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• W4228996977 abstract "We would like to thank Dr Jindal and coworkers for their interest in our work. Long story short, our manuscript describes a proof-of-concept study on the prognostic value of nonselective β-blocker (NSBB)-treatment-related (emphasis on “related”) changes in a noninvasive test (ie, von Willebrand factor antigen [VWF]). Although we find our hypothesis of VWF being a biomarker for nonhemodynamic effects of NSBB therapy very compelling, we have always abstained from claiming a causal relationship. Indeed, the discussion section explicitly states that “a causal relationship … cannot be proven due to the design of our study.” However, after revisiting our study in light of the Bradford Hill criteria for causation, we would like to emphasize that most of them are actually met. To begin with, the observed strength/effect size is clinically meaningful and changes in VWF/VWF-response were specific for NSBB-treated patients, because they did not occur in the untreated control subjects (see Supplementary information of our original article). Of note, we have not claimed that the prognostic value of changes in VWF is limited (ie, specific) to NSBB-treated patients. Similarly, the prognostic value of hepatic venous pressure gradient response is not specific for NSBB-therapy, although it is a generally accepted surrogate of the hemodynamic/pressure-lowering effect of NSBB-treatment.1Mandorfer M. et al.Curr Hepatol Rep. 2019; 18: 174-186Crossref Google Scholar Because the impact of etiologic therapies on VWF and patient outcomes is well-known,2Mandorfer M. et al.Hepatology. 2020; 71: 1023-1036Crossref PubMed Scopus (60) Google Scholar patients were censored at the time of etiologic therapy. However, most patients with alcoholic cirrhosis were already abstinent at baseline and antiviral therapies for hepatitis C in patients with decompensated cirrhosis (ie, interferon-free regimens) were not available during most of the study period. Temporality (VWF-response/nonresponse preceded the outcome) was clearly established, because we have performed a landmark analysis starting the follow-up 30 days after the ascertainment of VWF-response status. Moreover, there was some evidence for a biologic gradient/dose–response relationship, because more pronounced decreases in VWF were accompanied by (numerically) more pronounced decreases in markers of systemic inflammation (SI). Moreover, we find our hypothesis plausible, because previous studies have established that (1) NSBB-therapy decreases gut permeability and thereby ameliorates bacterial translocation (BT)/SI,3Reiberger T. et al.J Hepatol. 2013; 58: 911-921Abstract Full Text Full Text PDF PubMed Scopus (201) Google Scholar,4Jachs M. et al.Gut. 2021; 70: 1758-1767Crossref PubMed Scopus (14) Google Scholar that (2) associations between markers of BT/SI and VWF are independent of liver disease severity,5Mandorfer M. et al.Aliment Pharmacol Ther. 2018; 47: 980-988Crossref PubMed Scopus (45) Google Scholar,6Starlinger P. et al.Hepatology. 2021; (in press)Google Scholar and have also provided (3) experimental evidence for BT/SI causing endothelial dysfunction, and thus, factor VIII/VWF release.7Carnevale R. et al.J Hepatol. 2017; 67: 950-956Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar The latter study also indicates coherence between experimental evidence and clinical data. Finally, our observation is in analogy to the concept of hepatic venous pressure gradient response serving as a surrogate for the therapeutic benefit of NSBB-therapy.1Mandorfer M. et al.Curr Hepatol Rep. 2019; 18: 174-186Crossref Google Scholar Accordingly, 7 out of 9 Bradford Hill criteria are at least partially met, whereas the remaining criteria (consistency/reproducibility and experiment) may hopefully be established in upcoming prospective, and ideally randomized controlled, studies. Until such data become available, our findings can only be interpreted as an association, and not indicative of causality. We are also happy to reinsure that only patients with clinically stable decompensated cirrhosis (ie, no sepsis or other intercurrent conditions) were included and, as shown in detail in the Supplementary information of our original article, VWF was very stable over time in a control group of similar patients without NSBB-treatment initiation. In the same line, the assay showed a low coefficient of variation of only around 3% when assessing precision (based on a plasma sample with a VWF level that is representative of our cohort) and intermediate precision (based on quality assurance data). Of note, these important insights can be obtained by reviewing in the Supplementary information of our manuscript. Finally, varices (although some being low-risk without a history of bleeding) and not ascites was the indication for NSBB-therapy in all patients. Of note, this was/is in line with the respective national (Austrian) Billroth consensus recommendations8Reiberger T. et al.Wien Klin Wochenschr. 2017; 129: 135-158Crossref PubMed Scopus (70) Google Scholar (and previous versions), which were more proactive regarding the use of NSBB-therapy for primary prophylaxis in patients with low-risk varices throughout the whole study period, as compared with international guidelines. In conclusion, we hope that we were able to address Dr Jindal’s criticism regarding our study. We would like to emphasize that the extensive Supplementary information accompanying our manuscript contains a considerable amount of data that are highly relevant to our findings on the potential role of VWF as a noninvasive prognostic biomarker in NSBB-treated patients with decompensated cirrhosis. Von Willebrand Factor Level Indicate Response to β-Blockers in Cirrhosis: Need a Closer Look!Clinical Gastroenterology and HepatologyPreviewWe read with interest the retrospective study by Jachs et al1 on the role of von Willebrand factor (VWF) measurement as an indicator of nonselective β-blocker (NSBB) response and risk of further complications in decompensated cirrhosis. For wider use of NSBB in practice for this indication, they also advocated for prospective validation of noninvasive VWF measurement as an alternative to invasive hepatic venous pressure gradient measurement. Over time, it has become clear that VWF is an important hemostatic factor in cirrhosis and also can be linked pathologically to disease progression, which makes it a likely target for future therapeutic intervention. Full-Text PDF" @default.
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