Hepatic Venous Pressure Gradient Response Research Articles

Effect of midodrine on HVPG in advanced chronic liver disease and acute-on-chronic liver failure-A pilot study.

Nonselective beta-blockers (NSBB) are the mainstay for treatment of portal hypertension (PH), but require caution in decompensated cirrhosis (DC) or acute-on-chronic liver failure (ACLF) with hypotension, hyponatremia, acute kidney injury (AKI) or type 2 hepatorenal syndrome (HRS). Midodrine is oral, rapidly acting, α1-adrenergic agonist. We evaluated acute effects of midodrine on hepatic venous pressure gradient (HVPG) in DC and ACLF with contraindications to NSBB. Patients of DC (n = 30) with grade III ascites and serum sodium (Na) <130/systolic blood pressure (SBP) <90/type II HRS (group I) and ACLF patients (n = 30) with Na <130/SBP <90/AKI (group II) were included. HVPG was done at baseline and repeated 3 h after 10 mg midodrine. Primary outcome was HVPG response (reduction by >20% or to <12 mmHg). In group I, midodrine significantly reduced HVPG (19.2 ± 4.6 to 17.8 ± 4.2, p = .02) and heart rate (HR) (86.3 ± 11.6 to 77.9 ± 13.1, p < .01) and increased mean arterial pressure (MAP) (74.1 ± 6.9 to 81.9 ± 6.6 mmHg, p < .01). In group II also, midodrine reduced HVPG (19.1 ± 4.1 to 17.0 ± 4.2) and HR (92.4 ± 13.7 to 84.6 ± 14.1) and increased MAP (85.4 ± 7.3 to 91.2 ± 7.6 mmHg), p < .01 for all. HVPG response was achieved in 3/30 (10%) in group I and 8/30 (26.7%) in group II. On logistic regression analysis, prerenal AKI (OR 11.04, 95% CI 1.83-66.18, p < .01) and increase in MAP (OR 1.22, 95% CI 1.03-1.43, p = .02) were independent predictors of response. Increase in MAP by 8.5 mmHg with midodrine had best cut-off with AUROC of .76 for response. In decompensated cirrhosis and ACLF patients with contraindications to NSBB, midodrine is useful in decreasing HVPG. Dose of midodrine should be titrated to increase MAP atleast by 8.5 mmHg.

A283 HETEROGENEITY OF TREATMENT RESPONSE TO BETA-BLOCKERS IN THE TREATMENT OF PORTAL HYPERTENSION RELATED TO CIRRHOSIS

Abstract Background Non-selective beta-blockers (BB) improve clinical outcomes in patients with cirrhosis and portal hypertension. However, it has been suggested that only a proportion of patients treated with BB benefit from them. Indeed, patients who achieve a ampersand:003E20% reduction in Hepatic Venous Pressure Gradient (HVPG) with BB have an excellent prognosis, but only 30-50% achieve such response. This has been suggested as a reason for not using BB where no HVPG measurements are available. Aims In this study we aimed to quantify how heterogeneous is the response to BB in patients with cirrhosis, by analyzing trials in which the effects of BB on HVPG were compared with those of placebo. Methods For assessing the potential heterogeneity of treatment response to BB we conducted a meta-analysis of differences in variance between trial arms. The degree of heterogeneity of HVPG response to BB was quantified with the pooled variability ratio (VR) (SD of the HVPG at the end of the trial in the BB group divided by that in the placebo group). Results Our systematic search yielded 18 studies. Figure 1 shows a forest plot with the meta-analysis of the variability ratios (VR) in final HVPG. Pooled VR was 0.99 (95% CI 0.87-1.14). This indicates that there was no evidence for a higher average variability in the final HVPG in the beta-blocker treatment groups as compared to placebo groups, and hence there was no evidence to support that patients with cirrhosis exhibit a heterogeneous response to beta-blockers (i.e. there is no evidence to support that some patients responded to beta-blockers and others did not). Conclusions In conclusion, the analysis of RCTs comparing the HVPG response of beta-blockers with placebo in patients with cirrhosis does not suggest a heterogeneous hemodynamic response to beta-blockers. This, together with the fact that in most RCTs demonstrating the clinical benefits of beta-blockers treatment was not adjusted based on HVPG response, further supports the concept that there is no need to perform portal pressure measurements to guide treatment with beta-blockers. Funding Agencies None

Non-invasive candidate proteinsignature predicts hepatic venous pressure gradient reduction in cirrhotic patients after sustained virologic response.

A reduction in hepatic venous pressure gradient (HVPG) is the most accurate marker for assessing the severity of portal hypertension and the effectiveness of intervention treatments. This study aimed to evaluate the prognostic potential of blood-based proteomic biomarkers in predicting HVPG response amongst cirrhotic patients with portal hypertension due to Hepatitis C virus (HCV) and had achieved sustained virologic response (SVR). The study comprised 59 patients from two cohorts. Patients underwent paired HVPG (pretreatment and after SVR), liver stiffness (LSM), and enhanced liver fibrosis scores (ELF) measurements, as well as proteomics-based profiling on serum samples using SomaScan® at baseline (BL) and after SVR (EOS). Machine learning with feature selection (Caret, Random Forest and RPART) methods were performed to determine the proteins capable of classifying HVPG responders. Model performance was evaluated using AUROC (pROC R package). Patients were stratified by a change in HVPG (EOS vs. BL) into responders (greater than 20% decline in HVPG from BL, or <10 mmHg at EOS with >10 mmHg at BL) and non-responders. LSM and ELF decreased markedly after SVR but did not correlate with HVPG response. SomaScan (SomaLogic, Inc., Boulder, CO) analysis revealed a substantial shift in the peripheral proteome composition, reflected by 82 significantly differentially abundant proteins. Twelve proteins accurately distinguished responders from non-responders, with an AUROC of .86, sensitivity of 83%, specificity of 83%, accuracy of 83%, PPV of 83%, and NPV of 83%. A combined non-invasive soluble protein signature was identified, capable of accurately predicting HVPG response in HCV liver cirrhosis patients after achieving SVR.

Effect of beta-blockers on multiple haemodynamics in cirrhosis: A cross-over study by MR-imaging and hepatic vein catheterization.

Non-selective beta-blockers (NSBB) are widely used in the treatment of patients with cirrhosis. Only about 50% respond with a sufficient reduction in their hepatic venous pressure gradient (HVPG) and NSBB may induce detrimental cardiac and renal effects in the presence of severe decompensation. We aimed to assess the effects of NSBB on haemodynamics using magnetic resonance imaging (MRI) and to assess if these haemodynamic changes were related to the disease severity and HVPG response. A prospective cross-over study of 39 patients with cirrhosis. Patients underwent hepatic vein catheterization and MRI with assessments of HVPG, cardiac function, systemic and splanchnic haemodynamics before and after propranolol infusion. Propranolol induced significant decreases in cardiac output (-12%) and blood flow of all vascular compartments, with the largest reductions seen in the azygos venous (-28%), portal venous (-21%), splenic (-19%) and superior mesenteric artery (-16%) blood flow. Renal artery blood flow fell by -5% in the total cohort, with a more pronounced reduction in patients without ascites than in those with ascites (-8% vs. -3%, p = .01). Twenty-four patients were NSBB responders. Their changes in HVPG after NSBB were not significantly associated with other haemodynamic changes. The changes in cardiac, systemic and splanchnic haemodynamics did not differ between NSBB responders and non-responders. The effects of acute NSBB blockade on renal flow seem to depend on the severity of the hyperdynamic state, with the largest reduction in renal blood flow in compensated patients compared to decompensated patients with cirrhosis. However, future studies are needed to assess the effects of NSBB on haemodynamics and renal blood flow in patients with diuretic-resistant ascites.

Carvedilol Achieves Higher Hemodynamic Response and Lower Rebleeding Rates Than Propranolol in Secondary Prophylaxis

Carvedilol induces stronger decreases in hepatic venous pressure gradient (HVPG) than conventional nonselective β-blockers (ie, propranolol). Limited data exist on the efficacy of carvedilol in secondary prophylaxis of variceal bleeding. Patients undergoing paired HVPG measurements for guiding secondary prophylaxis with either carvedilol or propranolol were included in this retrospective analysis. All patients also underwent band ligation. Changes in HVPG and systemic hemodynamics were compared between the 2 groups. Long-term follow-up data on rebleeding, acute kidney injury, nonbleeding decompensation, and liver-related death were analyzed applying competing risk regression. Eighty-seven patients (carvedilol/propranolol, n= 45/42) were included in our study. The median baseline HVPG was 21 mm Hg (interquartile range, 18-24 mm Hg), and 39.1%/48.3%/12.6% had Child-Turcotte-Pugh A/B/C cirrhosis, respectively. Upon nonselective β-blocker initiation, HVPG decreased more strongly in carvedilol users (median relative decrease, -20% [interquartile range: -29% to -10%] vs -11% [-22% to -5%] for propranolol; P= .027), who also achieved chronic HVPG response more often (53.3% vs 28.6%; P= .034). Cumulative incidences for rebleeding (Gray test, P= .027) and liver-related death (P= .036) were significantly lower in patients taking carvedilol compared with propranolol. Notably, ascites development/worsening also was observed less commonly in carvedilol patients (P= .012). Meanwhile, acute kidney injury rates did not differ between the 2 groups (P= .255). Stratifying patients by HVPG response status yielded similar results. The prognostic value of carvedilol intake was confirmed in competing risk regression models. Carvedilol induces more marked reductions in HVPG than propranolol in secondary prophylaxis of variceal bleeding, and thus is associated with lower rates of rebleeding, liver-related death, and further nonbleeding decompensation.

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

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 pressure assessment, hepatic venous pressure gradient (HVPG) measurement is the gold-standard method to assess the presence of clinically significant portal hypertension (CSPH) which is defined as HVPG ≥ 10 mmHg [ [1] de Franchis R. Faculty B.V.I. Expanding consensus in portal hypertension: report of the Baveno VI Consensus Workshop: stratifying risk and individualizing care for portal hypertension. J Hepatol. 2015; 63: 743-752 Google Scholar ]. 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] de Franchis R. Faculty B.V.I. Expanding consensus in portal hypertension: report of the Baveno VI Consensus Workshop: stratifying risk and individualizing care for portal hypertension. J Hepatol. 2015; 63: 743-752 Google Scholar , [2] Garcia-Tsao G. Abraldes J.G. Berzigotti A. Bosch J. Portal hypertensive bleeding in cirrhosis: risk stratification, diagnosis, and management: 2016 practice guidance by the American Association for the study of liver diseases. Hepatology. 2017; 65: 310-335 Google Scholar ]. We read the recently published original article by Paternostro et al. [ [3] Paternostro R. Becker J. Hofer B.S. Panagl V. Schiffke H. Simbrunner B. et al. The prognostic value of HVPG-response to non-selective beta-blockers in patients with NASH cirrhosis and varices. Dig Liver Dis. 2022; 54: 500-508 Google Scholar ], 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. The prognostic value of HVPG-response to non-selective beta-blockers in patients with NASH cirrhosis and varicesDigestive and Liver DiseaseVol. 54Issue 4PreviewNon-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. Full-Text PDF Open Access

Clinical Outcomes in Patients with Advanced Chronic Liver Disease and Hepatic Venous Pressure Gradient ≤ 10mm Hg.

Clinically significant portal hypertension (CSPH), defined as hepatic venous pressure gradient (HVPG) ≥ 10mmHg predicts clinical decompensation (CD) in cirrhosis. A proportion of cirrhosis patients have HVPG 6-10mmHg. Their natural history is largely unknown. Consecutive patients with advanced chronic liver disease (aCLD) [histological cirrhosis(n = 196) or liver stiffness measurement (LSM) > 15kPa(n = 65)] and HVPG 6-10mmHg were included. Primary objective was to study their natural course and patterns of CD. We also analyzed the predictors of CD at presentation and on follow-up and response to carvedilol. Of 261patients with HVPG 6-10mmHg,129(49.4%) had CD at first presentation; 78(29.9%) had single and 51(19.5%) had ≥ 2CD. The most common CDs wereascites(n = 77) and jaundice(n = 65).A baseline HVPG ≥ 8mmHg was independently associated with greater risk of CD [HR:1.7; p-0.002, AUROC:0.85(95%CI-0.81-0.91)]. New CD developed in 14.4% patients with compensated aCLD (median duration-23.1months). Despite comparable baseline HVPG, patients developing new CD had higher HVPG on follow-up(15.3 ± 3.7 vs. 8 ± 2.1mmHg; p < 0.001). Baseline LSM > 26.6kPa, portosystemic shunt and serum albumin independently predicted newCD.Overall HVPG response to carvedilol(n = 60)was 23.3%, independent of baseline CD and HVPG. Five-year mortality was higher with ≥ 2CD compared to single or no CD (23.5, 10 and 3%, respectively; p < 0.001). Nearly one-half of aCLD patients with HVPG 6-10mmHg had CD, justifying the need to redefine CSPH. Interventions to reduce portal pressure in patients with HVPG ≥ 8mmHg might improve long-term outcomes.

Serum miR-181b-5p predicts ascites onset in patients with compensated cirrhosis

Background & AimsTreatment with non-selective beta-blockers (NSBBs) reduces the risk of ascites, which is the most common decompensating event in cirrhosis. This study aimed to assess the ability of a serum microRNA (miRNA) signature to predict ascites formation and the hemodynamic response to NSBBs in compensated cirrhosis.MethodsSerum levels of miR-452-5p, miR-429, miR-885-5p, miR-181b-5p, and miR-122-5p were analyzed in patients with compensated cirrhosis (N = 105). Hepatic venous pressure gradient (HVPG) was measured at baseline, after intravenous propranolol, and 1 year after randomization to NSBBs (n = 52) or placebo (n = 53) (PREDESCI trial). miRNAs were analyzed at baseline and at 1 year.ResultsNineteen patients (18%) developed ascites, of whom 17 developed ascites after 1 year. miR-181b-5p levels at 1 year, but not at baseline, were higher in patients that developed ascites. The AUC of miR-181b-5p at 1 year to predict ascites was 0.7 (95% CI 0.59–0.78). miR-429 levels were lower at baseline in acute HVPG responders to NSBBs (AUC 0.65; 95% CI, 0.53–0.76), but levels at baseline and at 1 year were not associated with the HVPG response to NSBBs at 1 year.ConclusionsSerum miR-181b-5p is a promising non-invasive biomarker to identify patients with compensated cirrhosis at risk of ascites development.Lay summaryAscites marks the transition from the compensated to decompensated stage in cirrhosis and indicates a worsening in prognosis. There are currently no easily accessible tools to identify patients with compensated cirrhosis at risk of developing ascites. We evaluated the levels of novel molecules termed microRNAs in the blood of patients with compensated cirrhosis and observed that miR-181b-5p can predict which patients are going to develop ascites.

Clinical algorithms for the prevention of variceal bleeding and rebleeding in patients with liver cirrhosis.

Portal hypertension (PH), a common complication of liver cirrhosis, results in development of esophageal varices. When esophageal varices rupture, they cause significant upper gastrointestinal bleeding with mortality rates up to 20% despite state-of-the-art treatment. Thus, prophylactic measures are of utmost importance to improve outcomes of patients with PH. Several high-quality studies have demonstrated that non-selective beta blockers (NSBBs) or endoscopic band ligation (EBL) are effective for primary prophylaxis of variceal bleeding. In secondary prophylaxis, a combination of NSBB + EBL should be routinely used. Once esophageal varices develop and variceal bleeding occurs, standardized treatment algorithms should be followed to minimize bleeding-associated mortality. Special attention should be paid to avoidance of overtransfusion, early initiation of vasoconstrictive therapy, prophylactic antibiotics and early endoscopic therapy. Pre-emptive transjugular intrahepatic portosystemic shunt should be used in all Child C10-C13 patients experiencing variceal bleeding, and potentially in Child B patients with active bleeding at endoscopy. The use of carvedilol, safety of NSBBs in advanced cirrhosis (i.e. with refractory ascites) and assessment of hepatic venous pressure gradient response to NSBB is discussed. In the present review, we give an overview on the rationale behind the latest guidelines and summarize key papers that have led to significant advances in the field.

Using MR elastography to assess portal hypertension and response to beta-blockers in patients with cirrhosis.

MR elastography can determine organ-related stiffness, which reflects the degree of fibrosis. Liver stiffness increases in cirrhosis, and stiffness increases further post-prandially due to increased portal blood in-flow. Non-selective beta-blockers (NSBB) reduce the portal venous inflow, but their effect on liver and spleen stiffness are disputed. To assess whether MR elastography of the liver or spleen reflects the severity of cirrhosis, whether treatment with NSBB changes liver and spleen stiffness and whether changes in stiffness can predict the effect of NSBB on portal pressure. Fifty-two patients with cirrhosis underwent liver vein catheterization and two-dimensional (2D) MR elastography on separate days. Thirty-six of the patients had a hepatic venous pressure gradient (HVPG) of ≥12mmHg and were tested prior to, and after, intravenous infusion of NSBB using HVPG measurement and MR elastography. HVPG showed a strong, positive, linear relationship with liver stiffness (r2 =0.92; P<.001) and spleen stiffness (r2 =0.94; P<.001). The cut-off points for identifying patients with a HVPG≥12mmHg were 7.7kPa for liver stiffness (sensitivity 0.78, specificity 0.64) and 10.5kPa for spleen stiffness (sensitivity 0.8, specificity 0.79). Intravenous administration of NSBB significantly decreased spleen stiffness by 6.9% (CI: 3.5-10.4, P<.001), but NSBB had no consistent effect on liver stiffness. However, changes in spleen stiffness were not related to the HVPG response (P=.75). Two-dimensional MR elastographic estimation of liver or spleen stiffness reflects the degree of portal hypertension in patients with liver cirrhosis, but changes in stiffness after NSBB do not predict the effect on HVPG.

Nonselective Beta-Blockers in Compensated Cirrhosis: Preventing Variceal Hemorrhage or Preventing Decompensation?

Nonselective Beta-Blockers in Compensated Cirrhosis: Preventing Variceal Hemorrhage or Preventing Decompensation?

Splenic non-infarction volume determines a clinically significant hepatic venous pressure gradient response to partial splenic embolization in patients with cirrhosis and hypersplenism.

This study aimed to investigate changes in the hepatic venous pressure gradient (HVPG) by partial splenic embolization (PSE) and to identify the determinants of a clinically meaningful postoperative HVPG reduction. Sixty-eight patients with cirrhosis and hypersplenism who underwent PSE at our department between September 2007 and June 2020 were included. The HVPG was evaluated pre- and immediately post-PSE. The patients were divided into three groups according to their preprocedural HVPG: low-HVPG (< 10mmHg, n = 22), intermediate-HVPG (10mmHg ≤ HVPG < 16mmHg, n = 33), and high-HVPG (≥ 16mmHg, n = 13). Overall, PSE significantly reduced HVPG from 12.2 ± 4.0 to 9.4 ± 3.6mmHg (p < 0.01) with a relative decrease of 22.2 ± 20.4%. In addition, HVPG reductions were 19.4 ± 28.7%, 24.0 ± 15.9%, and 22.5 ± 13.3% in the low-, intermediate-, and high-HVPG groups, respectively, indicating no significant difference in HVPG reduction between the groups. An HVPG decrease of ≥ 20% from the baseline, defined in this study as a clinically significant HVPG response to PSE, was achieved in 55.9% of all patients. Multivariate logistic regression and receiveroperating characteristic curve analyses identified splenic non-infarction volume as an independent determinant of a 20% decrease in HVPG (p < 0.05), with a cut-off of 139.2cm3 (sensitivity, 76.3%; specificity, 60.0%; p < 0.05). The splenic non-infarction volume, namely the residual functional spleen volume, independently determines a clinically significant HVPG response to PSE in patients with cirrhosis and hypersplenism.

Amelioration of systemic inflammation in advanced chronic liver disease upon beta-blocker therapy translates into improved clinical outcomes

ObjectiveSystemic inflammation promotes the development of clinical events in patients with advanced chronic liver disease (ACLD). We assessed whether (1) non-selective beta blocker (NSBB) treatment initiation impacts biomarkers of systemic...

Liver stiffness assessment as an alternative to hepatic venous pressure gradient for predicting rebleed after acute variceal bleed: A proof-of-concept study.

Background and AimHepatic venous pressure gradient (HVPG), although an important determinant in predicting rebleeding after an episode of acute variceal bleed (AVB), is seldom utilized in clinical practice. We aimed to study the role of liver stiffness measurement (LSM) after variceal bleeding as a potential noninvasive predictor of rebleed.MethodsThis was a post hoc analysis of clinical trial of patients undergoing HVPG (postbleed HVPG) and LSM (postbleed LSM) assessment within 3–5 days of index AVB. HVPG response was assessed after 4 weeks of pharmacotherapy. Comparative assessment of long‐term rebleeding rates stratified using postbleed LSM, postbleed HVPG, and HVPG response was performed. Decision curve analysis (DCA) was conducted to identify the most appropriate tool for routine use.ResultsLong‐term clinical and HVPG response data were available for 48 patients post‐AVB, of whom 45 patients had valid postbleed LSM. Rebleeding occurred in 13 (28%) patients over a median follow‐up of 4 years with no early rebleeds. Postbleed LSM >30 kPa and baseline HVPG >15 mm Hg were optimal cutoffs for identifying patients at high risk of rebleeding. Time‐dependent receiver operating characteristic curves and competing risk analysis accounting for death showed similar discriminative values for all three stratification tools. At usual risk thresholds, HVPG response had maximum benefit on DCA followed by postbleed LSM. On DCA, 50–60 additional HVPGs were required to detect one additional patient at high risk of rebleed.ConclusionLiver stiffness measurement during AVB can potentially be used as an alternative to portal pressure indices in decompensated cirrhosis to identify those at high risk of late‐onset rebleed.

Outcomes of Portal Pressure-Guided Therapy in Decompensated Cirrhosis With Index Variceal Bleed in Asian Cohort

Hemodynamic response to pharmacotherapy improves survival in patients with cirrhosis post variceal bleeding, but long-term outcomes remain unexplored especially in this part of the world. We aimed to study the long-term impact of portal pressure reduction on liver-related outcomes after index variceal bleed. Patients with hepatic venous pressure gradient (HVPG) more than 12mm Hg after index variceal bleed were given non-selective beta-blockers in combination with variceal band ligation. HVPG response was assessed after 4 weeks. Patients were followed up for rebleed events, survival, additional decompensation events and safety outcomes. Rebleed and other decompensations were compared using competing risks analysis, taking death as competing event, and survival was compared using Kaplan-Meier analysis. Forty-eight patients (29 responders and 19 non-responders) were followed up for a median duration of 45 (24-56) months. Rebleeding rates at 1, 3 and 5 years were 10.3%, 20.7% and 20.7% in responders and 15.8%, 44.7% and 51.1% in non-responders, respectively (Gray's test, P=0.044). Survival rates at 1, 3 and 5 years were 89.7%, 72.1% and 51.9% in responders and 89.5%, 44% and 37.7% in non-responders, respectively (log-rank test, P=0.1). Both severity of liver disease (MELD score, multivariate sub-distributional hazards ratio: 1.166 [1.014-1.341], P=0.030) and HVPG non-response (multivariate sub-distributional hazards ratio: 2.476 [1.87-7.030], P=0.045) predicted rebleeding risk while survival was dependent only on severity of liver disease (MELD>12, multivariate hazards ratio: 2.36 [1.04-5.38], P=0.041). Baseline severity of liver disease predicted survival and rebleed in these patients. Hemodynamic response, although associated with lower rebleeding rate, had limited impact on survival.

Long-term Outcomes with Carvedilol versus Propranolol in Patients with Index Variceal Bleed: 6-year Follow-up Study

There is limited information on comparison of clinical outcomes with carvedilol for secondary prophylaxis following acute variceal bleed (AVB) when compared with propranolol. We report long-term clinical and safety outcomes of a randomised controlled trial comparing carvedilol with propranolol with respect to reduction in hepatic venous pressure gradient (HVPG) in patients after AVB. We conducted a post-hoc analysis of patients recruited in an open-label randomized controlled trial comparing carvedilol and propranolol following AVB, and estimated long-term rates of rebleed, survival, additional decompensation events and safety outcomes. Rebleed and other decompensations were compared using competing risks analysis, taking death as competing event, and survival was compared using Kaplan-Meier analysis. Forty-eight patients (25 taking carvedilol; 23 propranolol) were followed up for 6 years from randomization. More number of patients on carvedilol had HVPG response when compared with those taking propranolol(72%- carvedilol versus 47.8% propranolol, p=0.047). Comparable 1-year and 3-year rates of rebleed (16.0% and 24.0% for carvedilol versus 8.9% and 36.7% for propranolol; p=0.457) and survival (94.7% and 89.0% for carvedilol versus 100.0% and 79.8% for propranolol; p=0.76) were obtained. New/worsening ascites was more common in those receiving propranolol (69.5% vs 40%; p=0.04). Other clinical decompensations and complications of liver disease occurred at comparable rates between two groups. Drug-related adverse-events were similar in both groups. Despite higher degree of HVPG response, long-term clinical, survival and safety outcomes in carvedilol are similar to those of propranolol in patients with decompensated cirrhosis after index variceal bleed with the exception of ascites that developed less frequently in patients with carvedilol.

Impact of beta blocker therapy on systemic inflammation stratified by hepatic venous pressure gradient response

Impact of beta blocker therapy on systemic inflammation stratified by hepatic venous pressure gradient response

A Prognostic Strategy Based on Stage of Cirrhosis and HVPG to Improve Risk Stratification After Variceal Bleeding.

A hepatic venous pressure gradient (HVPG) decrease of 20% or more (or ≤12mmHg) indicates a good prognosis during propranolol/nadolol treatment but requires two HVPG measurements. We aimed to simplify the risk stratification after variceal bleeding using clinical data and HVPG. A total of 193 patients with cirrhosis (62% with ascites and/or hepatic encephalopathy [HE]) who were within 7 days of bleeding had their HVPG measured before and at 1-3months of treatment with propranolol/nadolol plus endoscopic band ligation. The endpoints were rebleeding and rebleeding/transplantation-free survival for 4 years. Another cohort (n=231) served as the validation set. During follow-up, 45 patients had variceal bleeding and 61 died. The HVPG responders (n=71) had lower rebleeding risk (10% vs. 34%, P=0.001) and better survival than the 122 nonresponders (61% vs. 39%, P=0.001). Patients with HE (n=120) had lower survival than patients without HE (40% vs. 63%, P=0.005). Among the patients with ascites/HE, those with baseline HVPG≤16mmHg (n=16) had a low rebleeding risk (13%). In contrast, among patients with ascites/HE and baseline HVPG>16mmHg, only the HVPG responders (n=32) had a good prognosis, with lower rebleeding risk and better survival than the nonresponders (n=72) (respective proportions: 7% vs. 39%, P=0.018; 56% vs. 30% P=0.010). These findings allowed us to develop a strategy for risk stratification in which HVPG response was measured only in patients with ascites and/or HE and baseline HVPG>16mmHg. This method reduced the "gray zone" (i.e., high-risk patients who had not died on follow-up) from 46% to 35% and decreased the HVPG measurements required by 42%. The validation cohort confirmed these results. Restricting HVPG measurements to patients with ascites/HE and measuring HVPG response only if the patient's baseline HVPG is over 16mmHg improves detection of high-risk patients while markedly reducing the number of HVPG measurements required.

Hemodynamic Effects of Adding Simvastatin to Carvedilol for Primary Prophylaxis of Variceal Bleeding: A Randomized Controlled Trial.

Beta-blockers are the mainstay agents for portal pressure reduction and to modestly reduce hepatic venous pressure gradient (HVPG). We studied whether addition of simvastatin to carvedilol in cirrhotic patients for primary prophylaxis improves the hemodynamic response. Cirrhotic patients with esophageal varices and with baseline HVPG > 12 mm Hg were prospectively randomized for primary prophylaxis to receive either carvedilol (group A, n = 110) or carvedilol plus simvastatin (group B, n = 110). Primary objective was to compare hemodynamic response (HVPG reduction of ≥20% or <12 mm Hg) at 3 months, and secondary objectives were to compare first bleed episodes, death, and adverse events. The groups were comparable at baseline. The proportion of patients achieving HVPG response at 3 months was comparable between groups (group A-36/62 [58.1%], group B-36/59 [61%], P = 0.85). The degree of mean HVPG reduction (17.3% and 17.8%, respectively, P = 0.98) and hemodynamic response (odds ratio [OR]: 0.88; 95% confidence interval [CI]: 0.43-1.83, P = 0.74) was also not different between the groups. Patients who achieved target heart rate with no hypotensive episodes in either group showed better hemodynamic response (77.8% vs 59.2%, P = 0.04). Failure to achieve target heart rate (OR: 0.48; 95% CI: 0.22-1.06) and Child C cirrhosis (OR: 4.49; 95% CI: 1.20-16.8) predicted nonresponse. Three (3.7%) patients on simvastatin developed transient transaminitis and elevated creatine phosphokinase and improved with drug withdrawal. Two patients in each group bled (P = 0.99). Three patients and 1 patient, respectively, in group A and B died (P = 0.32), with sepsis being the cause of death. Addition of simvastatin to carvedilol for 3 months for primary prophylaxis of variceal bleeding does not improve hemodynamic response over carvedilol monotherapy. Simvastatin usage should be closely monitored for adverse effects in Child C cirrhotic patients.

Lowering Portal Pressure Improves Outcomes of Patients With Cirrhosis, With or Without Ascites: A Meta-Analysis

In unselected patients with cirrhosis, those with reductions in hepatic venous pressure gradient (HVPG) to below a defined threshold (responders) have a reduced risk of variceal hemorrhage (VH) and death. We performed a meta-analysis to compare this effect in patients with vs without ascites. We collected data from 15 studies of primary or secondary prophylaxis of VH that reported data on VH and death in responders vs nonresponders. We included studies in which data on ascites at baseline and on other relevant outcomes during follow-up evaluation were available. We performed separate meta-analyses for patients with vs without ascites. Of the 1113 patients included in the studies, 968 patients (87%) had been treated with nonselective β-blockers. In 993 patients (89%), HVPG response was defined as a decrease of more than 20% from baseline (>10% in 11% of patients) or to less than 12 mm Hg. In the 661 patients without ascites, responders (n= 329; 50%) had significantly lower odds of events (ascites, VH, or encephalopathy) than nonresponders (odds ratio [OR], 0.35; 95% CI, 0.22-0.56). Odds of death or liver transplantation were also significantly lower among responders than nonresponders (OR, 0.50, 95% CI, 0.32-0.78). In the 452 patients with ascites, responders (n= 188; 42%) had significantly lower odds of events (VH, refractory ascites, spontaneous bacterial peritonitis, or hepatorenal syndrome) than nonresponders (OR, 0.27; 95% CI, 0.16-0.43). Overall, odds of death or liver transplantation were lower among responders (OR, 0.47; 95% CI, 0.29-0.75). No heterogeneity was observed among studies. In a meta-analysis of clinical trials, we found that patients with cirrhosis with and without ascites who respond to treatment with nonselective β-blockers (based on reductions in HVPG) have a reduced risk of events, death, or liver transplantation.