia-Tsao G, Sanyal AJ, Grace ND, et al. Prevention and management of gastroesophageal varices and variceal hemorrhage 
in cirrhosis. Hepatology. 2007;46(3):922-38.
2.       Ge PS, Runyon BA. Treatment of patients with cirrhosis. N Engl J Med. 2016 25;375(8):767-77.
3.       Sersté T, Francoz C, Durand F, et al. Beta-blockers cause paracentesis-induced circulatory dysfunction in patients with cirrhosis 
and refractory ascites: a crossover study. J Hepatol. 2011; 55: 794-9.
4.       Sersté T, Melot C, Francoz C, et al. Deleterious effects of beta-blockers on survival in patients with cirrhosis and refractory ascites. Hepatology. 2010; 52: 1017-22.
5.       Mandorfer M, Bota S, Schwabl P, et al. Nonselective β blockers increase risk for hepatorenal syndrome and death in patients with cirrhosis 
and spontaneous bacterial peritonitis. Gastroenterology. 2014; 146(7): 1680-90.e1.
6.        Sersté T, Njimi H, Degré D, et al. The use of beta-blockers is associated with the occurrence of acute kidney injury in severe 
alcoholic hepatitis. Liver Int. 2015; 35: 1974-82.
7.       de Franchis R. Expanding consensus in portal hypertension: report of the Baveno VI Consensus Workshop: stratifying risk and
 individualizing care for portal hypertension. J Hepatol. 2015; 63: 743-52.
8.       Llach J, Ginès P, Arroyo V, et al. Prognostic value of arterial pressure, endogenous vasoactive systems, and renal function 
in cirrhotic patients admitted to the hospital for the treatment of ascites. Gastroenterology. 1988; 94: 482-7.

Alexander Kantorovich, PharmD, BCPS
Alexander Kantorovich, PharmD, BCPS
Alexander Kantorovich, PharmD, BCPS, is a Clinical Associate Professor of Pharmacy Practice at Chicago State University College of Pharmacy and Clinical Pharmacy Specialist at Advocate Christ Medical Center in Oak Lawn, Illinois. Dr. Kantorovich earned his Associate of Science degree with an emphasis in chemistry from William Rainey Harper College and received his Doctor of Pharmacy degree from the University of Illinois at Chicago College of Pharmacy. He went on to complete a 2-year pharmacotherapy residency with an emphasis in cardiology and critical care at the Cleveland Clinic and is board certified in pharmacotherapy. His research interests center around cardiovascular pharmacotherapy, anticoagulation, and anticoagulation reversal.