Improving primary prophylaxis of variceal bleeding by adapting therapy to the clinical stage of cirrhosis. A competing-risk meta-analysis of individual participant data

Càndid Villanueva; Victor Sapena; Gin-Ho Lo; Yeon Seok Seo; Hasnain Ali Shah; Virendra Singh; Dhiraj Tripathi; Michael Schepke; Cristian Gheorghe; Daniell Q Bonilha; Rome Jutabha; Huay-Min Wang; Susana G Rodrigues; Anna Brujats; Han Ah Lee; Zahid Azam; Pramod Kumar; Peter C Hayes; Tilman Sauerbruch; Wen-Chi Chen; Speranta Iacob; Ermelindo D Libera; Dennis M Jensen; Edilmar Alvarado; Ferran Torres; Jaume Bosch; Baveno Cooperation-a EASL Consortium

doi:10.1111/apt.17824

Improving primary prophylaxis of variceal bleeding by adapting therapy to the clinical stage of cirrhosis. A competing-risk meta-analysis of individual participant data

Aliment Pharmacol Ther. 2024 Feb;59(3):306-321. doi: 10.1111/apt.17824. Epub 2023 Dec 18.

Authors

Càndid Villanueva^{1

2}, Victor Sapena^{3

4}, Gin-Ho Lo⁵, Yeon Seok Seo⁶, Hasnain Ali Shah⁷, Virendra Singh⁸, Dhiraj Tripathi^{9

10

11}, Michael Schepke¹², Cristian Gheorghe¹³, Daniell Q Bonilha¹⁴, Rome Jutabha^{15

16}, Huay-Min Wang¹⁷, Susana G Rodrigues¹⁸, Anna Brujats¹, Han Ah Lee⁶, Zahid Azam¹⁹, Pramod Kumar⁸, Peter C Hayes¹¹, Tilman Sauerbruch²⁰, Wen-Chi Chen⁵, Speranta Iacob¹³, Ermelindo D Libera¹⁴, Dennis M Jensen^{21

22

23}, Edilmar Alvarado^{1

2}, Ferran Torres^{3

4}, Jaume Bosch^{2

18}; Baveno Cooperation-a EASL Consortium

Affiliations

¹ Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), Universitat Autònoma de Barcelona, Barcelona, Spain.
² Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain.
³ Biostatistics Unit, Medical School, Universitat Autònoma de Barcelona, Barcelona, Spain.
⁴ Medical Statistics Core Facility, IDIBAPS, Hospital Clinic, Barcelona, Spain.
⁵ Division of Gastroenterology, Department of Medicine, E-Da Hospital, I-Shou University, Kaohsiung, Taiwan.
⁶ Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea.
⁷ Section of Gastroenterology, Aga Khan University, Karachi, Pakistan.
⁸ Department of Hepatology, Post Graduate Institute of Medical Education and Research, Chandigarh, India.
⁹ University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.
¹⁰ Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK.
¹¹ Department of Hepatology, Royal Infirmary of Edinburgh, Edinburgh, UK.
¹² Helios Clinic Siegburg, Department Gastroenterology and Hepatology, Siegburg, Germany.
¹³ Center of Gastroenterology & Hepatology, Fundeni Clinical Institute, "Carol Davila" University of Medicine, Bucharest, Romania.
¹⁴ Department of Gastroenterology, Federal University of São Paulo, State University of Campinas, Campinas, Brazil.
¹⁵ University of Southern California (USC) School of Medicine, Los Angeles, USA.
¹⁶ Keck School of Medicine of University of Southern California and Clinical Outreach and Development, Los Angeles, USA.
¹⁷ Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Veterans, General Hospital, Kaohsiung, Taiwan, Republic of China.
¹⁸ University Clinic for Visceral Surgery and Medicine, Inselspital Bern University Hospital, Bern, Switzerland.
¹⁹ National Institute of Liver & GI Diseases, Dow University of Health Sciences, Karachi, Pakistan.
²⁰ Department of Internal Medicine I, University of Bonn, Bonn, Germany.
²¹ Department of Medicine, Division of Digestive Diseases, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
²² Center for the Health Sciences, Los Angeles, Veterans Administration Greater Los Angeles Healthcare System, Los Angeles, California, USA.
²³ Center for Ulcer Research and Education: Digestive Diseases Research Center.

PMID: 38108646
DOI: 10.1111/apt.17824

Abstract

Background & aims: Non-selective β-blockers (NSBBs) and endoscopic variceal-ligation (EVL) have similar efficacy preventing first variceal bleeding. Compensated and decompensated cirrhosis are markedly different stages, which may impact treatment outcomes. We aimed to assess the efficacy of NSBBs vs EVL on survival in patients with high-risk varices without previous bleeding, stratifying risk according to compensated/decompensated stage of cirrhosis.

Methods: By systematic review, we identified RCTs comparing NSBBs vs EVL, in monotherapy or combined, for primary bleeding prevention. We performed a competing-risk, time-to-event meta-analysis, using individual patient data (IPD) obtained from principal investigators of RCTs. Analyses were stratified according to previous decompensation of cirrhosis.

Results: Of 25 RCTs eligible, 14 failed to provide IPD and 11 were included, comprising 1400 patients (656 compensated, 744 decompensated), treated with NSBBs (N = 625), EVL (N = 546) or NSBB+EVL (N = 229). Baseline characteristics were similar between groups. Overall, mortality risk was similar with EVL vs. NSBBs (subdistribution hazard-ratio (sHR) = 1.05, 95% CI = 0.75-1.49) and with EVL + NSBBs vs either monotherapy, with low heterogeneity (I² = 28.7%). In compensated patients, mortality risk was higher with EVL vs NSBBs (sHR = 1.76, 95% CI = 1.11-2.77) and not significantly lower with NSBBs+EVL vs NSBBs, without heterogeneity (I² = 0%). In decompensated patients, mortality risk was similar with EVL vs. NSBBs and with NSBBs+EVL vs. either monotherapy.

Conclusions: In patients with compensated cirrhosis and high-risk varices on primary prophylaxis, NSBBs significantly improved survival vs EVL, with no additional benefit noted adding EVL to NSBBs. In decompensated patients, survival was similar with both therapies. The study suggests that NSBBs are preferable when advising preventive therapy in compensated patients.

Keywords: clinically significant portal hypertension; complications of cirrhosis; endoscopic variceal ligation; prevention of cirrhosis decompensation; primary prophylaxis; β-Blockers.

Publication types

Meta-Analysis
Review
Research Support, Non-U.S. Gov't

MeSH terms

Adrenergic beta-Antagonists / therapeutic use
Esophageal and Gastric Varices* / drug therapy
Esophageal and Gastric Varices* / prevention & control
Gastrointestinal Hemorrhage
Humans
Ligation
Liver Cirrhosis / complications
Liver Cirrhosis / drug therapy
Varicose Veins* / drug therapy

Substances

Adrenergic beta-Antagonists

Abstract

Publication types

MeSH terms

Substances

Grants and funding