Adrian J. Stanley

Outpatient management of patients with low-risk upper-gastrointestinal haemorrhage: multicentre validation and prospective evaluation

BACKGROUND Upper-gastrointestinal haemorrhage is a frequent reason for hospital admission. Although most risk scoring systems for this disorder incorporate endoscopic findings, the Glasgow-Blatchford bleeding score (GBS) is based on simple clinical and laboratory variables; a score of 0 identifies low-risk patients who might be suitable for outpatient management. We aimed to evaluate the GBS then assess the effect of a protocol based on this score for non-admission of low-risk individuals. METHODS Our study was undertaken at four hospitals in the UK. We calculated GBS and admission (pre-endoscopy) and full (post-endoscopy) Rockall scores for consecutive patients presenting with upper-gastrointestinal haemorrhage. With receiver-operating characteristic (ROC) curves, we compared the ability of these scores to predict either need for clinical intervention or death. We then prospectively assessed at two hospitals the introduction of GBS scoring to avoid admission of low-risk patients. FINDINGS Of 676 people presenting with upper-gastrointestinal haemorrhage, we identified 105 (16%) who scored 0 on the GBS. For prediction of need for intervention or death, GBS (area under ROC curve 0.90 [95% CI 0.88-0.93]) was superior to full Rockall score (0.81 [0.77-0.84]), which in turn was better than the admission Rockall score (0.70 [0.65-0.75]). When introduced into clinical practice, 123 patients (22%) with upper-gastrointestinal haemorrhage were classified as low risk, of whom 84 (68%) were managed as outpatients without adverse events. The proportion of individuals with this condition admitted to hospital also fell (96% to 71%, p<0.00001). INTERPRETATION The GBS identifies many patients presenting to general hospitals with upper-gastrointestinal haemorrhage who can be managed safely as outpatients. This score reduces admissions for this condition, allowing more appropriate use of in-patient resources.

Randomized controlled trial of carvedilol versus variceal band ligation for the prevention of the first variceal bleed

Current therapy for preventing the first variceal bleed includes beta‐blocker and variceal band ligation (VBL). VBL has lower bleeding rates, with no differences in survival, whereas beta‐blocker therapy can be limited by side effects. Carvedilol, a non‐cardioselective vasodilating beta‐blocker, is more effective in reducing portal pressure than propranolol; however, there have been no clinical studies assessing the efficacy of carvedilol in primary prophylaxis. The goal of this study was to compare carvedilol and VBL for the prevention of the first variceal bleed in a randomized controlled multicenter trial. One hundred fifty‐two cirrhotic patients from five different centers with grade II or larger esophageal varices were randomized to either carvedilol 12.5 mg once daily or VBL performed every 2 weeks until eradication using a multibander device. Seventy‐seven patients were randomized to carvedilol and 75 to VBL. Baseline characteristics did not differ between the groups (alcoholic liver disease, 73%; median Child‐Pugh score, 8; median age, 54 years; median follow‐up, 20 months). On intention‐to‐treat analysis, carvedilol had lower rates of the first variceal bleed (10% versus 23%; relative hazard 0.41; 95% confidence interval 0.19‐0.96 [P = 0.04]), with no significant differences in overall mortality (35% versus 37%, P = 0.71), and bleeding‐related mortality (3% versus 1%, P = 0.26). Six patients in the VBL group bled as a result of banding ulcers. Per‐protocol analysis revealed no significant differences in the outcomes. Conclusion: Carvedilol is effective in preventing the first variceal bleed. Carvedilol is an option for primary prophylaxis in patients with high‐risk esophageal varices. (HEPATOLOGY 2009.)

Hepatic granulomas: a 10 year single centre experience.

Background: Epithelioid granulomas have been reported in 2–15% of unselected liver biopsies, with numerous underlying aetiologies described. However, all UK series were reported before identification of hepatitis C virus (HCV). Aim: To evaluate the current aetiologies of hepatic granulomas and to assess the prognosis for the “idiopathic” group, in which all investigations for a recognised cause were negative or normal. Methods: A retrospective review of patient case notes between 1991 and 2001; all patients who had a liver biopsy at Glasgow Royal Infirmary revealing epithelioid granulomas had their case notes and liver biopsies reviewed and a standard proforma completed. Results: Over the study period, 1662 liver biopsies were performed. Hepatic granulomas were found in 63. Of those identified, 47 were female, with a mean age of 42 years (range, 17–81). Underlying aetiologies were as follows: primary biliary cirrhosis (PBC; 23.8%), sarcoidosis (11.1%), idiopathic (11.1%), drug induced (9.5%), HCV (9.5%), PBC/autoimmune hepatitis (AIH) overlap (6.3%), Hodgkin lymphoma (6.3%), AIH (4.8%), tuberculosis (4.8%), resolving biliary obstruction (3.2%), and other single miscellaneous causes (9.5%). Of the seven patients with idiopathic hepatic granulomas, one was lost to follow up, one died of stroke, and the remaining five were well with no liver related morbidity at a mean follow up of 6.2 years. Conclusions: The aetiology of hepatic granulomas is broad ranging, with HCV an important cause in this population. Despite extensive investigations, a 10–15% of patients still had “idiopathic” hepatic granulomas. However, the prognosis for this last group appears to be excellent.

Multicentre comparison of the Glasgow Blatchford and Rockall scores in the prediction of clinical end-points after upper gastrointestinal haemorrhage

Aliment Pharmacol Ther 2011; 34: 470–475

Restrictive versus liberal blood transfusion for acute upper gastrointestinal bleeding (TRIGGER): a pragmatic, open-label, cluster randomised feasibility trial

BACKGROUND Transfusion thresholds for acute upper gastrointestinal bleeding are controversial. So far, only three small, underpowered studies and one single-centre trial have been done. Findings from the single-centre trial showed reduced mortality with restrictive red blood cell (RBC) transfusion. We aimed to assess whether a multicentre, cluster randomised trial is a feasible method to substantiate or refute this finding. METHODS In this pragmatic, open-label, cluster randomised feasibility trial, done in six university hospitals in the UK, we enrolled all patients aged 18 years or older with new presentations of acute upper gastrointestinal bleeding, irrespective of comorbidity, except for exsanguinating haemorrhage. We randomly assigned hospitals (1:1) with a computer-generated randomisation sequence (random permuted block size of 6, without stratification or matching) to either a restrictive (transfusion when haemoglobin concentration fell below 80 g/L) or liberal (transfusion when haemoglobin concentration fell below 100 g/L) RBC transfusion policy. Neither patients nor investigators were masked to treatment allocation. Feasibility outcomes were recruitment rate, protocol adherence, haemoglobin concentration, RBC exposure, selection bias, and information to guide design and economic evaluation of the phase 3 trial. Main exploratory clinical outcomes were further bleeding and mortality at day 28. We did analyses on all enrolled patients for whom an outcome was available. This trial is registered, ISRCTN85757829 and NCT02105532. FINDINGS Between Sept 3, 2012, and March 1, 2013, we enrolled 936 patients across six hospitals (403 patients in three hospitals with a restrictive policy and 533 patients in three hospitals with a liberal policy). Recruitment rate was significantly higher for the liberal than for the restrictive policy (62% vs 55%; p=0·04). Despite some baseline imbalances, Rockall and Blatchford risk scores were identical between policies. Protocol adherence was 96% (SD 10) in the restrictive policy vs 83% (25) in the liberal policy (difference 14%; 95% CI 7-21; p=0·005). Mean last recorded haemoglobin concentration was 116 (SD 24) g/L for patients on the restrictive policy and 118 (20) g/L for those on the liberal policy (difference -2·0 [95% CI -12·0 to 7·0]; p=0·50). Fewer patients received RBCs on the restrictive policy than on the liberal policy (restrictive policy 133 [33%] vs liberal policy 247 [46%]; difference -12% [95% CI -35 to 11]; p=0·23), with fewer RBC units transfused (mean 1·2 [SD 2·1] vs 1·9 [2·8]; difference -0·7 [-1·6 to 0·3]; p=0·12), although these differences were not significant. We noted no significant difference in clinical outcomes. INTERPRETATION A cluster randomised design led to rapid recruitment, high protocol adherence, separation in degree of anaemia between groups, and non-significant reduction in RBC transfusion in the restrictive policy. A large cluster randomised trial to assess the effectiveness of transfusion strategies for acute upper gastrointestinal bleeding is both feasible and essential before clinical practice guidelines change to recommend restrictive transfusion for all patients with acute upper gastrointestinal bleeding. FUNDING NHS Blood and Transplant Research and Development.

Ten years' follow-up of 472 patients following transjugular intrahepatic portosystemic stent-shunt insertion at a single centre.

Background Transjugular intrahepatic portosystemic stent-shunt (TIPSS) is increasingly used for the management of portal hypertension. We report on 10 years’ experience at a single centre. Methods Data held in a dedicated database was retrieved on 497 patients referred for TIPSS. The efficacy of TIPSS and its complications were assessed. Results Most patients were male (59.4%) with alcoholic liver disease (63.6%), and bleeding varices (86.8%). Technical success was achieved in 474 (95.4%) patients. A total of 13.4% of patients bled at portal pressure gradients ⩽ 12 mmHg, principally from gastric and ectopic varices. Procedure-related mortality was 1.2%. The mean follow-up period of surviving patients was 33.3 ± 1.9 months. Primary shunt patency rates were 45.4% and 26.0% at 1 and 2 years, respectively, while the overall secondary assisted patency rate was 72.2%. Variceal rebleeding rate was 13.7%, with all episodes occurring within 2 years of TIPSS insertion, and almost all due to shunt dysfunction. The overall mortality rate was 60.4%, mainly resulting from end-stage liver failure (42.5%). Patients who bled from gastric varices had lower mortality than those from oesophageal varices (53.9% versus 61.5%, P < 0.01). The overall rate of hepatic encephalopathy was 29.9% (de novo encephalopathy was 11.5%), with pre-TIPSS encephalopathy being an independent predicting variable. Refractory ascites responded to TIPSS in 72% of cases, although the incidence of encephalopathy was high in this group (36.0%). Conclusions TIPSS is effective in the management of variceal bleeding, and has a low complication rate. With surveillance, good patency can be achieved. Careful selection of patients is needed to reduce the encephalopathy rate.

Longterm follow up of transjugular intrahepatic portosystemic stent shunt (TIPSS) for the treatment of portal hypertension: results in 130 patients.

BACKGROUND: Transjugular intrahepatic portosystemic stent shunts (TIPSS) are increasingly being used to manage the complications of portal hypertension. This study reports on the follow up on 130 patients who have undergone TIPSS. PATIENTS AND METHODS: One hundred and thirty patients (81 male), mean (SD) age 54.7 (12.5) years underwent TIPSS. The majority (64.6%) had alcoholic cirrhosis and 53.2% had Childs C disease. Indications were: variceal haemorrhage (76.2%), refractory ascites (13.1%), portal hypertensive gastropathy (4.6%), others (6.1%). Shunt function was assessed by Doppler ultrasonography and two then six monthly portography and mean follow up for survivors was 18.0 months (range 2-43.5). RESULTS: The procedure was successful in 119 (91.5%). Sixty three episodes of shunt dysfunction were observed in 45 (37.8%) patients. Variceal rebleeding occurred in 16 (13.4%) patients and was always associated with shunt dysfunction. Twenty (16.8%) patients had new or worse spontaneous encephalopathy after TIPSS and 11 (64.7%) patients had an improvement in resistant ascites. Thirty day mortality was 21.8% and one year survival 62.5%. CONCLUSION: TIPSS is an effective treatment for variceal bleeding, resistant ascites, and portal hypertensive gastropathy. Rebleeding is invariably associated with shunt dysfunction, the frequency of which increases with time, therefore regular and longterm shunt surveillance is required.

Toward a more complete understanding of the association between a hepatitis C sustained viral response and cause-specific outcomes

Sustained viral response (SVR) is the optimal outcome of hepatitis C virus (HCV) therapy, yet more detailed data are required to confirm its clinical value. Individuals receiving treatment in 1996‐2011 were identified using the Scottish HCV clinical database. We sourced data on 10 clinical events: liver, nonliver, and all‐cause mortality; first hospitalisation for severe liver morbidity (SLM); cardiovascular disease (CVD); respiratory disorders; neoplasms; alcohol‐intoxication; drug intoxication; and violence‐related injury (note: the latter three events were selected a priori to gauge ongoing chaotic lifestyle behaviours). We determined the association between SVR attainment and each outcome event, in terms of the relative hazard reduction and absolute risk reduction (ARR). We tested for an interaction between SVR and liver disease severity (mild vs. nonmild), defining mild disease as an aspartate aminotransferase‐to‐platelet ratio index (APRI) <0.7. Our cohort comprised 3,385 patients (mean age: 41.6 years), followed‐up for a median 5.3 years (interquartile range: 3.3‐8.2). SVR was associated with a reduced risk of liver mortality (adjusted hazard ratio [AHR]: 0.24; P < 0.001), nonliver mortality (AHR, 0.68; P = 0.026), all‐cause mortality (AHR, 0.49; P < 0.001), SLM (AHR, 0.21; P < 0.001), CVD (AHR, 0.70; P = 0.001), alcohol intoxication (AHR, 0.52; P = 0.003), and violence‐related injury (AHR, 0.51; P = 0.002). After 7.5 years, SVR was associated with significant ARRs for liver mortality, all‐cause mortality, SLM, and CVD (each 3.0%‐4.7%). However, we detected a strong interaction, in that ARRs were considerably higher for individuals with nonmild disease than for individuals with mild disease. Conclusions: The conclusions are 3‐fold: (1) Overall, SVR is associated with reduced hazard for a range of hepatic and nonhepatic events; (2) an association between SVR and behavioral events is consistent with SVR patients leading healthier lives; and (3) the short‐term value of SVR is greatest for those with nonmild disease. (Hepatology 2015;62:355–364

A comparison between gastric and oesophageal variceal haemorrhage treated with transjugular intrahepatic portosystemic stent shunt (TIPSS)

Background: Transjugular intrahepatic portosystemic stent‐shunts (TIPSS) are becoming widely used in the management of oesophageal variceal haemorrhage (OVH). Their place in the treatment of gastric variceal haemorrhage (GVH), a condition with a traditionally poor prognosis, remains unclear. The aims of our study were to compare portal haemodynamics and patient outcome in patients undergoing TIPSS for either GVH or OVH.

Acute and chronic haemodynamic and renal effects of carvedilol in patients with cirrhosis

BACKGROUND/AIMS Recent reports have suggested that the vasodilating beta-blocker carvedilol may have beneficial acute haemodynamic effects in cirrhotic portal hypertension. However, no data exist on chronic use or renal effects in this patient group. The aim of this study was to assess the acute and chronic haemodynamic and renal effects of carvedilol in cirrhotic patients. METHODS Seventeen cirrhotic patients (mean age 55.2+/-2.8, mean Child-Pugh score 7.4+/-0.5) were studied. Hepatic venous pressure gradient, cardiac output, systemic vascular resistance, mean arterial pressure, heart rate and hepatic blood flow were measured before and 1 h after 25 mg carvedilol. After 4 weeks of therapy with carvedilol 25 mg daily, these measurements were repeated before and after rechallenge with carvedilol. Urine volume, sodium excretion and creatinine clearance were also measured before and after 4 weeks of therapy. RESULTS Seven patients did not complete the 4-week carvedilol therapy due to hypotension or poor compliance. Hepatic venous pressure gradient fell by 20.8% acutely (p<0.001) and by 16.3% after 4 weeks of therapy (p<0.002). Heart rate, mean arterial pressure and cardiac output fell after acute administration of carvedilol, but only heart rate fell significantly after 4 weeks of treatment. Hepatic blood flow, urine volume, sodium excretion and creatinine clearance remained unchanged after therapy. CONCLUSION Carvedilol has beneficial effects on splanchnic haemodynamics following acute and chronic administration in cirrhosis, without compromising hepatic blood flow or renal function. However, a substantial number of patients cannot tolerate 25 mg daily.