Effect of time to pre-emptive transjugular intrahepatic portosystemic shunt on patient outcome, a UK multicentre cohort study.

BACKGROUND: Pre-emptive transjugular intrahepatic portosystemic shunt (pTIPSS) should be considered within 72 hours following acute oesophageal variceal bleeding. However, recent studies highlight the difficulty in providing pTIPSS within this narrow timeframe. Delaying pTIPSS beyond 72 hours has not been studied. AIM: To determine if the time taken to perform pTIPSS alters patient outcome. METHOD: Patients referred to 4 UK tertiary centres for pTIPSS between 01 January 2010 and 31 December 2018 were included. Time from endoscopy to pTIPSS was recorded and pre-defined clinically relevant outcomes were observed relative to two groups: early pTIPSS (<72 h) and late pTIPSS (72 h-28 days). The primary outcome was transplant-free survival at 1-year. Follow-up was until 31 December 2020. RESULTS: A total of 83 patients received early pTIPSS and 88 received late pTIPSS. Baseline characteristics were similar with no requirement for propensity score-matched analysis. There was no difference between early and late pTIPSS groups for patient outcomes; 1-year transplant-free survival rate (69.9% vs 71.6%, p = 0.73, HR 0.91, 95% CI 0.52-1.58), long-term survival (p = 0.52, HR 1.132, 95% CI 0.77-1.65), variceal rebleeding (4.82% vs 11.36%, p = 0.09, HR 0.411, 95% CI 0.14-1.17), hepatic encephalopathy (43.93% vs 34.61%, p = 0.26) and new or worsening ascites (16.6% vs 13.46%, p = 0.79). Death due to liver failure was significantly more prevalent in those undergoing early pTIPSS compared to late pTIPSS (44% vs 16%, p = 0.046, HR 2.79, 95%CI 1.02-8.32). CONCLUSION: Placement of pTIPSS within 72 hours offered similar short- and long-term survival benefits compared to pTIPSS placed between 72 hours and 28 days. Early pTIPSS may be associated with an increased risk of liver failure-related mortality. Further large, randomised studies are required to evaluate these findings.

Study protocol: a multicentre, open-label, parallel-group, phase 2, randomised controlled trial of autologous macrophage therapy for liver cirrhosis (MATCH).

INTRODUCTION: Liver cirrhosis is a growing global healthcare challenge. Cirrhosis is characterised by severe liver fibrosis, organ dysfunction and complications related to portal hypertension. There are no licensed antifibrotic or proregenerative medicines and liver transplantation is a scarce resource. Hepatic macrophages can promote both liver fibrogenesis and fibrosis regression. The safety and feasibility of peripheral infusion of ex vivo matured autologous monocyte-derived macrophages in patients with compensated cirrhosis has been demonstrated. METHODS AND ANALYSIS: The efficacy of autologous macrophage therapy, compared with standard medical care, will be investigated in a cohort of adult patients with compensated cirrhosis in a multicentre, open-label, parallel-group, phase 2, randomised controlled trial. The primary outcome is the change in Model for End-Stage Liver Disease score at 90 days. The trial will provide the first high-quality examination of the efficacy of autologous macrophage therapy in improving liver function, non-invasive fibrosis markers and other clinical outcomes in patients with compensated cirrhosis. ETHICS AND DISSEMINATION: The trial will be conducted according to the ethical principles of the Declaration of Helsinki 2013 and has been approved by Scotland A Research Ethics Committee (reference 15/SS/0121), National Health Service Lothian Research and Development department and the Medicine and Health Care Regulatory Agency-UK. Final results will be presented in peer-reviewed journals and at relevant conferences. TRIAL REGISTRATION NUMBERS: ISRCTN10368050 and EudraCT; reference 2015-000963-15.

Randomised clinical trial: standard of care versus early-transjugular intrahepatic porto-systemic shunt (TIPSS) in patients with cirrhosis and oesophageal variceal bleeding.

BACKGROUND: Early-transjugular intrahepatic porto-systemic shunt (TIPSS) has been recommended in international guidelines for high-risk patients with oesophageal variceal bleeding. AIM: To validate the results of a previous randomised control trial which supports use of early-TIPSS. METHODS: In a two-centre open-label parallel-group randomised control trial, patients with cirrhosis and acute variceal bleeding were recruited following haemostasis with vaso-active drugs and endoscopic band ligation. Participants were randomised to standard of care or early-TIPSS. The primary outcome was 1-year survival, secondary outcomes included early and late rebleeding, and complications of portal hypertension. RESULTS: Fifty-eight patients (58 ± 11.12 years; 32.7% female) were randomised. After one year, seven patients died in the standard of care group and six in the early-TIPSS group, a 1-year survival of 75.9% vs 79.3% respectively (P = 0.79). Variceal rebleeding occurred in eight patients in the standard of care group compared with three patients in the early-TIPSS group (P = 0.09). Not all participants randomised to early-TIPSS received the intervention in time. For those receiving TIPSS per-protocol, variceal rebleeding rates were reduced (0% vs 27.6%, P = 0.04) but this had no effect on survival (76.9% vs 75.9%, P = 0.91). Serious adverse events were similar in both treatment groups, except that rates of hepatic encephalopathy were higher in patients receiving TIPSS (46.1% vs 20.7%, P < 0.05). CONCLUSIONS: Early-TIPSS reduced variceal rebleeding, increased encephalopathy but had no effect on survival in high-risk patients with oesophageal variceal bleeding. Early-TIPSS may not be feasible in many centres however, larger studies are needed. ClinicalTrials.gov reference: NCT02377141.

Assessment of Haemodynamic Response to Nonselective Beta-Blockers in Portal Hypertension by Phase-Contrast Magnetic Resonance Angiography.

A significant unmet need exists for accurate, reproducible, noninvasive diagnostic tools to assess and monitor portal hypertension (PHT). We report the first use of quantitative MRI markers for the haemodynamic assessment of nonselective beta-blockers (NSBB) in PHT. In a randomized parallel feasibility study in 22 adult patients with PHT and a clinical indication for NSBB, we acquired haemodynamic data at baseline and after 4 weeks of NSBB (propranolol or carvedilol) using phase-contrast MR angiography (PC-MRA) in selected intra-abdominal vessels. T1 mapping of liver and spleen was undertaken to assess changes in tissue composition. Target NSBB dose was achieved in 82%. There was a substantial reduction from baseline in mean average flow in the superior abdominal aorta after 4 weeks of NSBB therapy (4.49 ± 0.98 versus 3.82 ± 0.86 L/min, P = 0.03) but there were no statistically significant differences in flow in any other vessels, even in patients with >25% decrease in heart rate (47% of patients). Mean percentage change in liver and spleen T1 following NSBB was small and highly variable. In conclusion, PC-MRA was able to detect reduction in cardiac output by NSBB but did not detect significant changes in visceral blood flow or T1. This trial was registered with the ISRCTN registry (ISRCTN98001632).

Serelaxin as a potential treatment for renal dysfunction in cirrhosis: Preclinical evaluation and results of a randomized phase 2 trial.

BACKGROUND: Chronic liver scarring from any cause leads to cirrhosis, portal hypertension, and a progressive decline in renal blood flow and renal function. Extreme renal vasoconstriction characterizes hepatorenal syndrome, a functional and potentially reversible form of acute kidney injury in patients with advanced cirrhosis, but current therapy with systemic vasoconstrictors is ineffective in a substantial proportion of patients and is limited by ischemic adverse events. Serelaxin (recombinant human relaxin-2) is a peptide molecule with anti-fibrotic and vasoprotective properties that binds to relaxin family peptide receptor-1 (RXFP1) and has been shown to increase renal perfusion in healthy human volunteers. We hypothesized that serelaxin could ameliorate renal vasoconstriction and renal dysfunction in patients with cirrhosis and portal hypertension. METHODS AND FINDINGS: To establish preclinical proof of concept, we developed two independent rat models of cirrhosis that were characterized by progressive reduction in renal blood flow and glomerular filtration rate and showed evidence of renal endothelial dysfunction. We then set out to further explore and validate our hypothesis in a phase 2 randomized open-label parallel-group study in male and female patients with alcohol-related cirrhosis and portal hypertension. Forty patients were randomized 1:1 to treatment with serelaxin intravenous (i.v.) infusion (for 60 min at 80 µg/kg/d and then 60 min at 30 µg/kg/d) or terlipressin (single 2-mg i.v. bolus), and the regional hemodynamic effects were quantified by phase contrast magnetic resonance angiography at baseline and after 120 min. The primary endpoint was the change from baseline in total renal artery blood flow. Therapeutic targeting of renal vasoconstriction with serelaxin in the rat models increased kidney perfusion, oxygenation, and function through reduction in renal vascular resistance, reversal of endothelial dysfunction, and increased activation of the AKT/eNOS/NO signaling pathway in the kidney. In the randomized clinical study, infusion of serelaxin for 120 min increased total renal arterial blood flow by 65% (95% CI 40%, 95%; p < 0.001) from baseline. Administration of serelaxin was safe and well tolerated, with no detrimental effect on systemic blood pressure or hepatic perfusion. The clinical study's main limitations were the relatively small sample size and stable, well-compensated population. CONCLUSIONS: Our mechanistic findings in rat models and exploratory study in human cirrhosis suggest the therapeutic potential of selective renal vasodilation using serelaxin as a new treatment for renal dysfunction in cirrhosis, although further validation in patients with more advanced cirrhosis and renal dysfunction is required. TRIAL REGISTRATION: ClinicalTrials.gov NCT01640964.

Utility of 3-dimensional image reconstruction in the diagnosis of small-bowel masses in capsule endoscopy (with video).

BACKGROUND: In small-bowel capsule endoscopy (SBCE), differentiating masses (ie, lesions of higher probability for neoplasia) requiring more aggressive intervention from bulges (essentially, false-positive findings) is a challenging task; recently, software that enables 3-dimensional (3D) reconstruction has become available. OBJECTIVE: To evaluate whether "coupling" 3D reconstructed video clips with the standard 2-dimensional (s2D) counterparts helps in distinguishing masses from bulges. DESIGN: Three expert and 3 novice SBCE readers, blind to others and in a random order, reviewed the s2D video clips and subsequently the s2D clips coupled with their 3D reconstruction (2D+3D). SETTING: Multicenter study in 3 community hospitals in Italy and a university hospital in Scotland. PATIENTS: Thirty-two deidentified 5-minute video clips, containing mucosal bulging (19) or masses (13). INTERVENTION: 3D reconstruction of s2D SBCE video clips. MAIN OUTCOME MEASURE: Differentiation of masses from bulges with s2D and 2D+3D video clips, estimated by the area under the receiver operating characteristic curve (AUC); interobserver agreement. RESULTS: AUC for experts and novices for s2D video clips was .74 and .5, respectively (P = .0053). AUC for experts and novices with 2D+3D was .70 (compared with s2D: P = .245) and .57 (compared s2D: P = .049), respectively. AUC for experts and novices with 2D+3D was similar (P = .1846). The interobserver agreement was good for both experts and novices with the s2D (k = .71 and .54, respectively) and the 2D+3D video clips (k = .58 in both groups). LIMITATIONS: Few, short video clips; fixed angle of 3D reconstruction. CONCLUSIONS: The adjunction of a 3D reconstruction to the s2D video reading platform does not improve the performance of expert SBCE readers, although it significantly increases the performance of novices in distinguishing masses from bulging.