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The need of HVPG-guided beta-blocker therapy for NASH cirrhosis with varices – Answer is still up in the air

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Abstract

In the recently published original article by Paternostro et al., analyzing the prognostic value of HVPG-response to (NSBB) in patients with NASH-related cirrhosis and varices, the authors reported that 55.3% of the patients achieved HVPG-response to NSBB. Presence of diabetes (adjusted odds ratio (aOR) 0.16, p = 0.038) and baseline mean arterial pressure (MAP) (aOR:1.07, p = 0.044) were independent predictors of NSBB- response. Child-Pugh stage B/C, MELD ≥ 15, and HVPG ≥ 20 mmHg but not HVPG response, predicted the composite endpoint of bleeding or decompensation at 90 days and 2 years. While this study adds to the limited existing literature on efficacy and outcomes of NSBB induced HVPG-response in patients with NASH cirrhosis, some issues need to be addressed.
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Correspondence
The need of HVPG-guided beta-blocker therapy for NASH
cirrhosis with varices –Answer is still up in the air
Dear Editor,
Portal pressure (PP) is a key predictor of the development
of liver decompensation and mortality in patients with advanced
chronic liver disease (aCLD). Among the methods of portal pres-
sure assessment, hepatic venous pressure gradient (HVPG) mea-
surement is the gold-standard method to assess the presence of
clinically significant portal hypertension (CSPH) which is defined
as HVPG 10 mmHg [1] . The assessment of response to non-
selective beta-blockers (NSBB) therapy is another indication for
HVPG, which also helps in the prognostication of the patients
with aCLD [ 1 , 2 ]. We read the recently published original arti-
cle by Paternostro et al. [3] , analyzing the prognostic value of
HVPG-response to (NSBB) in patients with NASH-related cirrho-
sis and varices. The authors reported that 55.3% of the patients
achieved HVPG-response to NSBB. Presence of diabetes (adjusted
odds ratio (aOR) 0.16, p = 0.038) and baseline mean arterial pres-
sure (MAP) (aOR:1.07, p = 0.044) were independent predictors of
NSBB- response. Child-Pugh stage B/C, MELD 15, and HVPG
20 mmHg but not HVPG response, predicted the composite end-
point of bleeding or decompensation at 90 days and 2 years. While
this study adds to the limited existing literature on efficacy and
outcomes of NSBB induced HVPG-response in patients with NASH
cirrhosis, some issues need to be addressed.
First, the study has a small sample size, making it underpow-
ered to study decompensation and mortality. The retrospective na-
ture may also have led to selection bias. In cirrhotic patients with
obesity, a lifestyle change through diet and exercise reduces body
weight and HVPG [1] . The difference in the proportion of patients
adhering to lifestyle modification practices and the difference in
the choice of NSBB in both groups may have led to a difference in
HVPG response.
Second, the study included patients on NSBB for both primary
and secondary prophylaxis and HVPG response was defined as re-
duction 10% or to < 12 mmHg. However, this cut-off is appli-
cable only for primary prophylaxis. For patients on secondary pro-
phylaxis, an HVPG reduction of 20% or to < 12 mmHg quali-
fies as a response [ 1 , 2 ]. Hence, using the same criteria for both
the patient category leads to a higher proportion of patients on
secondary prophylaxis being labeled as responders, which further
makes the comparison difficult.
Letter to original article : Paternostro R, Becker J, Hofer BS, Panagl V, Schiffke H,
Simbrunner B, et al. The prognostic val ue of HVPG-response to non-selective beta-
blockers in patients with NASH cirrhosis and varices . Dig and Liv Dis. 2021 Nov 16.
10.1016/j.dld.2021.09.009
DOI of original article: 10.1016/j.dld.2021.09.009
Third, details of the sedation protocol used for HVPG mea-
surement are missing from the study. In a previous study by Re-
verter et al. [4] , propofol and remifentanil-induced deep seda-
tion was found to be significantly associated with variation in
levels of HVPG and portal pressure gradient (PPG) in patients
with TIPS. Half of the patients were incorrectly classified based
on the target of a 10% reduction in HVPG. Similar findings were
reported in a recent study [5] , showing propofol to reduce the
wedged hepatic vein pressure values (WHVP) measurement lead-
ing to alterations in HVPG readings. Hence, it is important to take
this into account when estimating prognosis or targeting HVPG
reduction.
Fourth, the study reported that NSBB-response was neither pre-
dictive of the development of bleeding/decompensation at 90 days
( p = 0.172) nor at 2 years ( p = 0.993). Also, NSBB response did
not predict the 2-years transplant-free survival. So, whether HVPG-
guided therapy should be advocated for all patients with varices or
only high-risk patients, remains a question. The AASLD guidelines
also recommend against routine performance of HVPG for moni-
toring changes, outside clinical trials [2] .
Lastly, the levels of HVPG and WHVP in NASH patients are
lower than those in HCV patients at each stage of fibrosis [6] . In
a recent study, patients with NASH-related cirrhosis had a higher
prevalence of decompensation than patients with HCV at any cut-
off level of HVPG ( < 10, 10 –12 or > 12 mmHg) [7] . Among those
with HVPG < 10 mmHg, around 9% of patients had decompensa-
tion. Hence, a cut-off HVPG of 20 mmHg for predicting adverse
outcomes in NASH-related cirrhosis as suggested by the present ar-
ticle is going to overlook a lot of patients who still remain at risk
of decompensation.
While the technique of HVPG measurement is safe, feasible,
and reproducible, it is invasive. Additionally, HVPG has low ac-
ceptability among chronic liver disease patients and requires tech-
nical expertise typically only found in tertiary medical centers.
Hence, non-invasive methods of assessment are increasingly be-
coming popular. In a study of patients with biopsy-proven NASH,
APRI, FIB-4, and NAFLD fibrosis scores were found to have sim-
ilar AUC as HVPG for prediction of decompensation or mortality
[8] . Dynamic change in splenic stiffness ( SS) was found to be a
good predictor of hemodynamic response to NSBB prophylaxis in
patients with high-risk esophageal varices [9] . In another subse-
quent study, SS with a reduction of 10% was found to be pre-
dictive of the hemodynamic response, similar to HVPG [10] .
To conclude, disease behavior and progression in patients with
NASH-related cirrhosis are different from other etiologies of cirrho-
sis. Further, well-designed prospective studies with larger popula-
tion are needed to define thresholds for HVPG for the prediction of
decompensation and long-term outcomes in patients with NASH-
related cirrhosis and to study the performance of non-invasive
methods for assessment of response to NSBB.
https://doi.org/10.1016/j.dld.2021.11.019
1590-8658/© 2021 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
S. Giri Digestive and Liver Disease xxx (xxxx) xxx
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Conflict of interest
All authors have participated in (a) conception and design, or
analysis and interpretation of the data; (b) drafting the article or
revising it critically for important intellectual content; and (c) ap-
proval of the final version.
This manuscript has not been submitted to, nor is under review
at, another journal or other publishing venue.
The authors have no affiliation with any organization with a di-
rect or indirect financial interest in the subject matter discussed in
the manuscript
The following authors have affiliations with organizations with
direct or indirect financial interest in the subject matter discussed
in the manuscript: Dr. Suprabhat Giri, Seth GS Medical College and
KEM Hospital
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Suprabhat Giri
Department of Gastroenterology, Seth GS Medical College and KEM
Hospital, Mumbai, India
Corresponding author at: Department of Gastroenterology,
Seth GS Medical College and KEM Hospital, Acharya Donde
Marg, Parel, Mumbai, India-40 0 012.
E-mail address: supg19167@gmail.com
2
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Article
Full-text available
Background and Aims Non-alcoholic steatohepatitis has become a leading cause of cirrhosis. The prognostic value of (HVPG)-guided NSBB prophylaxis remains to be investigated in the setting of NASH cirrhosis. Methods Patients with NASH cirrhosis and varices undergoing HVPG-guided NSBB therapy were included. HVPG-response to NSBBs was evaluated within a median 52 (IQR:28–71) days after baseline measurement. HVPG-Response was defined as a decrease of ≥10% from baseline or below <12 mmHg. The composite endpoint was defined as variceal bleeding, decompensation, and liver-related death. Results Thirtyeight patients were included: Child-A/B:33(87%), Child-C:5(13%) median HVPG:19.7 ± 4.7 mmHg. 21(55.3%) patients achieved HVPG-response to NSBB. Presence of diabetes(aOR:0.16, p = 0.038) and arterial blood pressure (aOR:1.07, p = 0.044) were independently associated with NSBB-response. While NSBB-HVPG-responders showed fewer decompensations within 90 days (n = 1(5%) vs. n = 3(29%), p = 0.172), only Child-Pugh stage B/C (p = 0.001), MELD ≥ 15(p = 0.021) and HVPG ≥ 20 mmHg(p = 0.011) predicted the composite endpoint at 90 days. Similarly, after 2years of follow-up, only Child-Pugh stage (B:p = 0.001, C:p < 0.001), MELD ≥ 15 (p = 0.021), HVPG≥20 mmHg (p = 0.011) predicted the composite endpoint. Importantly, all bleeding events occurred in HVPG-NSBB non-responders. Conclusion HVPG-response to NSBB was achieved in 55.3% of NASH patients with varices and this seemed to protect from variceal bleeding. However, only baseline HVPG ≥ 20 mmHg, Child-Pugh stage B/C and MELD ≥ 15 were predictors of decompensation/death in patients with NASH cirrhosis and varices.
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Background Measurement of the hepatic venous pressure gradient (HVPG) is the gold standard to evaluate the presence and severity of portal hypertension. The procedure is generally safe and well tolerated, but nevertheless, some patients demand for sedation. However, it is unknown whether propofol sedation would impair the accuracy of portal pressure measurements. Methods This is a prospective observational cohort study including cirrhotic patients with suspected portal hypertension undergoing invasive measurement of HVPG. Measurements of HVPG were performed in awake condition as well as under sedation with propofol infusion. Results In total, 37 patients were included. Mean HVPG in awake condition was 15.9 mmHg (IQR 13–19) and during sedation 14.1 mmHg (IQR 12–17). While measures of free hepatic vein pressure (FHVP) were not altered after propofol sedation ( p = 0.34), wedged hepatic vein pressure values (WHVP) decreased in an average by 2.05 mmHg (95% CI − 2.46 to − 1.16; p < 0.001) which was proportional to the magnitude of HVPG. In 31 out of 37 patients (83.8%), portal hypertension with HVPG ≥ 12 mmHg was found. Under sedation with propofol, two patients (5.4%) with borderline values would have been incorrectly classified as < 12 mmHg. After adjustment for the average difference of − 10%, all patients were correctly classified. Intraclass correlation coefficient between HVPG measurement in awake condition and under propofol sedation was 0.927 (95% CI 0.594–0.975). Conclusions Propofol sedation during HVPG measurements is generally safe, however it may lead to relevant alterations of HVPG readings.
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Non-invasive diagnostic methods for liver fibrosis predict clinical outcomes in viral hepatitis and nonalcoholic fatty liver disease (NAFLD). We specifically evaluated prognostic value of non-invasive fibrosis methods in nonalcoholic steatohepatitis (NASH) against hepatic venous pressure gradient (HVPG) and liver histology. This was a retrospective cohort study of 148 consecutive patients who met the following criteria: transjugular liver biopsy with HVPG measurement; biopsy-proven NASH; absence of decompensation; AST-to-Platelets Ratio Index (APRI), fibrosis-4 (FIB-4), NAFLD fibrosis score, ultrasound, hepatic steatosis index and Xenon-133 scan available within 6 months from biopsy; a minimum follow-up of 1 year. Outcomes were defined by death, liver transplantation, cirrhosis complications. Kaplan-Meier and Cox regression analyses were employed to estimate incidence and predictors of outcomes, respectively. Prognostic value was expressed as area under the curve (AUC). During a median follow-up of 5 years (interquartile range 3-8), 16.2% developed outcomes, including 7.4% who died or underwent liver transplantation. After adjustment for age, sex, diabetes, the following fibrosis tools predicted outcomes: HVPG >10mmHg (HR=9.60; 95% confidence interval [CI] 3.07-30.12), histologic fibrosis F3-F4 (HR=3.14; 1.41-6.95), APRI >1.5 (HR=5.02; 1.6-15.7), FIB-4 >3.25 (HR=6.33; 1.98-20.2), NAFLD fibrosis score >0.676 (HR=11.9; 3.79-37.4). Prognostic value was as follows: histologic fibrosis stage, AUC=0.85 (95% CI 0.76-0.93); HVPG, AUC=0.81 (0.70-0.91); APRI, AUC=0.89 (0.82-0.96); FIB-4, AUC=0.89 (0.83-0.95); NAFLD fibrosis score, AUC=0.79 (0.69-0.91). Neither histologic steatosis nor non-invasive steatosis methods predicted outcomes (AUC<0.50). Non-invasive methods for liver fibrosis predict outcomes of patients with NASH. They could be used for serial monitoring, risk stratification and targeted interventions.
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Background Non-selective β-blocker (NSBB) therapy is the treatment of choice for primary prophylaxis of cirrhotic patients with high-bleeding risk esophageal varices (HRV). The hemodynamic response to NSBB is assessed by the measurement of the hepatic venous pressure gradient (HVPG). Recently, liver and spleen stiffness measurements (LSM and SSM) were proposed as non-invasive surrogates of HVPG. We aimed to evaluate LSM and SSM changes for assessing hemodynamic response in these patients.Methods Cirrhotic patients with HRV were prospectively enrolled and evaluated at our Department before starting NSBB and after 3 months. Correlation between changes (delta) of HVPG after NSBB treatment and those of LSM or SSM by transient elastography was performed.ResultsFrom the initial 59 patients considered for the study, 20 were finally included in the analysis. Fifteen (15) patients reached hemodynamic response to NSBB according to HVPG. Changes in LSM did not correlate with changes in HVPG (r = 0.107, p value = 0.655), unlike changes in SSM (r = 0.784, p value < 0.0001). Delta SSM presented excellent accuracy in identifying HVPG responders (AUROC 0.973; 95% CI 0.912–1). The best cut-off for delta SSM to identify responders was -10% (sensitivity 100%, specificity 60%, NPV 100% and PPV 90%).ConclusionsSSM could be a reliable non-invasive test for the assessment of hemodynamic response to NSBB therapy as primary prophylaxis for HRV. Similar to HVPG, SSM reduction ≥ 10% is able to assess hemodynamic response.Graphic abstract
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Background & Aims Non-selective beta-blockers (NSBBs) are the mainstay of primary prophylaxis of esophageal variceal bleeding in patients with liver cirrhosis. We investigated whether non-invasive markers of portal hypertension correlate with hemodynamic responses to NSBBs in cirrhotic patients with esophageal varices. Methods In this prospective cohort study, 106 cirrhotic patients with high-risk esophageal varices in the derivation cohort received carvedilol prophylaxis, and completed paired measurements of hepatic venous pressure gradient, liver stiffness (LS), and spleen stiffness (SS) at the beginning and end of dose titration. LS and SS were measured using acoustic radiation force impulse imaging. A prediction model for hemodynamic response was derived, and subject to an external validation in the validation cohort (63 patients). Results Hemodynamic response occurred in 59 patients (55.7%) in the derivation cohort, and in 33 patients (52.4%) in the validation cohort, respectively. Multivariate logistic regression analysis identified that ΔSS was the only significant predictor of hemodynamic response (odds ratio 0.039; 95% confidence interval 0.008–0.135; p <0.0001). The response prediction model (ModelΔSS = 0.0490–2.8345 × ΔSS; score = (exp[ModelΔSS])/(1 + exp[ModelΔSS]) showed good predictive performance (area under the receiver-operating characteristic curve [AUC] = 0.803) using 0.530 as the threshold value. The predictive performance of the ModelΔSS in the validation set improved using the same threshold value (AUC = 0.848). Conclusion A new model based on dynamic changes in SS exhibited good performance in predicting hemodynamic response to NSBB prophylaxis in patients with high-risk esophageal varices. Lay summary Non-selective beta-blockers are the mainstay of primary prophylaxis to prevent variceal bleeding in patients with cirrhosis and high-risk esophageal varices. This prospective study showed that a prediction model based on changes in spleen stiffness before vs. after dose titration might be a non-invasive marker for response to prophylactic non-selective beta-blocker (carvedilol) therapy in patients with cirrhosis and high-risk esophageal varices. ClinicalTrials.gov Identifier: NCT01943318.
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Background: Hepatic venous pressure gradient (HVPG) measurement correlates with staging of liver fibrosis. Patients with nonalcoholic steatohepatitis (NASH) have a different pattern of fibrosis compared with hepatitis C virus (HCV) with possible alterations in pressures. Aim: The aim of this study was to compare portal pressures with the stage of fibrosis in NASH in comparison with other liver diseases. Patients and methods: Records of all patients who had undergone transjugular liver biopsy with pressure measurements between January 2001 and June 2013 were reviewed. Wedge hepatic venous pressure (WHVP) and HVPG were compared with stages of fibrosis in liver diseases of different etiologies. Results: Among 142 patients included in this study, the liver disease etiology was as follows: HCV (26.6%) and NASH (24.6%), with the remaining (38.7%) grouped under other categories. The mean age of the patients was 51.2±11.5 years, with more men with HCV (73.1%) compared with NASH (51.4%) in terms of etiology (P=0.046). There were strong correlations between the stage of fibrosis with both the HVPG (r=0.64; P<0.0001) and the WHVP (r=0.63; P<0.0001) in NASH patients. Compared with HCV patients, NASH patients had a lower HVPG (3.4±2.4 vs. 7.5±11 mmHg/stage; P=0.01) with a coefficient estimate of -0.24 (P=0.017) and WHVP (9.6±5.5 vs. 14.6±15.2 mmHg/stage; P=0.03) for the stage of fibrosis. Conclusion: HVPG and WHVP measurements were strongly correlated with stages of fibrosis in NASH. Patients with NASH had lower HVPG and WHVP for each stage of fibrosis compared with HCV patients. This raises the concern of underestimation of pressures by HVPG in NASH etiology for the stage of disease or increased fibrosis despite lower pressures in them.
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Background & AimsMeasurement of the hepatic venous pressure gradient (HVPG) offers valuable prognostic information in patients with cirrhosis. In specific circumstances, (children, agitated patients, TIPS placement) deep sedation is required. This study aims to assess the impact of deep sedation on the accuracy of hepatic/portal pressure measurements. Methods Forty-four patients were included. Measurements of baseline HVPG (n=30), HVPG response to i.v. propranolol (n=11), portal pressure gradient (PPG) after TIPS (n=27) and of cardio-pulmonary pressures (n=25) were obtained in awake conditions and under deep sedation with propofol and remifentanil. ResultsDuring deep sedation, a marked oscillation within respiratory cycle was observed in abdominal pressures. End-expiratory sedated HVPG showed a better agreement with awake HVPG (intra-class correlation coefficient - ICC 0.864) than end-inspiratory HVPG (ICC 0.796). However, in almost half of the patients both values differed by more than 10%. Accuracy was not improved by using mean HVPG along the respiratory cycle. Similarly, changes in HVPG caused by propranolol while under sedation had a poor agreement to those obtained in awake conditions. Indeed, about a half of patients were misclassified according to the 10% HVPG reduction target. After TIPS, PPG values obtained under sedation were significantly different to awake PPG, usually underestimating the awake value. The systemic hemodynamic changes induced by sedation were not associated to a greater variability of PPG/HVPG measurements. Conclusion Deep sedation with propofol and remifentanil adds substantial variability and uncertainty to HVPG/PPG measurements. This must be considered when using these values to estimate prognosis, or targeting HVPG/PPG reductions.