Response to: “Anticoagulation is not associated with an increased risk of variceal bleeding under systemic therapy for advanced HCC”

We are grateful to the authors Manon Allaire, Philippe Sultanik, and Dominique Thabut for their letter. The authors report the occurrence of acute variceal bleeding (AVB) in a large series of patients with hepatocellular carcinoma (HCC) treated with atezolizumab/bevacizumab (atezo/bev) [1Sultanik P, Campani C, Larrey E, Campion B, Evain M, Roux C, et al. Portal hypertension is associated with poorer outcome and clinical liver decompensation in patients with HCC treated with Atezolizumab-Bevacizumab. Digestive and Liver Disease.Google Scholar]. All patients received a gastroscopy before starting systemic therapy and most had adequate AVB prophylaxis. The slightly higher occurrence of AVB in their cohort as compared to ours could be due to the differences in baseline characteristics of both studies [2Ben Khaled N. Möller M. Jochheim L.S. Leyh C. Ehmer U. Böttcher K. et al.Atezolizumab/bevacizumab or lenvatinib in hepatocellular carcinoma: Multi-center real world study with focus on bleeding and thromboembolic events.JHEP Reports. 2024; Abstract Full Text Full Text PDF PubMed Google Scholar]. There was a higher frequency of patients with esophageal varices at baseline and previous episodes of AVB in their study. More individuals with splenomegaly >12cm, and a lower median platelet count indicate a higher number of patients with significant portal hypertension. The presence of varices, previous AVB, and spleen size could be identified as predictive factors for gastrointestinal (GI) bleeding in our cohort. Another possible reason for the higher AVB occurrence is the longer follow-up period. Of relevance is the comparison of bleeding episodes in patients treated with atezo/bev versus sorafenib, which was recently published by the authors [1Sultanik P, Campani C, Larrey E, Campion B, Evain M, Roux C, et al. Portal hypertension is associated with poorer outcome and clinical liver decompensation in patients with HCC treated with Atezolizumab-Bevacizumab. Digestive and Liver Disease.Google Scholar]. The Imbrave150 study reported a slightly higher occurrence of AVB with atezo/bev as compared to sorafenib (2.4% vs 0.6%) [3Finn R.S. Qin S. Ikeda M. Galle P.R. Ducreux M. Kim T.-Y. et al.Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma.New England Journal of Medicine. 2020; 382: 1894-1905Crossref PubMed Scopus (3830) Google Scholar], but this highly selected cohort is limited in representing real-world conditions. One example is the exclusion of patients with therapeutic anticoagulation. The colleagues' study confirms that no higher frequency of bleeding was observed with atezo/bev as compared to sorafenib under real-world conditions. Anticoagulation did not increase the risk of AVB bleeding in their study and our cohort. A prerequisite is the systematic endoscopic screening combined with consequent management of portal hypertension and its complications to assure the safety of these treatments in patients with HCC [4Thabut D. Kudo M. Treatment of portal hypertension in patients with HCC in the era of Baveno VII.J Hepatol. 2023; 78: 658-662Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar]. We agree with the authors, that nonselective beta-blockers (NSBB) should be the mainstay in the primary and secondary prophylaxis of variceal bleeding. NSBB reduce portal hypertension as disease driver. They not only prevent GI (re)bleeding but can also reduce overall hepatic decompensation events [5Iwakiri Y. Trebicka J. Portal hypertension in cirrhosis: Pathophysiological mechanisms and therapy.JHEP Rep. 2021; 3100316PubMed Google Scholar, 6de Franchis R. Bosch J. Garcia-Tsao G. Reiberger T. Ripoll C. Abraldes J.G. et al.Baveno VII - Renewing consensus in portal hypertension.Journal of Hepatology. 2022; 76: 959-974Abstract Full Text Full Text PDF PubMed Scopus (1044) Google Scholar, 7Villanueva C. Albillos A. Genescà J. Garcia-Pagan J.C. Calleja J.L. Aracil C. et al.β blockers to prevent decompensation of cirrhosis in patients with clinically significant portal hypertension (PREDESCI): a randomised, double-blind, placebo-controlled, multicentre trial.Lancet. 2019; 393: 1597-1608Abstract Full Text Full Text PDF PubMed Scopus (394) Google Scholar]. Based on the findings of both studies we conclude, that (1) AVB bleeding episodes are not significantly more frequent in patients treated with atezo/bev versus the alternative first-line agents lenvatinib and sorafenib and (2) therapeutic anticoagulation does not represent a contraindication to atezo/bev. Future studies should aim at assessing the safety of the VEGF-inhibition-free regimen durvalumab/tremelimumab and its impact on portal hypertension in patients with HCC. This study was initiated by the IMMUreal study group and was supported by the Bavarian Cancer Research Center (BZKF). The funding bodies had no role in the design of the study, the collection, analysis, interpretation of data, or the writing of the manuscript. FPR and NBK designed the study and wrote the manuscript; FPR and NBK conducted data analyses and wrote the manuscript; all co-authors were involved in the data collection and preparation of the manuscript. Data is available upon request. NBK has received reimbursement of meeting attendance fees and travel expenses from EISAI and lecture honoraria from the Falk Foundation and AstraZeneca. ENDT has served as a paid consultant for AstraZeneca, Bayer, BMS, EISAI, Eli Lilly & Co, MSD, Mallinckrodt, Omega, Pfizer, IPSEN, Terumo and Roche. He has received reimbursement of meeting attendance fees and travel expenses from Arqule, Astrazeneca, BMS, Bayer, Celsion and Roche, and lecture honoraria from BMS and Falk. He has received third-party funding for scientific research from Arqule, AstraZeneca, BMS, Bayer, Eli Lilly, and IPSEN and Roche and is currently employed at Boehringer-Ingelheim. AG is an advisory board or steering committee member to AbbVie, Alexion, Bayer, BMS, CSL Behring, Eisai, Falk, Gilead, Heel, Intercept, Ipsen, Merz, MSD, Novartis, Pfizer, Roche, Sanofi-Aventis, and Sequana and a speaker for Advanz. FPR has received honoraria for lectures, consulting activities, and travel support from the Falk Foundation, AbbVie, Gilead, Ipsen, AstraZeneca, Roche and Novartis. All other authors report no conflicts of interest. The following are the Supplementary data to this article: Download .pdf (.43 MB) Help with pdf files Anticoagulation is not associated with an increased risk of variceal bleeding under systemic therapy for advanced HCCJHEP ReportsPreviewWe 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 (1). 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.