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Hepatology. 2019 Mar;69(3):1287-1299. doi: 10.1002/hep.30314. Epub 2019 Feb 9.

Prioritization of Therapeutic Targets and Trial Design in Cirrhotic Portal Hypertension.

Author information

1
Cirrhosis Care Clinic, Division of Gastroenterology (Liver Unit), Department of Medicine, CEGIIR, University of Alberta, Edmonton, Canada.
2
Translational Hepatology, Department of Internal Medicine I, University Clinic Frankfurt, Frankfurt, Germany.
3
European Foundation for the Study of Chronic Liver Failure, Institute for Bioengineering of Catalonia, Barcelona, Spain.
4
Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark.
5
Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, IN.
6
Gastroenterology Unit, Ospedale V. Cervello, Palermo, Italy.
7
Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of South Carolina, Charleston, SC.
8
Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN.
9
Swiss Liver Group, University Clinic for Visceral Medicine and Surgery (UVCM), Inselspital, University of Bern, Bern, Switzerland.
10
Hospital Clinic-IDIBAPS and CIBEREHD, University of Barcelona, Barcelona, Spain.
11
Digestive Diseases Section, Yale University School of Medicine; VA-CT Healthcare System, New Haven/West Haven, CT.

Abstract

Portal hypertension (PH) is the main driver of cirrhosis decompensation, the main determinant of death in patients with cirrhosis. PH results initially from increased intrahepatic vascular resistance. Subsequently, increased inflow from splanchnic vasodilation and increased cardiac output lead to a further increase in portal pressure (PP). Reducing PP in cirrhosis results in better outcomes. Removing the cause of cirrhosis might improve PP. However, this is a slow process and patients may continue to be at risk of decompensation. Additionally, for some chronic liver diseases, such as nonalcoholic fatty liver disease (NAFLD), etiological treatments are not yet available. Therefore, there is a need to develop better therapies specifically aimed at reducing PP. For over 35 years, the mainstay of such therapy has been the use of nonselective beta-blockers (NSBBs) that act by reducing portal venous inflow. Recently, many drugs (mainly targeting intrahepatic mechanisms) have shown promise in preclinical and early clinical studies and may act alone or synergistically with NSBBs in reducing PP in cirrhosis. The objective of this position paper is to propose a novel framework for the design of clinical trials (phase 1, 2, and 3) in patients with cirrhosis and PH and to prioritize targets and pharmacological therapies in this setting. We have focused the discussion on patients with compensated cirrhosis. The paper summarizes discussions held at The American Association for the Study of Liver Diseases (AASLD) Industry Colloquium in January 2018, with the participation of clinical and translational investigators, regulatory professionals, and industry partners.

PMID:
30318607
DOI:
10.1002/hep.30314
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