Anticoagulation is Not Associated with an Increased Risk of Variceal Bleeding under Systemic Therapy for Advanced HCC

We have read with great interest the original research conducted by Ben Khaled et al., which evaluated the risk of bleeding and thromboembolic events of patient with advanced Hepatocellular carcinoma (HCC) treated by Atezolizumab-Bevacizumab (AtezoBev) and Lenvatinib (1Ben Khaled N. Möller M. Jochheim L.S. et al.Atezolizumab/bevacizumab or lenvatinib in hepatocellular carcinoma: Multi-center real world study with focus on bleeding and thromboembolic events.JHEP Reports. 2024; 101065Abstract Full Text Full Text PDF Google Scholar). The occurrence of acute variceal bleeding (AVB) was low, around 3% in the two cohort of patients. Spleen size and the presence of large size varices were associated with AVB in univariate analysis but no multivariate analysis was performed due to the low number of patients concerned by AVB. Interestingly, in this article, therapeutic anticoagulation (29% in AtezoBev and 27% in Lenvatinib group) was not associated with an increased risk of AVB and gastrointestinal bleeding. This insight is particularly important, especially in the context of the perceived risk associated with anticoagulation, which might prevent some physicians from considering systemic therapies, such as AtezoBev, due to concerns about bleeding events. Our own series of 200 patients treated with AtezoBev in first line revealed a similar observation (2Sultanik P. Campani C. Larrey E. et al.Portal hypertension is associated with poorer outcome and clinical liver decompensation in patients with HCC treated with Atezolizumab-Bevacizumab.Dig Liver Dis. 2024; (S1590-8658(24)00304-00309)Abstract Full Text Full Text PDF Scopus (0) Google Scholar). To note, as for Imbrave150, all our patients benefited from upper endoscopy before starting AtezoBev treatment (3Finn R.S. Qin S. Ikeda M. Galle P.R. et al.Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma.N Engl J Med. 2020; 382: 1894-1905Crossref PubMed Scopus (3710) Google Scholar). Among 20% of these patients underwent therapeutic anticoagulation, 46% presented with portal vein tumor thrombosis (PVTT), 86% and 100% received adapted primary and secondary AVB prophylaxis respectively, and yet, anticoagulation was not associated with increased mortality (aHR=0.75, [95%CI:0.47-1.20]) or higher risk of AVB (aHR=1.34, [95%CI:0.48-3.72]) in univariate cox analysis. However, in our series, AVB incidence was higher, 12% at 12 months and was independently associated with the presence of PVTT (aHR=3.25, [95%CI:1.16-9.07]), history of AVB<6 months (aHR=4.32, [95%CI:1.17-15.92]) and varices regardless the size (aHR=3.22, [95%CI:1.02-10.14]) in Cox multivariate analysis. In the series of Ben Khaled et al., the percentage of AVB prophylactic therapy was 34% in the AtezoBev patients, which seems to be low at first sight, but the rate of patients with adapted AVB primary/secondary prophylaxis is missing in this series (meaning Non-Selective Beta-Blockers (NSBB) and/or ligation in the presence of varices) (1Ben Khaled N. Möller M. Jochheim L.S. et al.Atezolizumab/bevacizumab or lenvatinib in hepatocellular carcinoma: Multi-center real world study with focus on bleeding and thromboembolic events.JHEP Reports. 2024; 101065Abstract Full Text Full Text PDF Google Scholar). However, we believe that if AVB prophylaxis is meticulously managed, anticoagulation should not preclude the use of systemic therapy, especially AtezoBev. Achieving this, of course, necessitates thorough screening for portal hypertension with systematic upper endoscopy as Baveno criteria appear not performant in patients with advanced HCC (4Allaire M. Campion B. Demory A. L et al.Baveno VI and VII criteria are not suitable for screening for large varices or clinically significant portal hypertension in patients with hepatocellular carcinoma.Aliment Pharmacol Ther. 2023; Google Scholar). The recent AASLD guidelines propose that patients with large varices should likely undergo at least one session of band ligation prior to AtezoBev initiation, although carvedilol may also be effective(5Singal AG, Llovet JM, Yarchoan M, et al. AASLD practice guidance on prevention, diagnosis, and treatment of hepatocellular carcinoma. Hepatology. :10.1097/HEP.0000000000000466.Google Scholar). Rather than systematic band ligation in patients with large varices, we advocate for the consideration of NSBB as primary prophylaxis in all patients with esophageal varices, regardless of their size (6Allaire M. Thabut D. Portal hypertension and variceal bleeding in patients with liver cancer: Evidence gaps for prevention and management.Hepatology. 2024; 79: 213-223Crossref Scopus (2) Google Scholar, 7Franchis R de Bosch J. Garcia-Tsao G. et al.Baveno VII – Renewing consensus in portal hypertension.Journal of Hepatology. 2022; 76: 959-974Abstract Full Text Full Text PDF Scopus (965) Google Scholar). First, because it can be difficult to distinguish between small- and medium-sized EVs and, second, because portal hypertension levels might be impacted by HCC treatment, and third because band ligation might delay the initiation of the treatment due to the fear of bleeding under Bevacizumab after the procedure. Hence, these findings defy the notion that AtezoBev for advanced HCC should be contraindicated in patients undergoing therapeutic anticoagulation, provided that portal hypertension screening is meticulously conducted, and AVB prophylaxis is appropriately administered. None Manon Allaire wrote the letter. Philippe Sultanik and Dominique Thabut revised and approved the final version of the letter. All authors approved the final version of the manuscript. None Atezolizumab/bevacizumab or lenvatinib in hepatocellular carcinoma: Multi-center real world study with focus on bleeding and thromboembolic eventsJHEP ReportsPreviewAtezolizumab/bevacizumab (atezo/bev) and lenvatinib have demonstrated efficacy as first-line therapies for hepatocellular carcinoma (HCC). However, VEGF-inhibition with these therapies may be associated with the risk of bleeding and thromboembolic events. In this study, we evaluated the efficacy and safety with focus on bleeding and thromboembolic events of atezo/bev versus lenvatinib in a large, multi-center real-world population. Full-Text PDF Open Access