Prioritization of Therapeutic Targets and Trial Design in Cirrhotic Portal Hypertension

Juan G. Abraldes, Jonel Trebicka, Naga Chalasani, Gennaro D’Amico, Don C. Rockey, Vijay H. Shah, Jaime Bosch, Guadalupe Garcia-Tsao

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1287-1299
Number of pages13
JournalHepatology
Volume69
Issue number3
DOIs
StatePublished - Mar 1 2019

Fingerprint

Portal Hypertension
Portal Pressure
Fibrosis
Therapeutics
Industry
Phase III Clinical Trials
Clinical Trials, Phase I
Viscera
Drug Delivery Systems
Vasodilation
Cardiac Output
Vascular Resistance
Liver Diseases
Chronic Disease
Research Personnel
Pharmacology

ASJC Scopus subject areas

  • Hepatology

Cite this

Abraldes, J. G., Trebicka, J., Chalasani, N., D’Amico, G., Rockey, D. C., Shah, V. H., ... Garcia-Tsao, G. (2019). Prioritization of Therapeutic Targets and Trial Design in Cirrhotic Portal Hypertension. Hepatology, 69(3), 1287-1299. https://doi.org/10.1002/hep.30314

Prioritization of Therapeutic Targets and Trial Design in Cirrhotic Portal Hypertension. / Abraldes, Juan G.; Trebicka, Jonel; Chalasani, Naga; D’Amico, Gennaro; Rockey, Don C.; Shah, Vijay H.; Bosch, Jaime; Garcia-Tsao, Guadalupe.

In: Hepatology, Vol. 69, No. 3, 01.03.2019, p. 1287-1299.

Research output: Contribution to journalArticle

Abraldes, JG, Trebicka, J, Chalasani, N, D’Amico, G, Rockey, DC, Shah, VH, Bosch, J & Garcia-Tsao, G 2019, 'Prioritization of Therapeutic Targets and Trial Design in Cirrhotic Portal Hypertension', Hepatology, vol. 69, no. 3, pp. 1287-1299. https://doi.org/10.1002/hep.30314
Abraldes JG, Trebicka J, Chalasani N, D’Amico G, Rockey DC, Shah VH et al. Prioritization of Therapeutic Targets and Trial Design in Cirrhotic Portal Hypertension. Hepatology. 2019 Mar 1;69(3):1287-1299. https://doi.org/10.1002/hep.30314
Abraldes, Juan G. ; Trebicka, Jonel ; Chalasani, Naga ; D’Amico, Gennaro ; Rockey, Don C. ; Shah, Vijay H. ; Bosch, Jaime ; Garcia-Tsao, Guadalupe. / Prioritization of Therapeutic Targets and Trial Design in Cirrhotic Portal Hypertension. In: Hepatology. 2019 ; Vol. 69, No. 3. pp. 1287-1299.
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