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Decreasing von Willebrand Factor Levels Upon Nonselective Beta Blocker Therapy Indicate a Decreased Risk of Further Decompensation, Acute-on-chronic Liver Failure, and Death

  • Mathias Jachs
    Affiliations
    Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria

    Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria

    Christian Doppler Laboratory for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria
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  • Lukas Hartl
    Affiliations
    Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria

    Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria

    Christian Doppler Laboratory for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria
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  • Benedikt Simbrunner
    Affiliations
    Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria

    Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria

    Christian Doppler Laboratory for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria
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  • David Bauer
    Affiliations
    Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria

    Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria

    Christian Doppler Laboratory for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria
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  • Rafael Paternostro
    Affiliations
    Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria

    Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria
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  • Bernhard Scheiner
    Affiliations
    Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria

    Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria
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  • Philipp Schwabl
    Affiliations
    Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria

    Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria

    Christian Doppler Laboratory for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria
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  • Albert F. Stättermayer
    Affiliations
    Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria

    Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria
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  • Matthias Pinter
    Affiliations
    Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria

    Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria
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  • Ernst Eigenbauer
    Affiliations
    IT4Science, Medical University of Vienna, Vienna, Austria
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  • Peter Quehenberger
    Affiliations
    Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria
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  • Michael Trauner
    Affiliations
    Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
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  • Thomas Reiberger
    Correspondence
    Reprint requests Address requests for reprints to: Thomas Reiberger, MD, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria. phone: +43 1 40400 47440; fax: +43 1 40400 47350.
    Affiliations
    Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria

    Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria

    Christian Doppler Laboratory for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria
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  • Mattias Mandorfer
    Affiliations
    Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria

    Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria

    Christian Doppler Laboratory for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria
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Open AccessPublished:July 09, 2021DOI:https://doi.org/10.1016/j.cgh.2021.07.012

      Background & Aims

      Nonselective beta blockers (NSBBs) exert beneficial effects beyond lowering hepatic venous pressure gradient (HVPG), which may be particularly relevant in patients with decompensated cirrhosis (DC), in whom bacterial translocation and bacterial-induced systemic inflammation drive the development of complications such as acute-on-chronic liver failure (ACLF). We evaluated whether NSBB-related changes in von Willebrand factor (VWF) may serve as a biomarker for these effects.

      Methods

      In this retrospective analysis, 159 prospectively characterized patients with clinically stable DC (ie, without acute decompensation) who underwent paired HVPG/VWF assessments before/on NSBB therapy were classified as ‘VWF-responders’ (as defined by a ≥5% decrease in VWF) versus ‘VWF-non-responders.’

      Results

      There were no major differences in baseline characteristics between VWF-responders (61%) and VWF-non-responders. VWF-responders showed more pronounced decreases in inflammation (procalcitonin), whereas rates of HVPG-response were similar. In line, NSBB-related changes in VWF correlated with the dynamics of bacterial translocation/inflammation (lipopolysaccharide-binding protein, C-reactive protein, and procalcitonin), rather than those of HVPG. Interestingly, VWF-responders also showed less pronounced NSBB-related decreases in mean arterial pressure, suggesting an amelioration of systemic vasodilatation. Finally, VWF-response was associated with decreased risks of further decompensation (adjusted hazard ratio [aHR], 0.555; 95% confidence interval [CI], 0.337-0.912; P = .020), ACLF (aHR, 0.302; 95% CI, 0.126-0.721; P = .007), and liver-related death (aHR, 0.332; 95% CI, 0.179-0.616; P < .001) in Cox regression models adjusted for prognostic factors including changes in HVPG.

      Conclusions

      Decreases in VWF upon NSBB therapy reflect their anti-inflammatory activity, are accompanied by less pronounced adverse effects on systemic hemodynamics, and are independently associated with a decreased risk of further decompensation, ACLF, and death. VWF-response may discriminate between decompensated patients who benefit from NSBB treatment and have a favorable prognosis versus patients with poor outcomes.

      Graphical abstract

      Keywords

      Abbreviations used in this paper:

      ACLF (Acute-on-chronic liver failure), aHR (adjusted hazard ratio), AKI (acute kidney injury), AUROC (area under the receiver operating characteristic curve), BL (baseline), BT (bacterial translocation), CI (confidence interval), CRP (C-reactive protein), CSPH (clinically significant portal hypertension), DC (decompensated cirrhosis), FU (clinical follow-up), HCC (hepatocellular carcinoma), HVPG (hepatic venous pressure gradient), IL-6 (interleukin-6), IQR (interquartile range), LBP (lipopolysaccharide-binding protein), MAP (mean arterial pressure), NIT (noninvasive test), NSBB (nonselective beta blocker), OLT (orthotopic liver transplantation), PCT (procalcitonin), SBP (spontaneous bacterial peritonitis), SI (systemic inflammation), TIPS (transjugular intrahepatic portosystemic shunt), VWF (von Willebrand factor)

       Background

      Nonselective beta blockers (NSBBs) may prevent acute-on-chronic liver failure development by modulating systemic inflammation. Biomarkers for monitoring these nonhemodynamic effects are lacking. Von Willebrand factor (VWF) indicates inflammation-induced endothelial dysfunction and predicts outcomes, independently of portal hypertension severity.

       Findings

      Decreases in VWF upon NSBB therapy reflect their anti-inflammatory activity and are accompanied by less pronounced adverse effects on systemic hemodynamics. ‘VWF-responders’ showed lower rates of decompensation, acute-on-chronic liver failure, and liver-related death.

       Implications for patient care

      VWF response may discriminate between decompensated patients who benefit from NSBB treatment and have a favorable prognosis versus patients with poor outcomes.
      Nonselective beta blockers (NSBBs) are the cornerstone in the medical treatment of portal hypertension.
      • de Franchis R.
      Baveno VI Faculty. Expanding consensus in portal hypertension: report of the Baveno VI Consensus Workshop: Stratifying risk and individualizing care for portal hypertension.
      However, they are not equally effective throughout all patients.
      • Mandorfer M.
      • Hernández-Gea V.
      • Reiberger T.
      • et al.
      Hepatic venous pressure gradient response in non-selective beta-blocker treatment—is it worth measuring?.
      There is an ongoing debate regarding the risk/benefit-ratio of NSBBs in decompensated patients
      • Reiberger T.
      • Mandorfer M.
      Beta adrenergic blockade and decompensated cirrhosis.
      ,
      • Jachs M.
      • Reiberger T.
      Prevention of variceal bleeding and rebleeding by NSBB – a tailored approach.
      in whom NSBB treatment achieves less pronounced decreases in hepatic venous pressure gradient (HVPG).
      • Alvarado-Tapias E.
      • Ardevol A.
      • Garcia-Guix M.
      • et al.
      Short-term hemodynamic effects of beta-blockers influence survival of patients with decompensated cirrhosis.
      Specifically, NSBB treatment has been associated with increased mortality in patients with refractory ascites
      • Sersté T.
      • Melot C.
      • Francoz C.
      • et al.
      Deleterious effects of beta-blockers on survival in patients with cirrhosis and refractory ascites.
      and spontaneous bacterial peritonitis (SBP),
      • Mandorfer M.
      • Bota S.
      • Schwabl P.
      • et al.
      Nonselective beta blockers increase risk for hepatorenal syndrome and death in patients with cirrhosis and spontaneous bacterial peritonitis.
      as it may impair cardiac function and systemic hemodynamics
      • Mandorfer M.
      • Bota S.
      • Schwabl P.
      • et al.
      Nonselective beta blockers increase risk for hepatorenal syndrome and death in patients with cirrhosis and spontaneous bacterial peritonitis.
      ,
      • Tellez L.
      • Ibanez-Samaniego L.
      • Perez Del Villar C.
      • et al.
      Non-selective beta-blockers impair global circulatory homeostasis and renal function in cirrhotic patients with refractory ascites.
      in a subgroup of patients, thereby possibly worsening kidney function
      • Tellez L.
      • Ibanez-Samaniego L.
      • Perez Del Villar C.
      • et al.
      Non-selective beta-blockers impair global circulatory homeostasis and renal function in cirrhotic patients with refractory ascites.
      and promoting acute kidney injury (AKI).
      • Mandorfer M.
      • Bota S.
      • Schwabl P.
      • et al.
      Nonselective beta blockers increase risk for hepatorenal syndrome and death in patients with cirrhosis and spontaneous bacterial peritonitis.
      Accordingly, there is a need for novel biomarkers to assess the expectable benefits in an individual patient, because the assessment of HVPG response is invasive and only available in few academic centers.
      • Mandorfer M.
      • Hernández-Gea V.
      • Reiberger T.
      • et al.
      Hepatic venous pressure gradient response in non-selective beta-blocker treatment—is it worth measuring?.
      Moreover, NSBB therapy exerts additional nonhemodynamic effects,
      • Gimenez P.
      • Garcia-Martinez I.
      • Frances R.
      • et al.
      Treatment with non-selective beta-blockers affects the systemic inflammatory response to bacterial DNA in patients with cirrhosis.
      • Reiberger T.
      • Ferlitsch A.
      • Payer B.A.
      • et al.
      Vienna Hepatic Hemodynamic Lab
      Non-selective betablocker therapy decreases intestinal permeability and serum levels of LBP and IL-6 in patients with cirrhosis.
      • Jachs M.
      • Hartl L.
      • Schaufler D.
      • et al.
      Amelioration of systemic inflammation in advanced chronic liver disease upon beta-blocker therapy translates into improved clinical outcomes.
      which could be the mechanisms by which NSBB treatment prevents SBP
      • Senzolo M.
      • Cholongitas E.
      • Burra P.
      • et al.
      beta-Blockers protect against spontaneous bacterial peritonitis in cirrhotic patients: a meta-analysis.
      and ameliorates the course of acute-on-chronic liver failure (ACLF).
      • Mookerjee R.P.
      • Pavesi M.
      • Thomsen K.L.
      • et al.
      CANONIC Study Investigators of the EASL-CLIF Consortium
      Treatment with non-selective beta blockers is associated with reduced severity of systemic inflammation and improved survival of patients with acute-on-chronic liver failure.
      ,
      • Kumar M.
      • Kainth S.
      • Choudhury A.
      • et al.
      Treatment with carvedilol improves survival of patients with acute-on-chronic liver failure: a randomized controlled trial.
      Von Willebrand factor (VWF) is a marker of endothelial dysfunction and has primarily been studied as a noninvasive test (NIT) for clinically significant portal hypertension (CSPH) in patients with compensated advanced chronic liver disease.
      • Mandorfer M.
      • Hernandez-Gea V.
      • Garcia-Pagan J.C.
      • et al.
      Noninvasive diagnostics for portal hypertension: a comprehensive review.
      Importantly, in patients with CSPH, high VWF is linked to poor prognosis, even after adjusting for the severity of portal hypertension (ie, HVPG),
      • La Mura V.
      • Reverter J.C.
      • Flores-Arroyo A.
      • et al.
      Von Willebrand factor levels predict clinical outcome in patients with cirrhosis and portal hypertension.
      ,
      • Mandorfer M.
      • Schwabl P.
      • Paternostro R.
      • et al.
      Vienna Hepatic Hemodynamic Lab
      Von Willebrand factor indicates bacterial translocation, inflammation, and procoagulant imbalance and predicts complications independently of portal hypertension severity.
      indicating that VWF is more than a NIT for portal hypertension. Pathological bacterial translocation (BT) from the gut directly worsens endothelial dysfunction via toll-like receptor 4 activation by endotoxins/lipopolysaccharides,
      • Carnevale R.
      • Raparelli V.
      • Nocella C.
      • et al.
      Gut-derived endotoxin stimulates factor VIII secretion from endothelial cells. Implications for hypercoagulability in cirrhosis.
      thereby triggering the release of VWF into the portal and the systemic circulation.
      • Praktiknjo M.
      • Trebicka J.
      • Carnevale R.
      • et al.
      Von Willebrand and factor VIII portosystemic circulation gradient in cirrhosis: implications for portal vein thrombosis.
      Accordingly, VWF may also serve as a marker of BT and resulting systemic inflammation (SI) – important pathophysiologic mechanisms that are particularly relevant in decompensated cirrhosis (DC) as they drive the development of further hepatic decompensation (ie, ‘unstable decompensated cirrhosis’) and are main determinants of ACLF development.
      • Trebicka J.
      • Fernandez J.
      • Papp M.
      • et al.
      PREDICT STUDY group of the EASL-CLIF Consortium
      The PREDICT study uncovers three clinical courses of acutely decompensated cirrhosis that have distinct pathophysiology.
      The close association of VWF with the postulated nonhemodynamic effects of NSBB therapy on the one hand, and clinical endpoints on the other hand, indicate that VWF changes in response to NSBB therapy may serve as a surrogate for its therapeutic benefit.
      Thus, we evaluated the association between NSBB-related changes in VWF and the development of further decompensation, AKI, ACLF, and mortality in thoroughly characterized patients with DC who underwent paired HVPG and VWF measurements.

      Methods

       Patient Cohorts and Study Design

      In this retrospective analysis, we included prospectively characterized patients (ie, standardized clinical and hemodynamic evaluation) who underwent paired assessments of HVPG and VWF in the course of primary/secondary prophylaxis of variceal bleeding at the Vienna Hepatic Hemodynamic Lab of the Medical University of Vienna between 2006 and 2019 and who fulfilled the following criteria: (1) HVPG >12 mm Hg at baseline (BL; ie, without NSBB treatment); (2) stable NSBB intake at the time of follow-up (NSBB-HVPG) measurement with a maximum time interval of 90 days between BL and NSBB measurements. This time interval was chosen to minimize the impact of the natural history of the underlying liver disease on the obtained measurements. Importantly, (3) only outpatients with clinically stable DC at BL were included, as evident from a history of hepatic decompensation in the past with no evidence of acute decompensation at BL.
      Patients with a history of: (1) occlusive portal vein thrombosis, (2) noncirrhotic portal hypertension, (3) hepatocellular carcinoma (HCC), (4) transjugular intrahepatic portosystemic shunt (TIPS), or (5) orthotopic liver transplantation (OLT), as well as (6) bacterial infection/antibiotic treatment except for rifaximin at the time of BL or NSBB measurement were excluded.
      Information on TIPS, OLT, events indicating further hepatic decompensation, AKI, ACLF, or death were recorded. Moreover, information on risk-modifying events/treatments during clinical follow-up (FU) (ie, diagnosis of HCC, alcohol abstinence in alcoholic liver disease, or initiation of antiviral therapy), was obtained.
      In addition, we recruited stable DC patients with paired VWF measurements but without NSBB treatment initiation from the prospective Vienna Cirrhosis Study (VICIS, NCT: NCT03267615). Details are provided in the Supplementary Methods.

       Measurement of HVPG and VWF and Biomarkers of BT and SI

      HVPG measurements were conducted following a standardized operating procedure described elsewhere.
      • Reiberger T.
      • Schwabl P.
      • Trauner M.
      • et al.
      Measurement of the hepatic venous pressure gradient and transjugular liver biopsy.
      Laboratory tests were performed at the ISO-certified Department of Laboratory Medicine of the Medical University of Vienna. VWF was measured by a latex agglutination assay (STA LIATEST vWF, Diagnostica Stago, Asnieres, France). Assessments of precision/intermediate precision (Supplementary Methods) yielded a coefficient of variation of approximately 3%.

       Definition of DC

      History of variceal bleeding or past/current ascites/hepatic encephalopathy defined DC.
      • European Association for the Study of the Liver
      EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis.
      See Supplementary Methods for details.

       Definition of VWF-Response

      A relative change in VWF by −2% was the best cutoff for liver-related mortality during FU, as determined by Youden’s index. However, due to the precision/intermediate precision of the assay and observations in ‘untreated’ patients, decreases in VWF ≥5% at the time of NSBB HVPG measurement identified ‘VWF-responders’ in this proof-of-concept study.

       Definition of Clinical Events During FU

      Clinical events during FU that were considered in our analyses comprised variceal bleeding, development of admission due to hepatic encephalopathy, paracentesis, TIPS implantation, SBP or other major bacterial infections, ACLF, and liver-related death.
      • European Association for the Study of the Liver
      EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis.
      More detailed information is given in the Supplementary Methods.

       Statistical Analysis

      Statistical analysis was conducted using R 4.0.2 (R Core Team, R Foundation for Statistical Computing, Vienna, Austria) and GraphPad Prism 8 (GraphPad Software, La Jolla, CA). To evaluate the prognostic value of relative VWF changes from BL to NSBB-HVPG, time-dependent area under the receiver operating characteristic (AUROC) curve analysis was performed. For time-to-event analyses, 2 different approaches were applied: (1) Kaplan-Meier method and log-rank test stratified by VWF-response group status and (2) multivariate Cox regression incorporating a time-dependent variable for VWF-response. A landmark of 30 days after NSBB-HVPG for the assignment of VWF-response status was chosen for both strategies to reduce the risk of bias, which is further explained in the Supplementary Methods.

       Ethics

      This study was conducted in accordance with the Declaration of Helsinki and approved by the institutional review board of the Medical University of Vienna (Nos. 1493/2016 and 1971/2016). No written informed consent was required for this retrospective analysis, whereas informed consent was obtained for inclusion in the VICIS study.

      Results

       Patient/Treatment Characteristics

      One hundred fifty-nine patients were included. Detailed information on patient/treatment characteristics is provided in the Supplementary Tables 1 and 2.
      The median time between BL and NSBB-HVPG was 33 days (interquartile range [IQR], 28-41 days).
      Of note, no patient achieved alcohol abstinence or was prescribed antiviral therapy between BL and NSBB assessments, nor was any patient treated with antibiotics besides chronic rifaximin therapy for hepatic encephalopathy (n = 11; 6.9%). Seven patients (4.4%) were on chronic statin treatment at BL, which remained unchanged from BL to NSBB measurement.

       Dynamics of VWF in Stable DC Without NSBB Therapy Initiation

      There were no spontaneous dynamics in VWF (median relative change, 1% [IQR, −3 to 4%]; P = .888), and ‘VWF-response’ was uncommon (n = 11/66; 16.7%) (Supplementary Methods).

       NSBB Treatment-related Changes in HVPG/VWF and Systemic Hemodynamics

      NSBB treatment was associated with pronounced relative changes in HVPG (median, −11.1%; 21 mmHg [IQR, 18-24 mm Hg] at BL to 18 mm Hg [IQR, 15-21 mm Hg] at NSBB-HVPG; P < .001), VWF (median, −8.0%; 350% [IQR, 291%-420% ] at BL to 322% [IQR, 253%-398%] at NSBB-HVPG; P < .001), and C-reactive protein (CRP) (n = 138; median, −19.8%; 0.50 mg/dL [IQR, 0.20-1.22 mg/dL] at BL to 0.44 mg/dL [IQR, 0.17-0.88 mg/dL] at NSBB-HVPG; P < .001). Of note, the relative change in VWF clearly differed from the above-mentioned ‘untreated’ cohort (P < .001).
      Information on systemic hemodynamics at NSBB HVPG and paired comparisons to BL values are shown in Supplementary Tables 1 and 2.

       Comparison of Dynamics of HVPG, VWF, and Systemic Hemodynamics Between VWF-Responders and VWF-Non-responders

      Interestingly, relative changes in HVPG (VWF-responders, −11.1% [IQR, −23.5% to −3.9% ] vs VWF-non-responders, −11.5% [IQR, −24.7% to −3.5%]; P = .973) and the proportion of patients achieving HVPG-response (VWF-responders, 48 [49.5%] vs. VWF-non-responders, 29 [56.8%]; P = .864) (Table 1) were similar between VWF-response groups.
      Table 1Comparison of Patient Characteristics at BL (ie, Before NSBB Therapy), NSBB Treatment Characteristics, and Treatment-related Changes Between VWF-Non-Responders (<5% Decrease in VWF Levels from BL to NSBB-HVPG) and VWF-Responders (≥5% Decrease in VWF levels from BL to NSBB-HVPG)
      Patient characteristicVWF-non-responders, (n = 62)VWF-responders, (n = 97)P
      Sex, male/female (% male)49/13 (79.0)69/28 (71.1).355
      Age, years55.9 ± 10.755.4 ± 10.4.795
      BMI, kg/m225.8 (23.4–29.8)24.7 (21.6–28.1).121
      Etiology of ACLD
       ALD41 (66.1)62 (63.9).324
       Viral8 (12.9)7 (7.2)
       ALD + viral4 (6.5)13 (13.4)
       NAFLD4 (6.5)3 (3.1)
       Other/cryptogenic5 (8.1)12 (12.4)
      Alcohol consumption
       Abstinent42 (67.7)65 (67.0).466
       Below threshold
      >30 g/day and >20 g/day for males and females, respectively.
      6 (9.7)5 (5.2)
       Above threshold
      >30 g/day and >20 g/day for males and females, respectively.
      14 (22.6)27 (27.8)
      BL CTP score, points8 (7–9)7 (6–9).204
      NSBB CTP score, points7 (6–9)7 (6–8).080
      BL MELD (2016), points11 (10–16)12 (10–18).399
      NSBB MELD (2016), points12 (10–17)11 (9–15).205
      BL albumin, g/L32.10 (29.92–35.80)33.40 (30.20–37.80).271
      BL bilirubin, mg/dL1.59 (1.07–2.45)1.75 (1.06–2.60).846
      BL INR1.3 (1.2–1.5)1.4 (1.2–1.5).767
      BL creatinine, mg/dL0.82 (0.72–0.98)0.76 (0.66–1.00).351
      BL sodium, mmol/L136 (134–138)137 (133–140).868
      Varices
       Small25 (40.3)29 (29.9).237
       Large37 (59.7)68 (70.1)
      History of bleeding24 (38.7)35 (36.1).868
      Ascites
       No9 (14.5)22 (22.47).429
       Mild/moderate42 (67.7)61 (62.9)
       Severe/refractory11 (17.7)14 (14.4)
      HE22 (35.5)28 (28.9).631
      Type of NSBB therapy
       Carvedilol34 (54.8)73 (75.3).012
       Propranolol28 (45.2)24 (24.7)
      BL MAP, mm Hg100 (91–112)98 (90–107).362
      BL MAP <65 mm Hg0 (0)0 (0)N/A
      NSBB MAP, mm Hg90 (80–96)90 (84–100).368
      NSBB MAP <65 mm Hg4 (6.5)2 (2.1).322
      ΔMAP, absolute, mm Hg−13 (−19 to −3)−8 (−15 to 0).064
      ΔMAP, relative, %−12.2 (−18.5 to −2.8)−8.0 (−15.0 to 0).044
      BL HVPG, mm Hg21 (17–25)21 (18–24).577
      NSBB HVPG, mm Hg18 (15–21)18 (15–21).914
      ΔHVPG, absolute, mm Hg−2 (−5 to −1)−2 (−5 to −1).960
      ΔHVPG, relative, %−11.5 (−24.7 to −3.5)−11.1 (−23.5 to −3.9).973
      HVPG decrease ≥10%34 (54.8)57 (58.8).746
      HVPG decrease ≥20%22 (35.5)34 (35.1)1.000
      HVPG-response
      Defined by an HVPG decrease to ≤12 mm Hg or by ≥10% in primary and ≥20% in secondary prophylaxis of variceal bleeding.
      29 (56.8)48 (49.5).864
      BL VWF, %328 (260–410)366 (304–466).016
      NSBB VWF, %361 (284–419)305 (246–378).024
      ΔVWF, absolute, %9 (−2 to 33)−53 (−85 to −29)< .001
      ΔVWF, relative, %3.2 (−0.4 to 10.3)−14.7 (−21.4 to −10.0)< .001
      BL CRP,
      CRP values available in n = 146 at BL and in n = 143 at FU.
      mg/dL
      0.50 (0.17–1.21)0.53 (0.21–1.22).947
      NSBB CRP,
      CRP values available in n = 146 at BL and in n = 143 at FU.
      mg/dL
      0.53 (0.17–1.13)0.37 (0.18–0.84).172
      ΔCRP, absolute, mg/dL−0.02(−0.20 to 0.03)−0.09 (−0.42 to 0.02).148
      ΔCRP, relative, %−3.5 (−33.1 to 10.0)−26.2 (−50.0 to 11.8).050
      BL PCT,
      PCT values available in n = 36 at BL and in n = 36 at FU.
      ng/mL
      0.10 (0.06–0.16)0.13 (0.11–0.20).215
      NSBB PCT,
      PCT values available in n = 36 at BL and in n = 36 at FU.
      ng/mL
      0.15 (0.07–0.19)0.09 (0.06–0.14).125
      ΔPCT, absolute, ng/mL0.01 (0.01–0.04)−0.02 (−0.04 to −0.01).008
      ΔPCT, relative, %20.0 (11.7–36.4)−20.2 (−34.1 to −3.8).001
      BL IL-6,
      IL-6 values available in n = 35 at BL and in n = 37 at FU.
      pg/nL
      10.85 (7.88–20.49)15.46 (7.79–33.27).614
      NSBB IL-6,
      IL-6 values available in n = 35 at BL and in n = 37 at FU.
      pg/nL
      14.88 (7.40–21.65)11.83 (7.58–20.39).556
      ΔIL-6, absolute, pg/nL−2.52 (−4.19 to 0.99)−0.26 (−10.89 to 4.95).858
      ΔIL-6, relative,%−13.4 (−30.0 to 7.5)−8.3 (−43.1 to 25.4).921
      BL LBP,
      LBP values available in n = 35 at BL and in n = 38 at FU.
      μg/mL
      6.28 (5.16–8.34)8.32 (6.48–9.63).129
      NSBB LBP,
      LBP values available in n = 35 at BL and in n = 38 at FU.
      μg/mL
      6.53 (5.02–9.76)7.32 (5.46–8.43).683
      ΔLBP, absolute, μg/mL0.22 (−0.62 to 0.83)−0.66 (−1.93 to 0.42).073
      ΔLBP, relative, %4.6 (−8.4 to 13.0)−8.2 (−22.7 to 7.4).111
      Note: Data are presented as number (%), mean ± standard deviation, or median (interquartile range). Boldface P values indicate statistical significance.
      ACLD, Advanced chronic liver disease; ALD, alcoholic liver disease; BL, baseline; BMI, body mass index; CRP, C-reactive protein; CTP, Child-Turcotte-Pugh; FU, clinical follow-up; HE, hepatic encephalopathy; HVPG, hepatic venous pressure gradient; IL-6, interleukin-6; INR, international normalized ratio; LBP, lipopolysaccharide-binding protein; MAP, mean arterial pressure; MELD, Model of End-stage Liver Disease; NAFLD, non-alcoholic fatty liver disease; NSBB, nonselective beta blocker; PCT, procalcitonin; VWF, von Willebrand factor
      a >30 g/day and >20 g/day for males and females, respectively.
      b Defined by an HVPG decrease to ≤12 mm Hg or by ≥10% in primary and ≥20% in secondary prophylaxis of variceal bleeding.
      c CRP values available in n = 146 at BL and in n = 143 at FU.
      d PCT values available in n = 36 at BL and in n = 36 at FU.
      e IL-6 values available in n = 35 at BL and in n = 37 at FU.
      f LBP values available in n = 35 at BL and in n = 38 at FU.
      The median relative decrease in VWF levels in the VWF-response group was −14.7% (IQR, −21.4 to −10.0%), whereas VWF-non-responders showed a median relative increase of 3.2% (IQR, −0.4% to 10.3%) from BL to NSBB-HVPG measurement (P < .001).
      Interestingly, patients with VWF response showed less pronounced NSBB therapy-associated relative decreases in mean arterial pressure (MAP) (VWF-responders, −8.0% [IQR, −15.0 to 0%] vs VWF-non-responders, −12.2% [IQR, −18.5% to −2.8%]; P = .044).

       Comparison of BL/Treatment Characteristics Between VWF-Responders and VWF-Non-Responders

      NSBB treatment initiation was paralleled by ≥5% VWF decreases from BL to NSBB measurement (‘VWF-response’) in 97 patients (61.0%). Of note, there were no significant differences in BL HVPG, severity of hepatic dysfunction, or BL levels of markers of SI (ie, CRP, procalcitonin [PCT], and interleukin-6 [IL-6]), and BT (ie, lipopolysaccharide-binding protein [LBP]) between the 2 groups (Table 1).
      Notably, a higher proportion of patients with VWF-response were on carvedilol (VWF-responders, 75.3% vs VWF-non-responders, 54.8%; P = .012).

       Correlates of VWF as Well as its NSBB Treatment-related Changes

      BL VWF correlated positively with BL HVPG (Spearman’s ρ, 0.192; P = .016) and BL CRP (ρ, 0.305; P < .001) as well as trend-wise with BL PCT (ρ, 0.312; P = .064) and BL IL-6 (ρ, 0.334; P = .051), whereas no correlation with BL LBP (ρ, 0.021; P = .907) was found (Table 1). A heat map of correlations between BL values of VWF, HVPG, and markers of BT/SI is shown in Figure 1.
      Figure thumbnail gr1
      Figure 1Correlations of BL (ie, before NSBB therapy) values of HVPG, VWF, and biomarkers of BT/SI. CRP, PCT, IL-6, and LBP values were available in n = 146, n = 36, n = 35, and n = 35 patients, respectively. ∗Indicates P-values < .05, whereas ∗∗denotes P-values < .001.
      VWF-response was accompanied by stronger NSBB therapy-related relative decreases in PCT (available in n = 31; VWF-responders, −20.2% [IQR, −34.1% to −3.8%] vs VWF-non-responders, 20.0% [IQR,11.7%–36.4%]; P = .001) and CRP (available in n = 138; VWF-responders, −26.2% [IQR, −50.0% to 11.8%] vs VWF-non-responders, −3.5% [IQR, −33.1% to 10.0%]; P = .050), and a tendency towards stronger decreases in LBP (available in n = 32; VWF-responders, −8.2% [IQR, −22.7% to 7.4%] vs VWF-non-responders, 4.6% [IQR, −8.4% to 13.0%]; P = .111). In contrast, there was no difference in relative changes in IL-6 (available in n = 32; VWF-responders, −8.3% [IQR, −43.1% to 25.4%] vs VWF-non-responders, −13.4% [IQR, −30.0% to 7.5%]; P = .921).
      Furthermore, the magnitude of VWF decrease was linked to the dynamics of several markers of BT/SI (Figure 2).
      Figure thumbnail gr2
      Figure 2Comparison of relative changes in markers of bacterial translocation and systemic inflammation ([A] CRP, n = 138; [B] PCT, n = 31; [C] IL-6, n = 32; and [D] LBP, n = 32) upon NSBB therapy, stratified by the dynamics of VWF: Stable/increasing VWF levels versus reductions below or above/equal to the median relative VWF decrease (14.7%) that was observed in the group of patients who showed NSBB treatment-related decreases in VWF.
      Finally, although relative changes in VWF levels did neither correlate with relative changes in HVPG (Spearman’s ρ, −0.087; P = .278) nor with relative changes in IL-6 (ρ, 0.092; P = .615), we observed direct correlations of weak (CRP: ρ, 0.257; P = .002; LBP: ρ, 0.352; P = .049) to moderate strength (PCT: ρ, 0.661; P < .001) with relative changes in markers of BT/SI.

       Clinical FU

      Patients were followed-up for a median of 25.1 months (IQR, 9.8–46.0 months). Detailed information about FU events is provided in the Supplementary Methods.

       Prognostic Value of NSBB Therapy-related VWF Response for Further Decompensation, AKI Development, and ACLF Development, as Well as Liver-related Death

      In time-dependent AUROC analysis, relative NSBB therapy-related changes in VWF from BL to NSBB measurement were of superior prognostic value as compared to changes in CRP (Figure 3), which did not yield prognostic information in this context.
      Figure thumbnail gr3
      Figure 3Time-dependent receiver operating characteristic curves for the prediction of liver-related death within 3 years of FU by changes in VWF (AUROC for relative Δ, 0.707; 95% CI, 0.594–0.821) and CRP (AUROC for relative Δ, 0.538; 95% CI, 0.394–0.682) upon NSBB treatment initiation.
      Nineteen patients developed events or were censored before the landmark of 30 days after NSBB-HVPG (Supplementary Figure 1), and thus were excluded from Kaplan-Meier/log-rank test analyses. In the remaining 140 patients, we observed lower incidences of further decompensation (P = .046), AKI (P = .010), ACLF (P = .001), and liver-related death (P = .014) in VWF-responders (Figure 4).
      Figure thumbnail gr4
      Figure 4Landmark Kaplan-Meier analyses with further hepatic decompensation (A), AKI development (B), and ACLF development (C), as well as liver-related mortality (D) as outcomes of interest. Patients were censored upon etiologic treatments/HCC diagnosis, and transplantation (all models), as well as non-liver-related mortality (models A and D) and death (models B and C). Importantly, all patients who were censored or developed an outcome of interest before 30 days after the second measurement (ie, the defined landmark) were not considered for the analyses (n = 19 for all models).
      In a multivariate Cox regression model considering VWF-response upon NSBB therapy initiation as a time-dependent covariate (Supplementary Figure 1), the achievement of VWF-response was independently associated with a decrease in the risks of further decompensation (adjusted hazard ratio [aHR], 0.555; 95% confidence interval [CI], 0.337–0.912; P = .020; adjusted for BL VWF, Child-Turcotte-Pugh stage, serum creatinine, BL HVPG, and relative HVPG change from BL to NSBB-HVPG).
      In addition, VWF-response was found to be associated with a reduced risk of AKI (aHR, 0.367; 95% CI, 0.167–0.803; P = .012); adjusted for the same factors as above) and was also independently protective of ACLF development (aHR, 0.302; 95% CI, 0.126–0.721; P = .007; adjusted for the same factors as above).
      Finally, VWF-response was found to be independently associated with a profoundly decreased risk of liver-related mortality (aHR, 0.332; 95% CI, 0.179–0.616; P < .001; adjusted for the same factors as above).
      Detailed information regarding the multivariate Cox regression models for the respective outcomes of interest are shown in Supplementary Table 3.

      Discussion

      We observed VWF changes following NSBB therapy initiation in clinically stable outpatients with DC, which were independent of those of HVPG. VWF changes correlated with the dynamics in biomarkers of BT/SI, confirming our previous findings obtained in an one-time assessment.
      • Mandorfer M.
      • Schwabl P.
      • Paternostro R.
      • et al.
      Vienna Hepatic Hemodynamic Lab
      Von Willebrand factor indicates bacterial translocation, inflammation, and procoagulant imbalance and predicts complications independently of portal hypertension severity.
      Importantly, patients who showed a decrease in VWF after NSBB treatment initiation (ie, ‘VWF-responders’) had strongly reduced risks of further decompensation, AKI development, and ACLF development, even after adjusting for other prognostic factors, including HVPG-response. Finally, the risk of liver-related mortality was more than halved in VWF-responders, indicating that ≥5% VWF decreases upon NSBB treatment translate into a clinically meaningful benefit.
      Although NSBB therapy has recently been found to prevent the development of DC,
      • Villanueva C.
      • Albillos A.
      • Genesca J.
      • et al.
      beta blockers to prevent decompensation of cirrhosis in patients with clinically significant portal hypertension (PREDESCI): a randomised, double-blind, placebo-controlled, multicentre trial.
      ,
      • Mandorfer M.
      • Simbrunner B.
      Prevention of first decompensation in advanced chronic liver disease.
      its beneficial effects are especially well-established and important in secondary prophylaxis and/or once DC has developed: In these patients, NSBB therapy is the key component of combination treatment, as it reduces mortality.
      • Albillos A.
      • Zamora J.
      • Martinez J.
      • et al.
      Baveno Cooperation
      Stratifying risk in the prevention of recurrent variceal hemorrhage: Results of an individual patient meta-analysis.
      ,
      • Pfisterer N.
      • Dexheimer C.
      • Fuchs E.-M.
      • et al.
      Betablockers do not increase efficacy of band ligation in primary prophylaxis but they improve survival in secondary prophylaxis of variceal bleeding.
      Moreover, NSBB therapy is particularly effective if HVPG-response is obtained
      • Mandorfer M.
      • Hernández-Gea V.
      • Reiberger T.
      • et al.
      Hepatic venous pressure gradient response in non-selective beta-blocker treatment—is it worth measuring?.
      – a finding which also extends to the subgroup of patients with ascites (ie, patients who do not necessarily have a history of bleeding).
      • Turco L.
      • Villanueva C.
      • La Mura V.
      • et al.
      Lowering portal pressure improves outcomes of patients with cirrhosis, with or without ascites: a meta-analysis.
      However, the sequential HVPG measurements that are required to assess hemodynamic response to NSBB therapy are invasive, resource-intensive, and not broadly available. The diagnostic performance of NIT (ie, spleen stiffness measurement) for HVPG-response varied considerably throughout studies,
      • Kim H.Y.
      • So Y.H.
      • Kim W.
      • et al.
      Non-invasive response prediction in prophylactic carvedilol therapy for cirrhotic patients with esophageal varices.
      ,
      • Marasco G.
      • Dajti E.
      • Ravaioli F.
      • et al.
      Spleen stiffness measurement for assessing the response to beta-blockers therapy for high-risk esophageal varices patients.
      and most importantly, NSBB-related changes in spleen stiffness measurement did not translate into improved clinical outcomes.
      • Kim H.Y.
      • So Y.H.
      • Kim W.
      • et al.
      Non-invasive response prediction in prophylactic carvedilol therapy for cirrhotic patients with esophageal varices.
      Accordingly, there is currently no NIT that may serve as a surrogate for the efficacy of NSBB therapy.
      • Mandorfer M.
      • Hernandez-Gea V.
      • Garcia-Pagan J.C.
      • et al.
      Noninvasive diagnostics for portal hypertension: a comprehensive review.
      NSBB therapy seems to exert additional, so-called nonhemodynamic effects, which are independent of hemodynamic response.
      • Reiberger T.
      • Ferlitsch A.
      • Payer B.A.
      • et al.
      Vienna Hepatic Hemodynamic Lab
      Non-selective betablocker therapy decreases intestinal permeability and serum levels of LBP and IL-6 in patients with cirrhosis.
      Moreover, a post-hoc analysis of the CANONIC study
      • Mookerjee R.P.
      • Pavesi M.
      • Thomsen K.L.
      • et al.
      CANONIC Study Investigators of the EASL-CLIF Consortium
      Treatment with non-selective beta blockers is associated with reduced severity of systemic inflammation and improved survival of patients with acute-on-chronic liver failure.
      suggested that NSBB therapy ameliorates the course of ACLF, and carvedilol treatment decreased 28-day mortality in patients with ACLF by preventing SBP/infections, AKI, and ACLF progression in a randomized controlled trial.
      • Kumar M.
      • Kainth S.
      • Choudhury A.
      • et al.
      Treatment with carvedilol improves survival of patients with acute-on-chronic liver failure: a randomized controlled trial.
      Of note, clinically applicable surrogate markers to monitor these important, likely nonhemodynamic effects of NSBB treatment have yet to be developed.
      Based on previous observations on VWF that are outlined in the introduction section, we hypothesized that VWF decreases upon NSBB treatment initiation reflect beneficial nonhemodynamic effects, and thus, may be of prognostic value.
      VWF decreased by ≥5% in 61% of NSBB-treated patients, a number that was profoundly different from the rate of spontaneous VWF decreases ≥5% in stable ‘untreated’ patients with DC and higher than the HVPG-response rate in our study (48%) and previous reports.
      • Mandorfer M.
      • Hernández-Gea V.
      • Reiberger T.
      • et al.
      Hepatic venous pressure gradient response in non-selective beta-blocker treatment—is it worth measuring?.
      Of note, the higher proportion of patients who achieved VWF response also fits the previous notion that the proportion of patients who benefit from NSBB therapy may exceed the rate of hemodynamic response.
      • Thalheimer U.
      • Bosch J.
      • Burroughs A.K.
      How to prevent varices from bleeding: shades of grey–the case for nonselective beta blockers.
      To minimize the impact of the natural history of the underlying liver disease
      • Mandorfer M.
      • Kozbial K.
      • Schwabl P.
      • et al.
      Changes in hepatic venous pressure gradient predict hepatic decompensation in patients who achieved sustained virologic response to interferon-free therapy.
      ,
      • Semmler G.
      • Binter T.
      • Kozbial K.
      • et al.
      Non-invasive risk stratification after HCV-eradication in patients with advanced chronic liver disease.
      or intercurrent conditions
      • Reuken P.A.
      • Kussmann A.
      • Kiehntopf M.
      • et al.
      Imbalance of von Willebrand factor and its cleaving protease ADAMTS13 during systemic inflammation superimposed on advanced cirrhosis.
      on VWF levels, we restricted the time interval between the assessments, evaluated only clinically stable outpatients (ie, without acute decompensation), and additionally excluded patients with bacterial infections or antibiotic treatments other than rifaximin. Although a causal relationship between NSBB treatment and changes in VWF cannot be proven due to the design of our study, we have made all reasonable effort to rule out potential confounding factors and also included a control group of stable ‘untreated’ DC patients, in whom the dynamics of VWF were clearly different. Moreover, this limitation is not in any way specific to our study, as it equally applies to landmark studies that established the prognostic value of chronic HVPG-response to NSBB therapy – a generally accepted surrogate.
      • Mandorfer M.
      • Hernández-Gea V.
      • Reiberger T.
      • et al.
      Hepatic venous pressure gradient response in non-selective beta-blocker treatment—is it worth measuring?.
      Interestingly, NSBB therapy-related VWF changes were unrelated to those of HVPG, which may be explained by the weak correlation between HVPG and VWF at high values and by the increasing contribution of BT/SI in these patients. The substantially higher importance of BT/SI (vs portal hypertension) as a determinant of the dynamics of VWF is also supported by its (weak to moderate) correlations with (changes in) inflammatory markers.
      Intriguingly, VWF responders also showed less pronounced NSBB therapy-related decreases in MAP, although carvedilol use was more common in this group. MAP reflects renal perfusion
      • Tellez L.
      • Ibanez-Samaniego L.
      • Perez Del Villar C.
      • et al.
      Non-selective beta-blockers impair global circulatory homeostasis and renal function in cirrhotic patients with refractory ascites.
      and provides guidance for the safe use of NSBB therapy in patients with DC.
      • Tergast T.L.
      • Kimmann M.
      • Laser H.
      • et al.
      Systemic arterial blood pressure determines the therapeutic window of non-selective beta blockers in decompensated cirrhosis.
      The observation of smaller NSBB-related decreases in MAP in VWF-responders may be explained by the more pronounced amelioration of SI – and thus, systemic vasodilatation – upon NSBB therapy in these patients.
      We evaluated the prognostic value of relative changes in VWF by time-dependent AUROC analysis for liver-related mortality and determined the optimal cutoff for defining VWF-response by Youden’s index, which was −2%. Since this is a first proof-of-concept study, we simply compared patients with or without a meaningful decrease (≥5%) in VWF in all further analyses. Of note, we also evaluated the relative changes in CRP – a readily available laboratory test for SI with profound prognostic implications in patients with CSPH
      • Mandorfer M.
      • Schwabl P.
      • Paternostro R.
      • et al.
      Vienna Hepatic Hemodynamic Lab
      Von Willebrand factor indicates bacterial translocation, inflammation, and procoagulant imbalance and predicts complications independently of portal hypertension severity.
      – as a comparator, which showed no association with liver-related mortality, highlighting the particular relevance of VWF in this context of NSBB therapy.
      VWF-response was consistently associated with a favourable clinical course as indicated by lower incidences/risks of further decompensation, AKI, ACLF, and liver-related death, independently of established prognostic indicators. After validation, VWF-response may serve as a valuable NIT/biomarker to discriminate between patients with DC who benefit (the most) from NSBB treatment and have a favorable prognosis versus patients with poor outcomes. The latter patients may be candidates for emerging therapies that target the pathophysiologic mechanisms underlying elevated VWF levels, such as statins,
      • Abraldes J.G.
      • Villanueva C.
      • Aracil C.
      • et al.
      BLEPS Study Group
      Addition of simvastatin to standard therapy for the prevention of variceal rebleeding does not reduce rebleeding but increases survival in patients with cirrhosis.
      albumin,
      • Caraceni P.
      • Riggio O.
      • Angeli P.
      • et al.
      ANSWER Study Investigators
      Long-term albumin administration in decompensated cirrhosis (ANSWER): an open-label randomised trial.
      or possibly TIPS,
      • Garcia-Pagan J.C.
      • Saffo S.
      • Mandorfer M.
      • et al.
      Where does TIPS fit in the management of patients with cirrhosis?.
      and should preferably be evaluated early for OLT.
      The lack of a validation cohort receiving NSBB therapy is a main limitation of our study. In addition, only patients undergoing paired HVPG measurements were considered, and thus, our study population may not be fully representative of the population of patients with DC treated at our and other institutions. Only 16% of patients had recurrent/refractory ascites, which may be explained by safety concerns and NSBB intolerance. However, the potential clinical relevance of NSBB-related VWF-response is limited to patients who are considered eligible for or tolerate NSBB therapy. Moreover, a subset of patients lacked a strong indication for NSBB treatment according to the international recommendations that were in place at the time of treatment initiation; however, Austrian consensus recommendations were more proactive regarding the use of NSBB therapy for primary prophylaxis in patients with low-risk varices throughout the whole study period. Of note, our study was not designed to evaluate the prognostic relevance of NSBB therapy-related HVPG changes, as patients with HVPG-non-response and large varices but without a history of bleeding were considered for additional endoscopic therapies at our center. Finally, we did not assess the impact of ABO blood type on VWF; however, its impact in advanced chronic liver disease – in particular DC – is comparatively small,
      • Scheiner B.
      • Northup P.G.
      • Gruber A.B.
      • et al.
      The impact of ABO blood type on the prevalence of portal vein thrombosis in patients with advanced chronic liver disease.
      and it appears unlikely that ABO blood type significantly impacted the NSBB-related VWF changes.

      Conclusions

      A VWF decrease upon NSBB therapy reflects its anti-inflammatory activity and is accompanied by less pronounced adverse effects on systemic hemodynamics as well as decreased risks of further decompensation, ACLF, and death. Thus, VWF is a promising biomarker to assess the therapeutic benefit of NSBB treatment in patients with DC: Patients with VWF-response benefit from NSBB treatment and have a favorable prognosis – accordingly, discontinuation of NSBB therapy should be carefully scrutinized. In contrast, the absence of a VWF-response identifies patients with poor outcomes, who may require additional treatments to prevent significant morbidity and mortality.

      Acknowledgments

      The authors thank Elias L. Meyer for providing helpful statistical support.

      CRediT Authorship Contributions

      Mathias Jachs, MD (Conceptualization: Equal; Data curation: Equal; Formal analysis: Equal; Investigation: Equal; Methodology: Equal; Software: Lead; Visualization: Lead; Writing – original draft: Equal)
      Lukas Hartl, MD (Data curation: Equal; Writing – review & editing: Equal)
      Benedikt Simbrunner, MD (Data curation: Equal; Writing – review & editing: Equal)
      David Bauer, MD (Data curation: Equal; Writing – review & editing: Equal)
      Rafael Paternostro, MD (Data curation: Equal; Writing – review & editing: Equal)
      Bernhard Scheiner, MD (Data curation: Equal; Writing – review & editing: Equal)
      Philipp Schwabl, MD (Data curation: Equal; Writing – review & editing: Equal)
      Albert F. Stättermayer, MD (Data curation: Equal; Writing – review & editing: Equal)
      Matthias Pinter, MD, PhD (Data curation: Equal; Writing – review & editing: Equal)
      Ernst Eigenbauer (Data curation: Equal; Software: Supporting)
      Peter Quehenberger, MD (Data curation: Equal; Methodology: Equal; Writing – review & editing: Equal)
      Michael Trauner, MD (Supervision: Supporting; Writing – review & editing: Equal)
      Thomas Reiberger, MD (Conceptualization: Equal; Supervision: Lead; Writing – review & editing: Equal)
      Mattias Mandorfer, MD, PhD (Conceptualization: Equal; Data curation: Equal; Formal analysis: Equal; Investigation: Equal; Methodology: Equal; Writing – original draft: Equal; Writing – review & editing: Equal)

      Supplementary Methods

       Detailed/Additional Information on the Cohort of Stable Patients With Decompensated Cirrhosis With Paired von Willebrand Factor Measurements but Without Nonselective Beta Blocker Treatment Initiation

      We have retrospectively identified all patients with decompensated cirrhosis (DC) who were included in the prospective Vienna Cirrhosis Study (VICS, IRB vote No. 1493/2016) between the first quarter of 2017 and the fourth quarter of 2020 (von Willebrand factor [VWF] assessments within extended routine blood draws in patients with advanced chronic liver disease who did not undergo hepatic venous pressure gradient (HVPG) measurements were introduced in quarter 1 of 2017 at our clinic) who (1) were seen at our outpatient clinic twice within 14–90 days (ie, within the time frame that was also applied for the inclusion in our main cohort) with paired information on VWF; (2) showed stable DC (ie, no decompensation between measurements and a maximum change in Model of End-stage Liver Disease score by 2 points); and (3) either were not on nonselective beta blocker (NSBB) treatment or were already on stable chronic NSBB intake before the first VWF assessment.

       Detailed/Additional Information on Measurement of HVPG/VWF and Biomarkers of Bacterial Translocation/Systemic Inflammation

      After local anesthesia, a catheter introducer sheath was placed in the right internal jugular vein. A specifically designed balloon catheter with an angled tip
      • Ferlitsch A.
      • Bota S.
      • Paternostro R.
      • et al.
      Evaluation of a new balloon occlusion catheter specifically designed for measurement of hepatic venous pressure gradient.
      was advanced into the inferior vena cava and placed in a large hepatic vein under fluoroscopic guidance. HVPG was calculated by subtracting the free from the wedged hepatic venous pressure. The mean of 3 measurements was used for further analyses. Chronic hemodynamic response was evaluated during a second (NSBB-HVPG) measurement and HVPG-response was defined as recommended by the Baveno VI consensus (ie, HVPG reduction by ≥10% [primary prophylaxis], ≥20% [secondary prophylaxis], or to an absolute value of ≤12 mm Hg
      • de Franchis R.
      Baveno VI Faculty. Expanding consensus in portal hypertension: Report of the Baveno VI Consensus Workshop: Stratifying risk and individualizing care for portal hypertension.
      ).
      All laboratory analyses were performed from central venous blood samples that were obtained at the time of baseline (BL) and NSBB-HVPG measurement.
      To evaluate the precision (ie, the variability in the data from replicate determinations of the same homogenous sample under stable operating conditions) of the assay at plasma VWF levels that are representative of our study population, we used a blood sample obtained from an individual patient with DC with a plasma VWF level of 330%. Thus, this sample was close to the median VWF detected in the main cohort of our study, which were 350% at BL and 322% at the second HVPG measurement (NSBB-HVPG). Importantly, when conducting 10 sequential measurements, the coefficient of variation was only 3%. To evaluate intermediate precision (ie, the variability in data from replicate determinations of the same sample at different time points) we reviewed quality assurance data from our clinical laboratory service throughout the study period, which revealed a similar coefficient of variation (around 3%) that was very stable over time.
      Standard laboratory methods were used for the assessment of routine laboratory tests (eg, C-reactive protein). Commercially available chemiluminescent immunometric assays were used for the measurement of procalcitonin, interleukin-6, and lipopolysaccharide-binding protein.

       Detailed/Additional Information on the Definition of DC and Clinical Events

      Patients’ medical records were searched for the following events that defined DC: (1) History of acute variceal bleeding, as evidenced by active bleeding from varices observed during endoscopy or clinical evidence of upper gastrointestinal bleeding in patients with varices and in the absence of another source of bleeding; (2) history of large volume paracentesis and/or presence of ascites/diuretic treatment at BL; and/or (3) history of admission due to overt hepatic encephalopathy (HE) and/or presence of overt HE/anti-HE treatment at BL.
      European Association for the Study of the Liver
      EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis.
      The following events were defined as further decompensation: acute variceal bleeding, development of overt HE as evidenced by initiation of anti-HE therapies or admission due to/development of West-Haven grade III–IV HE, development of ascites as evidenced by initiation of diuretic treatment or requirement of large volume paracentesis/transjugular intrahepatic portosystemic shunt implantation for ascites control, spontaneous bacterial peritonitis or other bacterial infections, acute-on-chronic liver failure (ACLF) development, and liver-related death. Spontaneous bacterial peritonitis was diagnosed if the ascitic fluid polymorphonuclear leukocyte count was >250 cells/mL in the absence of other intra-abdominal sources of infection.
      European Association for the Study of the Liver
      EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis.
      We also recorded episodes of acute kidney injury (AKI) stage 1b or higher, as defined by an acute increase in serum creatinine ≥0.3 mg/dL or by ≥50% to a final value of ≥1.5 mg/dL.
      European Association for the Study of the Liver
      EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis.
      ACLF was diagnosed according to European Association for the Study of the Liver – Chronic Liver Failure (EASL-CLIF) criteria.
      European Association for the Study of the Liver
      EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis.

       Detailed/Additional Information on Statistical Analysis

      Group comparisons of categorial variables were performed using the Fisher's exact test. For unpaired comparisons of continuous variables, the unpaired Student t-test or the Mann-Whitney U/Kruskal-Wallis test were applied, whereas the Wilcoxon signed-rank test was used for the comparison of paired continuous variables. Spearman’s rank correlation was used to investigate associations between (changes in) VWF and HVPG as well as biomarkers of bacterial translocation/systemic inflammation.
      Time-dependent area under the receiver operating characteristic curve analysis was performed using the R package timeROC,
      • Blanche P.
      • Dartigues J.-F.
      • Jacqmin-Gadda H.
      Estimating and comparing time-dependent areas under receiver operating characteristic curves for censored event times with competing risks.
      and the optimal relative ΔVWF cutoff point (‘VWF response’) for prognostication of liver-related mortality was calculated by Youden’s index using the R package cutpointr.
      • López-Ratón M.
      • Rodríguez-Álvarez M.X.
      • Cadarso-Suárez C.
      • et al.
      OptimalCutpoints: an R package for selecting optimal cutpoints in diagnostic tests.
      For time-to-event analyses, 2 different approaches (Supplementary Figure 1) were used to minimize immortal time bias/reverse causality, which may have occurred due to the design of the study.
      First, for comparing the incidences of clinical events between VWF-responders and VWF-non-responders, Kaplan-Meier and log-rank analyses were performed. To minimize bias from immortal time and/or reverse causality, patients entered the Kaplan-Meier models 30 days after the second measurement (determination of VWF response), which was chosen as the landmark for this analysis. Accordingly, 140 patients were considered in the Kaplan-Meier outcome analyses, whereas 19 patients had developed events before the landmark or had been censored.
      Second, to establish the predictive value of VWF-response for further decompensation, AKI, and ACLF, as well as liver-related death, we applied multivariate Cox regression incorporating a time-dependent variable for VWF-response: All patients were classified as VWF-non-responders upon entering our models at BL (ie, the first HVPG measurement). Patients who attained VWF-response at the time of NSBB-HVPG measurement were reclassified as VWF-responders 30 days thereafter. In all Cox regression models, we included VWF-response as well as variables that were considered clinically relevant (ie, BL VWF, Child-Turcotte-Pugh stage, serum creatinine, BL HVPG, and relative HVPG change from BL to NSBB-HVPG).
      A P-value ≤ .05 was considered statistically significant.

       Detailed/Additional Information on the Dynamics of VWF in Stable DC Without NSBB Therapy Initiation

      We identified 66 patients who met all of the above-mentioned criteria, of whom 48 were on chronic NSBB therapy at both VWF measurements, whereas 18 were NSBB-naïve. Indeed, VWF levels remained stable in the vast majority of these subjects and did not change in paired comparison (P = .888) (Supplementary Figure 2). The median relative change in VWF levels was 1% (interquartile range, −3% to 4%), and thus clearly differed from our main cohort (ie, patients in whom NSBB treatment was initiated between the VWF measurements (−8% [interquartile range, −17 to 1%]; P < .001). Of note, despite the between-group differences in the changes in VWF, changes in Model of End-stage Liver Disease score were similar between the 2 patient groups (P = .741).

       Detailed/Additional Information on Clinical Clinical Follow-up

      Twelve patients (overall, 7.5%; VWF-responders, 9.3% vs VWF-non-responders, 4.8%) were diagnosed with hepatocellular carcinoma during clinical follow-up (FU). Moreover, 17 patients (10.7%; VWF-responders, 9.3% vs VWF-non-responders, 12.9%) achieved abstinence from alcohol and 6 patients (3.8%; VWF-responders, 3.1% vs VWF-non-responders, 4.8%) were prescribed antiviral therapy. Fifteen patients (9.4%; VWF-responders, 8.2% vs VWF-non-responders, 11.3%) underwent orthotopic liver transplantation.
      Eighty-eight patients (55.3%; VWF-responders, 50.5% vs VWF-non-responders, 62.9%) developed at least 1 event of further decompensation during FU.
      AKI was diagnosed in 31 patients (19.5%; VWF-responders, 12.4% vs VWF-non-responders, 30.6%).
      Twenty-seven patients (17.0%; VWF-responders, 9.3% vs VWF-non-responders, 29.0%) developed ACLF during FU.
      Finally, 48 patients (30.2%; VWF-responders, 24.7% vs VWF-non-responders, 38.7%) and 6 patients (3.8%; VWF-responders, 4.1% vs VWF-non-responders, 3.2%) died from liver- or non-liver-related causes, respectively.
      Figure thumbnail fx2
      Supplementary Figure 1A schematic summary of the most relevant time points of the study, including (1) BL measurement of HVPG and VWF; (2) the determination of VWF-response under chronic NSBB intake (NSBB-HVPG) after a median of 33 days (interquartile range, 28–41 days); and (3) the landmark set 30 days after NSBB-HVPG for Kaplan-Meier analyses. All patients entered the Cox regression models as VWF-non-responders at study inclusion and - if applicable - were assigned to the VWF-responder group at 30 days after NSBB-HVPG measurement. A total of 140 patients were included in the landmark Kaplan-Meier/log-rank test analyses.
      Figure thumbnail fx3
      Supplementary Figure 2Changes in plasma VWF levels (A) and MELD score (B) in patients with stable DC. BL, Baseline; FU, clinical follow-up; MELD, Model of End-stage Liver Disease.
      Supplementary Table 1Patient Characteristics at BL (ie, Before NSBB Therapy), NSBB Treatment Characteristics, and Treatment-related Changes From BL to Second HVPG Measurement on NSBB Treatment
      Patient characteristicAll patients, (n = 159)
      Sex, male/female (% male)118/41 (74.2)
      Age, years55.6 ± 10.5
      BMI, kg/m225.1 (22.2–28.7)
      Etiology of CLD
       ALD103 (64.8)
       Viral15 (9.4)
       ALD + viral17 (10.7)
       NAFLD7 (4.4)
       Others/cryptogenic17 (10.7)
      Alcohol consumption
       No107 (67.3)
       Below threshold
      >30 g/day and >20 g/day for males and females, respectively.6
      11 (6.9)
       Above threshold
      >30 g/day and >20 g/day for males and females, respectively.6
      41 (25.8)
      BL CTP score, points8 (6–9)
      NSBB CTP score, points7 (6–8)
      BL MELD (2016) score, points12 (10–17)
      NSBB MELD (2016) score, points11 (10–16)
      BL albumin, g/L33.0 (30.2–37.3)
      BL bilirubin, mg/dL1.71 (1.06–2.59)
      BL INR1.4 (1.2–1.5)
      BL creatinine, mg/dL0.79 (0.68–1.00)
      BL sodium, mmol/L136 (134–139)
      Varices
       Small54 (34.0)
       Large105 (66.0)
      History of bleeding59 (37.1)
      Ascites
       No31 (19.5)
       Mild/moderate103 (64.8)
       Severe/refractory25 (15.7)
      HE50 (31.4)
      Type of NSBB therapy
       Carvedilol107 (67.3)
       Propranolol52 (32.7)
      BL MAP, mm Hg99 (90–109)
      BL MAP <65 mm Hg0 (0)
      NSBB MAP, mm Hg90 (82–99)
      NSBB MAP <65 mm Hg6 (3.8)
      ΔMAP, absolute, mm Hg−8 (−16 to −2)
      ΔMAP, relative, %−8.9 (−16.0 to −2.0)
      BL HVPG, mm Hg21 (18–24)
      NSBB-HVPG, mm Hg18 (15–21)
      ΔHVPG, absolute, mm Hg−2 (−5 to −1)
      ΔHVPG, relative, %−11.1 (−23.5 to −3.6)
      HVPG decrease ≥10%91 (57.2)
      HVPG decrease ≥20%56 (35.2)
      HVPG-response, %
      Defined by an HVPG decrease to ≤12 mm Hg or by ≥10% in primary and ≥20% in secondary prophylaxis of variceal bleeding.
      77 (48.4)
      BL VWF, %350 (291–420)
      NSBB VWF, %322 (253–398)
      ΔVWF, absolute, %−26 (−60 to 2)
      ΔVWF, relative, %−8.0 (−16.8 to 0.9)
      VWF-response (%)
      Defined by an HVPG decrease to ≤12 mm Hg or by ≥10% in primary and ≥20% in secondary prophylaxis of variceal bleeding.
      BL CRP,
      CRP values available in n = 146 at BL and in n = 143 at NSBB-HVPG.
      mg/dL
      0.50 (0.20–1.22)
      NSBB CRP,
      CRP values available in n = 146 at BL and in n = 143 at NSBB-HVPG.
      mg/dL
      0.44 (0.17–0.88)
      ΔCRP, absolute, mg/dL−0.04 (−0.35 to 0.03)
      ΔCRP, relative, %−19.8 (−48.8 to 11.3)
      BL PCT,
      PCT values available in n = 36 at BL and in n = 36 at NSBB-HVPG.
      ng/mL
      0.11 (0.07–0.20)
      NSBB PCT,
      PCT values available in n = 36 at BL and in n = 36 at NSBB-HVPG.
      ng/mL
      0.12 (0.07–0.16)
      ΔPCT, absolute, ng/mL−0.01 (−0.03 to 0.01)
      ΔPCT, relative, %−7.1 (−26.1 to 17.4)
      BL IL-6,
      IL-6 values available in n = 35 at BL and in n = 37 at NSBB-HVPG.
      pg/nL
      11.61 (7.81–26.28)
      NSBB IL-6,
      IL-6 values available in n = 35 at BL and in n = 37 at NSBB-HVPG.
      pg/nL
      13.08 (7.40–21.65)
      ΔIL-6, absolute, pg/nL−1.55 (−6.98 to 4.48)
      ΔIL-6, relative, %−10.9 (−40.9 to 23.0)
      BL LBP,
      LBP values available in n = 35 at BL and in n = 38 at NSBB-HVPG.
      μg/mL
      7.36 (5.54–9.46)
      NSBB LBP,
      LBP values available in n = 35 at BL and in n = 38 at NSBB-HVPG.
      μg/mL
      6.96 (5.02–8.68)
      ΔLBP, absolute, μg/mL−0.16 (−1.26 to 0.64)
      ΔLBP, relative, %−2.3 (−17.8 to 9.8)
      Note: Data are presented as number (%), mean ± standard deviation, or median (interquartile range).
      ACLD, Advanced chronic liver disease; ALD, alcoholic liver disease; BL, baseline; BMI, body mass index; CLD, chronic liver disease; CRP, C-reactive protein; CTP, Child-Turcotte-Pugh; FU, clinical follow-up; HE, hepatic encephalopathy; HVPG, hepatic venous pressure gradient; IL-6, interleukin-6; INR, international normalized ratio; LBP, lipopolysaccharide-binding protein; MAP, mean arterial pressure; MELD, Model of End-stage Liver Disease; NAFLD, non-alcoholic fatty liver disease; NSBB, nonselective beta blocker; PCT, procalcitonin; VWF, von Willebrand factor
      a >30 g/day and >20 g/day for males and females, respectively.
      European Association for the Study of the Liver (EASL)
      European Association for the Study of Diabetes (EASD); European Association for the Study of Obesity (EASO). EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease.
      b Defined by an HVPG decrease to ≤12 mm Hg or by ≥10% in primary and ≥20% in secondary prophylaxis of variceal bleeding.
      c CRP values available in n = 146 at BL and in n = 143 at NSBB-HVPG.
      d PCT values available in n = 36 at BL and in n = 36 at NSBB-HVPG.
      e IL-6 values available in n = 35 at BL and in n = 37 at NSBB-HVPG.
      f LBP values available in n = 35 at BL and in n = 38 at NSBB-HVPG.
      Supplementary Table 2Systemic Hemodynamics at BL (ie, Before NSBB Therapy) and Second HVPG Measurement on NSBB Treatment
      Hemodynamic characteristicsBL-HVPGNSBB-HVPGP
      Heart rate, bpm80 (70; 93)64 (58; 72)< .001
      Systolic arterial pressure, mm Hg130 (119; 145)118 (108; 131)< .001
      Diastolic arterial pressure, mm Hg80 (74; 89)73 (67; 82)< .001
      Mean arterial pressure, mm Hg99 (90; 109)90 (82; 99)< .001
      BL, Baseline; HVPG, hepatic venous pressure gradient; NSBB, nonselective beta blocker.
      Supplementary table 3Multivariate Cox Regression Analyses With Further Hepatic Decompensation, AKI Development, and ACLF Development, as Well as Liver-related Mortality as Events of Interest
      Adjusted HR95% CIP
      LowerUpper
      Model A – further hepatic decompensation
       VWF-response0.5550.3370.912.020
       BL VWF, per 10%1.0080.9891.026.428
       CTP stage
      B vs A1.3010.7722.194.323
      C vs A2.4461.1735.101.017
       Serum creatinine, per mg/dL1.8981.2162.963.005
       BL HVPG, per mmHg1.0561.0111.104.014
       ΔHVPG, per % change1.0050.9911.0190.480
      Model B – AKI development
       VWF-response0.3670.1670.803.012
       BL VWF, per 10%1.0030.9701.037.848
       CTP stage
      B vs A5.1401.38719.041.014
      C vs A8.7971.79243.188.007
       Serum creatinine, per mg/dL3.6361.8747.052< .001
       BL HVPG, per mm Hg1.0220.9561.092.528
       ΔHVPG, per % change0.9990.9781.020.891
      Model C – ACLF development
       VWF-response0.3020.1260.721.007
       BL VWF, per 10%0.9770.9391.017.262
       CTP stage
      B vs A3,7371.06713.094.039
      C vs A12.2072.42961.336.002
       Serum creatinine, per mg/dL2.3200.8386.425.105
       BL HVPG, per mm Hg1.0350.9621.113.358
       ΔHVPG, per % change0.9980.9761.020.845
      Model D – Liver-related death
       VWF-response0.3320.1790.616< .001
       BL VWF, per 10%1.0180.9921.045.171
       CTP stage
      B vs A1.3830.6652.877.385
      C vs A3.1981.2008.523.020
       Serum creatinine, per mg/dL1.7010.6744.294.261
       BL HVPG, per mm Hg1.0510.9931.113.087
       ΔHVPG, per % change1.0020.9841.021.813
      Note: Results are presented as adjusted HRs with 95% CIs and corresponding P-values. All models incorporated a time-dependent variable for exposure to VWF-response and were adjusted for BL VWF, CTP stage, BL HVPG, and relative change in HVPG. Patients were censored at the time of etiological treatments/hepatocellular carcinoma diagnosis and liver transplantation (all models), as well as non-liver-related mortality (models A and D) and death (models B and C). Boldface P values indicate statistical significance.
      ACLF, Acute-on-chronic liver failure; AKI, acute kidney injury; BL, baseline; CI, confidence interval; CTP, Child-Turcotte-Pugh; HR, hazard ratio; HVPG, hepatic venous pressure gradient, VWF, von Willebrand factor.

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      Linked Article

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