Retrospective Cohort Study
Copyright ©The Author(s) 2018. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Clin Cases. Nov 6, 2018; 6(13): 611-623
Published online Nov 6, 2018. doi: 10.12998/wjcc.v6.i13.611
Impact of an acute hemodynamic response-guided protocol for primary prophylaxis of variceal bleeding
José Ignacio Fortea, Ángela Puente, Patricia Ruiz, Iranzu Ezcurra, Javier Vaquero, Antonio Cuadrado, María Teresa Arias-Loste, Joaquín Cabezas, Susana Llerena, Paula Iruzubieta, Carlos Rodríguez-Lope, Patricia Huelin, Fernando Casafont, Emilio Fábrega, Javier Crespo
José Ignacio Fortea, Ángela Puente, Patricia Ruiz, Iranzu Ezcurra, Antonio Cuadrado, María Teresa Arias-Loste, Joaquín Cabezas, Susana Llerena, Paula Iruzubieta, Carlos Rodríguez-Lope, Patricia Huelin, Fernando Casafont, Emilio Fábrega, Javier Crespo, Servicio de Aparato Digestivo, Hospital Universitario Marqués de Valdecilla, Santander 39008, Cantabria, Spain
José Ignacio Fortea, Ángela Puente, Antonio Cuadrado, María Teresa Arias-Loste, Joaquín Cabezas, Susana Llerena, Paula Iruzubieta, Carlos Rodríguez-Lope, Patricia Huelin, Fernando Casafont, Emilio Fábrega, Javier Crespo, Instituto de Investigación Sanitaria Marqués de Valdecilla, Santander 39011, Cantabria, Spain
José Ignacio Fortea, Ángela Puente, Javier Vaquero, Antonio Cuadrado, María Teresa Arias-Loste, Joaquín Cabezas, Susana Llerena, Paula Iruzubieta, Carlos Rodríguez-Lope, Patricia Huelin, Fernando Casafont, Emilio Fábrega, Javier Crespo, Centro de Investigación Biomédica Red de Enfermedades Hepáticas y Digestivas, Madrid 28029, Madrid, Spain
Javier Vaquero, Laboratorio de Investigación en Hepatología y Gastroenterología, Hospital General Universitario Gregorio Marañón-Instituto de Investigación Sanitaria Gregorio Marañón, Madrid 28007, Madrid, Spain
Author contributions: Fortea JI, Puente A and Crespo J designed the research; Fortea JI, Puente A, Ruiz P, Ezcurra I, Cuadrado A, Arias-Loste MT, Cabezas J, Llerena S, Iruzubieta P, Rodríguez-Lope C, Huelin P, Casafont F, and Fábrega E performed the research; Fortea JI analyzed the data; Fortea JI and Vaquero J wrote the paper; Fortea JI, Puente A, Crespo J, Vaquero J, Cuadrado A, Fábrega E and Casafont F critically revised the manuscript for important intellectual content.
Supported by Instituto de Investigación Sanitaria Marqués de Valdecilla, No. NVAL17/07 (to Fortea JI); Instituto Carlos III, No. PI15/01083 (to Vaquero J).
Institutional review board statement: The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki (6th revision, 2008) as reflected in a priori approval by the Clinical Research Ethics Committee of Cantabria.
Informed consent statement: A waiver of informed consent was provided since the study was considered a retrospective review both by the Clinical Research Ethics Committee of Cantabria and the Spanish Agency of Medicines and Health Products (AEMPS).
Conflict-of-interest statement: Crespo J reports grant support and/or consultancy and lecture fees from AbbVie, Gilead Sciences, Bristol-Myers Squibb, Janssen, and MSD. The remaining authors declare no conflicts of interest.
Open-Access: This is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: José Ignacio Fortea, MD, PhD, Attending Doctor, Research Scientist, Servicio de Aparato Digestivo, Hospital Universitario Marques de Valdecilla, Av. Valdecilla s/n, Santander 39008, Cantabria, Spain. jifortea@gmail.com
Telephone: +34-94-2202520 Fax: +34-94-2202520
Received: July 23, 2018
Peer-review started: July 23, 2018
First decision: August 25, 2018
Revised: September 3, 2018
Accepted: October 9, 2018
Article in press: October 9, 2018
Published online: November 6, 2018
Processing time: 107 Days and 19.6 Hours
ARTICLE HIGHLIGHTS
Research background

Traditional nonselective beta-blockers (NSBBs) (i.e. propranolol and nadolol) and carvedilol are valid first-line treatments in patients starting primary prophylaxis of variceal bleeding. Although no clinical trial has adequately compared their efficacy head-to-head, several randomized controlled trials and a meta-analysis have shown that carvedilol is more effective in reducing portal pressure. NSBB-induced reductions in hepatic venous pressure gradient (HVPG) > 10% from baseline have been associated with a lower risk of decompensation and death. The acute hemodynamic test (i.e. HVPG response after 20 min of the intravenous injection of 0.15 mg/kg propranolol) has been proposed as a valid and more cost-effective alternative to separate HVPG procedures. Supporting this notion, recent studies in patients treated with traditional NSBB showed that the risk of decompensation was lower in those who had an acute response than in those who were acute nonresponders. The acute test also predicted the chronic hemodynamic response.

Research motivation

Since the acute test enables the earlier identification of chronic nonresponders to traditional NSBB and carvedilol has a greater efficacy for reducing portal pressure, this test could guide the type of NSBB to be used in patients starting primary prophylaxis of variceal bleeding.

Research objectives

The primary endpoint was development of first or further decompensation of cirrhosis. Secondary endpoints included death from any cause, association between acute and chronic hemodynamic response, and baseline clinical and laboratory variables related to the acute hemodynamic response.

Research methods

We retrospectively reviewed all patients starting primary prophylaxis of variceal bleeding following an acute hemodynamic response-guided protocol. Acute or chronic hemodynamic response was defined as a decrease in HVPG to < 12 mmHg or as a ≥ 10% reduction in HVPG from baseline. According to our institutional protocol, 52 acute responders to intravenous propranolol were treated with traditional NSBB (i.e. propranolol or nadolol) and 24 acute nonresponders received carvedilol. A second hemodynamic study was performed in 27 and 13 patients, respectively. Follow-up data (i.e. medical history, laboratory values, imaging tests and treatment compliance) were recorded in each visit (i.e. within 1 mo after the performance of the baseline hemodynamic study, and every 3-6 mo thereafter).

Research results

The risk of first or further decompensation was similar in both groups at 1, 2 and 3 years of follow-up. A previous episode of hepatic encephalopathy was the only independent predictor of decompensation. Mortality rates were also similar between groups. No clinical, laboratory, or endoscopic variables at baseline were able to predict neither the acute nor the chronic hemodynamic response. A high proportion of acute nonresponders (69.2%) achieved a chronic hemodynamic response with carvedilol and there was a strong correlation between the acute and chronic changes in HVPG in the traditional NSBB group.

Research conclusions

The early identification of acute nonresponders and their treatment with carvedilol resulted in risks of decompensation and death that were comparable to those of acute responders treated with propranolol. These findings suggest that carvedilol improved the long-term outcome of acute nonresponders, presumably by its greater effects on reducing portal pressure, and should be the preferred choice over NSBB for primary prophylaxis of variceal bleeding when hemodynamic testing is not available.

Research perspectives

The design of our study cannot definitively conclude that carvedilol should become the beta-blocker of choice in patients starting primary prophylaxis of variceal bleeding. In order to confirm this possibility, a randomized controlled trial with a control group of acute nonresponders treated with traditional NSBB would be needed.