MD Kristina Åhsberg
email: kristina.ahsberg@med.lu.se

Peter Höglund

Christer Staël

Von Holstein

Keywords: Peptic ulcer disease < Disease-based, Stomach and duodenum < Organ-based, Non-variceal bleeding < Topics, NSAIDs < peptic ulcer, bleeding, aspirin, NSAID, mortality, warfarin, comorbidty

Mortality from peptic ulcer bleeding: impact of co-morbidity and use of bleeding promoting drugs.

Hospitalisation rates for peptic ulcer are therefore declining [START_REF] Kang | Recent trends in hospital admissions and mortality rates for peptic ulcer in Scotland 1982-2002[END_REF][START_REF] Lewis | Hospitalization and mortality rates from peptic ulcer disease and GI bleeding in the 1990s: Relationship to sales of Nonsteroidal Anti-Inflammatory Drugs and acid suppression medications[END_REF][START_REF] Post | Declining incidence of peptic ulcer but not of its complications: a nation-wide study in The Netherlands[END_REF] . During the same period, the prescriptions of low dose aspirin, other non-steroidal anti-inflammatory drugs (NSAIDs), oral anticoagulants (warfarin) as well as selective serotonin reuptake inhibitors (SSRIs) have increased several fold, especially among the elderly 4 . These drugs interfere with the defence mechanisms of the gastric mucosa and/or influence the haemostasis leading to an increased risk of developing upper gastrointestinal (GI) bleeding [START_REF] De Abajo | Association between selective serotonin reuptake inhibitors and upper gastrointestinal bleeding: population based casecontrol study[END_REF][START_REF] James | Assessment of non-steroidal anti-inflammatory drug (NSAID) damage in the human gastrointestinal tract[END_REF][START_REF] Nielsen | Risk of hospitalization resulting from upper gastrointestinal bleeding among patients taking corticosteroids: a register-based cohort study[END_REF] , of which peptic ulcer bleeding (PUB) constitutes around 50 per cent [START_REF] Laine | Bleeding peptic ulcer[END_REF][START_REF] Van Leerdam | Epidemiology of acute upper gastrointestinal bleeding[END_REF] . Fortunately however, so far, the outcome of PUB has not been shown to be negatively influenced by these drugs [START_REF] Blatchford | Acute upper gastrointestinal haemorrhage in west of Scotland: case ascertainment study[END_REF][START_REF] Mose | Thirty-day mortality after peptic ulcer bleeding in hospitalized patients receiving low-dose aspirin at time of admission[END_REF][START_REF] Van Leerdam | Acute upper GI bleeding: did anything change? Time trend analysis of incidence and outcome of acute upper GI bleeding between 1993/1994 and 2000[END_REF] .

The aim of this study was to make a detailed time-trend evaluation of all patients hospitalised for PUB during three distinct time periods, 1984, 1994 and 2004 at the Department of Surgery, Lund University Hospital, Sweden. Special attention was made towards the impact of age, gender, co-morbidity and use of drugs promoting PUB on outcome.

Methods

A retrospective review was done of the medical records for all (in total 766) hospitalisations with a discharge diagnosis of gastrointestinal bleeding according to the International Classification of Diseases, the 8 th , 9 th and 10 th Revisions during three distinct time periods : 1984, 1994 Lund University Hospital in Sweden. Two records were missing. Twenty-two cases were excluded as non bleeders. Additionally 193 hospitalisations for unspecified peptic ulcer were evaluated as a Swedish national validation study has shown a diagnostic misclassification of PUB in 34-50 % of unspecified ulcer cases [START_REF] Åhsberg | Hospitalisation of and mortality from bleeding ulcer in Sweden. A nation-wide time-trend analysis[END_REF] . Seven of 63 (11.1 per cent) in 1984, four of 41 (9.8 per cent) in 1994 and 24 of 89 (27 per cent) in 2004 were found to be misclassified bleeding ulcers and consequently added to the PUB group.

In this study we wanted to evaluate only PUB patients. Only patients who had signs of GI bleeding and a verified peptic ulcer considered to be the bleeding source were eligible. Hospitalisations with incorrect diagnoses were transferred to the correct diagnostic group. Only the index hospitalisation was included if a patient had recurrent hospitalisations for PUB during the same year. Thus 94 hospitalisations/patients for PUB from 1984, 65 from 1994 and 93 from 2004 were included in the study. Hospitalisations of all other causes of GI bleeding during these years are presented in another paper.

Recorded data for every patient included age, gender, history of previous ulcer or GI bleed, co-morbidity, drug use, clinical signs of bleeding, haemodynamic instability and serum haemoglobin level at admission, in hospital pharmacological treatment, endoscopic therapy, surgery and in hospital mortality.

Haemodynamic instability was defined as syncope or a systolic blood pressure ≤100 mmHg. Acid reducing therapy in forms of H2RA and PPIs were analysed together.

Co-morbidity was analysed as follows; cardiovascular disease included conditions like cardiac arrhythmia, ischemic heart disease, chronic heart failure, hypertension but also previous history of cerebrovascular insult and cardiac infarction. Pulmonary and acute (e.g. pneumonia) conditions. Kidney failure included both mild forms (e.g. having an abnormal serum creatinine value) and severe forms (e.g. regular need of dialysis). Liver failure included both mild forms (e.g. having an abnormal serum bilirubin value) and severe forms (e.g. end-stage liver failure). For malignant disease only diagnosis within one year or end-stage malignancy was included.

Lund University Hospital provides highly specialised health care for rare conditions in the population in the Southern part of Sweden but for common emergency conditions like GI bleeding it serves the population in a defined catchment area in the mid-west of Skane county. The population in the catchment area grew from 151 711 in 1984, to 170 727 in 1994 and 289 560 in 2004.

Statistical analysis

Incidence and mortality rates per 100 000 inhabitants were calculated by Poisson regression with 95 per cent confidence intervals (CI) and Tukey corrected p-values for multiple comparisons. In univariate analyses Kruskal-Wallis or Wilcoxon tests were used for continuous variables and Fisher's exact test for categorical variables.

Logistic regression models were used in the multivariable analyses. The level of significance was set at p<0.05. Data were analysed using the Hmisc and Design packages of the R software (R Foundation for Statistical Computing, Vienna, Austria), version 2.6.2.

The study was approved by Lund University Research Ethics Committee.

Results

The hospitalisation rate of peptic ulcer bleeding decreased from 62.0 (CI 50. 3 -75.3) almost 60 per cent were on aspirin and 17 per cent were on warfarin in 2004. The use of other NSAIDs was stable at around 10 per cent. In 2004, 75 per cent of patients were prescribed at least one and 15 per cent two or more drugs enhancing the risk of ulcer bleed -aspirin, warfarin, non-aspirin NSAIDs, steroids or SSRIs.

(Further on these drugs will be referred to as "risk drugs"). The rate of patients with haemodynamic instability was stable but median serum haemoglobin level decreased between the years. Clinical presentation in form of haematemesis or blood in Data by ulcer location in 2004 is shown in table 3. History of previous ulcer or GI bleed and endoscopic interventions were more common among duodenal ulcer patients whereas use of any "risk drug" was related to gastric ulcer disease.

Table 4 shows data for PUB patients by mortality. Patients who died during hospitalisation were older, had more co-morbidities (mean number of co-morbidities (+/-SD) was 2.15 (+/-0.90) compared with 0.94 (+/-0.83)) and had lower serum haemoglobin levels at presentation in comparison with those who were alive at discharge. Use of "risk drugs" at presentation did not negatively influence the fatality rate although they can be seen as surrogate markers of co-morbidities. Patients who died had a higher rate of haematemesis at presentation compared with those who were alive at discharge, 11/13 (85 per cent) and127/239 (53 per cent) respectively (p=0.042). Melena were equally frequent.

In the multivariable logistic regression model shown in table 5, age above 65 years, number of co-morbidities and haemodynamic instability were independent risk factors for in hospital mortality whereas the use of aspirin at start of bleed decreased the risk of mortality significantly.

Discussion

Hospitalisations for PUB per 100 000 inhabitants decreased significantly in this study between 1984 and 1994. A decrease in bleeding ulcer during the same period is found also by others [START_REF] Kang | Recent trends in hospital admissions and mortality rates for peptic ulcer in Scotland 1982-2002[END_REF][START_REF] Hermansson | Decreasing incidence of peptic ulcer complications after the introduction of the proton pump inhibitors, a study of the Swedish population from 1974-2002[END_REF] , although not agreed on by all [START_REF] Higham | Recent trends in admissions and mortality due to peptic ulcer in England: increasing frequency of haemorrhage among older subjects[END_REF][START_REF] Paimela | Current features of peptic ulcer disease in Finland: incidence of surgery, hospital admissions and mortality for the disease during the past twenty-five years[END_REF] , and is probably due to a cohort phenomenon with decreasing prevalence of H. pylori in the population. This effect was probably enhanced by the introduction of PPIs in the late 1980's and the spreading knowledge of eradication therapies against H. pylori. The hospitalisation rate per 100 000 inhabitants in our study was unchanged between 1994 and 2004 and the same was found in Danish and Dutch studies from the same time period [START_REF] Van Leerdam | Acute upper GI bleeding: did anything change? Time trend analysis of incidence and outcome of acute upper GI bleeding between 1993/1994 and 2000[END_REF][START_REF] Lassen | Complicated and uncomplicated peptic ulcers in a Danish county 1993-2002: a population-based cohort study[END_REF] . A potential further decrease was perhaps counterbalanced by the increasing prescription rate of low dose aspirin, other antiplatelet agents and warfarin seen during this period [START_REF] Silwer | Patterns of drug use during a 15 year period: data from a Swedish county, 1988--2002[END_REF] .

In this time trend analysis of PUB over twenty years in Lund, the patients got older and the rate of cardiovascular co-morbidity increased. Consequently the use of aspirin and warfarin increased, both as single drugs and in combination. Four of six patients with concurrent low dose aspirin and warfarin use, also had another antiplatelet agent (clopidogrel) added. The prescriptions of these drugs have naturally increased also in the aging back-ground population during this period [START_REF] Silwer | Patterns of drug use during a 15 year period: data from a Swedish county, 1988--2002[END_REF] .

However, in comparison with the sales statistics from the Swedish Pharmacy 18 the use of low dose aspirin in our study was around three times higher in age-groups 45 to 74 years and 50 per cent higher in the age-group 75 to 84 years among PUB study patients in 2004. Warfarin use was not higher in age-groups between 45 and 75 years but was five times higher in the age-groups over 75 years among study patients. The use of NSAIDs was higher only in the age-group above 85 years while the use of SSRIs was lower and the use of corticosteroids was the same in study patients in comparison with the back-ground population. Aspirin and warfarin are shown in other studies to cause a 2-fold increase as single drugs [START_REF] Hallas | Use of single and combined antithrombotic therapy and risk of serious upper gastrointestinal bleeding: population based case-control study[END_REF][START_REF] Laine | Review article: gastrointestinal bleeding with low-dose aspirin -what's the risk?[END_REF][START_REF] Weil | Prophylactic aspirin and risk of peptic ulcer bleeding[END_REF] and a 5-fold increase in combination [START_REF] Hallas | Use of single and combined antithrombotic therapy and risk of serious upper gastrointestinal bleeding: population based case-control study[END_REF] , in the risk for PUB.

However, aspirin, non-aspirin NSAIDs and warfarin did not increase the risk of fatal outcome in this study, which is similar to findings reported by others 10-12, 22, 23 , though in contrast with two studies [START_REF] Thomsen | Outcome of peptic ulcer bleeding among users of traditional non-steroidal anti-inflammatory drugs and selective cyclo-oxygenase-2 inhibitors[END_REF][START_REF] Lanas | A nationwide study of mortality associated with hospital admission due to severe gastrointestinal events and those associated with nonsteroidal antiinflammatory drug use[END_REF] . Aspirin use at admission was in our study even [START_REF] Sung | Continuation of low-dose aspirin therapy in peptic ulcer bleeding: a randomized trial[END_REF] where patients after endoscopic haemostasis of a PUB were given low dose aspirin or placebo for 8 weeks. Aspirin recipients had a higher risk of rebleeding but lower mortality, although some deaths in the placebo group were from causes not normally prevented by aspirin. The international consensus recommendations have recently also concluded that patients with upper GI bleeding who require secondary cardiovascular prophylaxis should resume the low-dose aspirin therapy as soon as the cardiovascular risks outweigh the gastrointestinal risks [START_REF] Barkun | International consensus recommendations on the management of patients with nonvariceal upper gastrointestinal bleeding[END_REF] .

The usual regimen in our department, when an aspirin or warfarin recipient is admitted for gastrointestinal haemorrhage, is to discontinue the therapy as long as there is a high risk of rebleeding. The anticoagulative effect of warfarin can be reversed by vitamin K but the antithrombotic effect of aspirin is prolonged for several days after discontinuation, which could have influenced the case fatality rate among aspirin users in our study. We separated aspirin from non-aspirin NSAIDs in our analyses as there is a difference between the drugs in pharmacokinetics and pharmacodynamics. Both drugs impair the capacity of platelets to aggregate by blocking cox-1, but the effect of non-aspirin NSAIDs is reversible while the effect of aspirin is irreversible and consequently persists during the whole life-span of platelets 20, 28 . The separate analyses in our study might explain the difference between our results and others, who did not separate aspirin from other NSAIDs [START_REF] Blatchford | Acute upper gastrointestinal haemorrhage in west of Scotland: case ascertainment study[END_REF][START_REF] Van Leerdam | Acute upper GI bleeding: did anything change? Time trend analysis of incidence and outcome of acute upper GI bleeding between 1993/1994 and 2000[END_REF][START_REF] Rockall | Risk assessment after acute upper gastrointestinal haemorrhage[END_REF] .

Desmopressin counteracts the antiplatelet effect of aspirin and NSAIDs on haemostasis and was given to 7 patients in 2004. All patients were low dose aspirin recipients and two of them were also taking clopidogrel. One of the patients died. . This is reflected in our study, as in others [START_REF] Blatchford | Acute upper gastrointestinal haemorrhage in west of Scotland: case ascertainment study[END_REF][START_REF] Rockall | Incidence and mortality from acute upper gastrointestinal haemorrhage in the United Kingdom. Steering committee and members of the National Audit of Acute Upper Gastrointestinal Haemorrhage[END_REF] , by a higher mortality among patients who start to bleed while hospitalised for another reason than among patients who start to bleed at home. It may also partly explain why the case fatality rate in our study was unchanged between 1984 and 2004. The effect of improved therapy against bleeding with intravenous pharmacological treatment and more frequent haemostatic endoscopic procedures were probably outweighed by the fact that patients were older with more co-morbidities.

In our study, patients with a history of previous ulcer or GI bleed were taking significantly less aspirin and other "risk drugs" although they were equally co-morbid. Doctors had prescribed acid reducing therapy to a higher extent (23 per cent) to those with, compared to those without (5 per cent), previous ulcer or GI bleed.

According to the recent international consensus recommendations [START_REF] Barkun | International consensus recommendations on the management of patients with nonvariceal upper gastrointestinal bleeding[END_REF] , patients with indications for secondary cardiovascular profylaxis with aspirin or warfarin should receive these drugs, as the risk to die of cardiovascular events exceeds the risk to die of PUB. To increase gastrointestinal safety an increase in prophylactic prescription of PPIs to risk groups and eradication therapies against H. pylori in the presence of infection is recommended [START_REF] Lanas | Prevention of anti-inflammatory drug-induced gastrointestinal damage: benefits and risks of therapeutic strategies[END_REF] .

The strength of this study is the thorough evaluation of the medical records and validation of diagnoses. Every record of a gastrointestinal bleeding diagnosis and a diagnosis of unspecified ulcer during 1984, 1994 and 2004 at Department of Surgery was evaluated giving us a complete data set. All the same the number of patients and hospitalisations is small, and this is of course the main weakness of the study.

We analysed in-hospital mortality as we wanted to evaluate outcome undoubtedly related to the bleeding episode. A longer follow-up of for instance 30 days is also interesting but then alternative causes of death also have to be considered.

In the multivariable model we have adjusted for factors that we believe increase the risk of fatal outcome. Patient characteristics in forms of gender, age, number of comorbidities, drug use, ulcer location and previous history of ulcer or GI bleed were considered important. The severity of the bleeding was adjusted for in form of presence of haemodynamic instability. We have tried to control for some changes in management and standard of care of peptic ulcer bleeding patients that have occurred during these 20 years by adjusting for year 1994 and 2004 with 1984 as reference.

In conclusion we found that PUB incidence decreased despite higher prescription rates of aspirin, warfarin and other drugs enhancing the risk of PUB between the three study periods 1984, 1994 and 2004. This is probably due to a decreasing prevalence of H. pylori in the population and an increasing awareness among doctors of the benefits of H. pylori eradication and concurrent use of PPIs to increase GI safety. In-hospital mortality was unchanged between years. The effect of improved emergency therapy against PUB is to some degree probably outweighed by the fact that patients have become older with more co-morbidities. Aspirin use on admission was however found to reduce the risk of fatal outcome. This finding warrants further investigations. Abbreviations: GI=gastrointestinal, NSAIDs=non-steroidal anti-inflammatory drugs, SSRIs=selective serotonin re-uptake inhibitors, PUB=peptic ulcer bleeding, H2RA=histamin-2 receptor antagonists, PPIs=proton pump inhibitors

F o r P e e r R e v i e w

Introduction

  During several decades we have seen a steady decreasing prevalence of Helicobacter pylori (H. pylori) infection in the Swedish population, and the introduction of effective antisecretory drugs together with eradication therapies against H. pylori, have dramatically improved the possibilities to treat peptic ulcer.

  and 2004 at the Department of Surgery (and the Department of Emergency conditions due to re-organisation) at

  chronic (e.g. bronchitis or chronic obstructive lung disease)

  nasogastric tube (around 55 per cent of patients) and melena (around 75 per cent of patients) did not change between years Co-morbidity was equally frequent among patients with and without a history of previous ulcer or GI bleed [any co-morbidity 57/84 (68 per cent) and 115/168 (68 per cent)], cardiovascular disease 44/84 [(52 per cent) and 102/168 (61 per cent) (p=0.22)] but the use of aspirin was less frequent [20/84 (24 per cent) and 66/168 (40 per cent) (p=0.016)] and the use of H2RA or PPI was more frequent [19/84 (23 per 8/168 (5 per cent) (p<0.001)] among patients with, compared with those without, a history of previous ulcer or GI bleed.Therapy and outcomeData of in hospital treatment, discharge status and mortality rates are found in table2. Intravenous pharmacological treatment with H2RAs/PPIs, tranexamic acid and desmopressin (not available in 1984) increased significantly from 1984 to 2004. The few patients not subjected to upper GI endoscopy went immediately to surgery (3 patients 1984 and 3 patients in 1994) or had been hospitalised and diagnosed with an ulcer very recently. One ulcer was diagnosed by autopsy. Data of Forrest classification was not reliable in this retrospective study. The indication for endoscopic intervention nowadays at our department is a bleeding ulcer with Forrest grade 1 or 2. In 1984, no endoscopic intervention was performed, but the frequency of endoscopic intervention increased from 8 to 45 per cent among all PUB patients from 1994 to 2004. The frequency of a second endoscopy and endoscopic intervention also increased between years whereas surgery became less frequent. In 1984 three gastric resections and five local procedures (gastro/duodenotomy and suture ligation) were performed. In six of the eight patients a vagotomy was added. In 1994 one gastric resection and six local procedures were performed and in two of the seven operations a vagotomy was added. In 2004 only one surgical intervention (local procedure) was performed. Prescriptions at discharge of H2RA or PPI and eradication therapy against H. pylori increased. Case fatality rate ranged between 4 and 8 per cent (not significant). Patients who started to bleed while they were hospitalised for another reason had a higher mortality (13, 17, 14 per cent) compared with those who started to bleed at home (2, 4, 4 per cent) (p=0.004). Around 15 per were transferred to another department at discharge and 85 per cent could be sent home. These figures did not change between years.

  the risk of in-hospital mortality, which is in line with the results of a recently published randomised trial

11 Causes

 11 of mortality after PUB are shown to more often be related to cardiac or multiorgan failure in these old and co-morbid patients rather than the bleeding itself29, 30

  Abbreviations: GU=gastric ulcer, DU=duodenal ulcer, GI=gastrointestinal, NSAIDs=non-steroidal anti-inflammatory drugs, SSRIs=selective serotonin re-uptake inhibitors, PUB=peptic ulcer bleeding, H2RA=histamin-2 receptor antagonists, PPIs=proton pump inhibitors

Table 1 .

 1 Bleeding ulcer patient characteristics 1984, 1994 and 2004.

	1984 n=94	1994 n=65	2004 n=93	p values

Table 2 .

 2 Time trend analysis of in hospital treatment and outcome for patients hospitalised for bleeding ulcer 1984, 1994 and 2004.Tests used: Fisher's exact test[START_REF] Kang | Recent trends in hospital admissions and mortality rates for peptic ulcer in Scotland 1982-2002[END_REF] and Kruskal-Wallis test 2 for differences between years.

	1984	1994	2004
	n=94	n=65	n=93	p values

Table 3 .

 3 Bleeding ulcer patients in 2004 by ulcer locationTests used: Fisher's exact test 1 Wilcoxon test 2 .

	Gastric ulcer	Duodenal ulcer
	n=41	n=51	p-value

Table 4 .

 4 All bleeding ulcer patients from1984, 1994, 2004 by in-hospital mortalityTests used: Fisher's exact test[START_REF] Kang | Recent trends in hospital admissions and mortality rates for peptic ulcer in Scotland 1982-2002[END_REF] and Kruskal-Wallis test 2 # (with upper and lower quartile) * syncope or systolic blood pressure <100 mmHg Abbreviations: GU=gastric ulcer, DU=duodenal ulcer, GI=gastrointestinal, NSAIDs=non-steroidal anti-inflammatory drugs,

	Alive at discharge	Deceased in hospital
	n=239	n=13	p-value

Table 5 .

 5 Association between variables and in-hospital mortality after bleeding ulcer

	Factor

Acknowledgements

We want to acknowledge the Bengt Ihre Foundation and the Erik and Angelica Sparre Foundation for financial support.


Dr Lori A Button

Dr Stephen E Roberts

Adrian Evans

Prof Michael J Goldacre

Ashley Akbari

Steven Macey

Prof John G Williams

Rohan Dsilva

Ashley Mr

Akbari

Mr Rohan Dsilva

Steven Mr

Macey

A record linkage study

Keywords: Non-variceal bleeding < Topics, Varices < upper gastrointestinal bleeding, hospitalised incidence, case fatality, day of admission

Hospitalised incidence and case fatality for upper gastrointestinal bleeding from 1999 to 2007

Introduction

Upper gastrointestinal (GI) bleeding is the most common emergency managed by gastroenterologists with approximately 25 000 inpatient admissions annually in the UK. [START_REF] Palmer | Haematemesis and melaena[END_REF] Upper GI bleeding occurs largely among people in older age groups, and has a higher incidence in males than in females. [2][START_REF] Holman | Value of a centralised approach in the management of haematemesis and melaena: experience in a district general hospital[END_REF][START_REF] Blatchford | Acute upper gastrointestinal haemorrhage in west of Scotland: case ascertainment study[END_REF] Upper GI bleeding in the UK and in Europe has been caused most frequently by peptic ulcer -particularly duodenal ulcer -followed by other aetiologies including varices, gastritis/erosions, oesophagitis, Mallory-Weiss tear, upper GI malignancies, duodenitis, gastric antral vascular ectasia and portal hypertension. [START_REF] Vreeburg | Acute upper gastrointestinal bleeding in the Amsterdam area: incidence, diagnosis and clinical outcome[END_REF][START_REF] Williams | Gastroenterology services in the UK. The burden of disease, and the organisation and delivery of services for gastrointestinal and liver disorders: a review of the evidence[END_REF][START_REF] Hearnshaw | Use of endoscopy for management of acute upper gastrointestinal bleeding in the UK: results of a nationwide audit[END_REF] Many upper GI bleeds are caused by long term use of non-steroidal anti-inflammatory drugs, especially among older people, although patterns of prescribing have changed over time. [START_REF] Thompson | Long-term NSAID use in primary care: changes over a decade and NICE risk factors for gastrointestinal adverse events[END_REF] Other upper GI bleeding aetiologies are linked to alcohol consumption -such as oesophageal varices, Mallory-Weiss tear and oesophageal malignancies -which are increasing over time in some regions. [START_REF] Williams | Gastroenterology services in the UK. The burden of disease, and the organisation and delivery of services for gastrointestinal and liver disorders: a review of the evidence[END_REF][START_REF] Fleming | Incidence and prevalence of cirrhosis in the United Kingdom, 1992-2001: a general population-based study[END_REF] With an ageing population, and with sharp increases in alcohol consumption in the UK in the last 50 years, [START_REF] Johnson | National statistics for diet, alcohol consumption, and chronic pancreatitis in England and Wales, 1960-88[END_REF][START_REF] Pincock | Binge drinking on rise in UK and elsewhere. Government report shows increases in alcohol consumption, cirrhosis, and premature deaths[END_REF] upper GI bleeding is an important disorder.

The incidence of upper GI bleeding varies across the UK, with highest incidence reported in Scotland, [START_REF] Blatchford | Acute upper gastrointestinal haemorrhage in west of Scotland: case ascertainment study[END_REF][START_REF] Masson | Upper gastrointestinal bleeding in an open-access dedicated unit[END_REF][START_REF] Johnston | Epidemiology and course of gastrointestinal haemorrhage in North-east Scotland[END_REF] compared with lower rates often reported in southern England. 2,[START_REF] Holman | Value of a centralised approach in the management of haematemesis and melaena: experience in a district general hospital[END_REF][START_REF] Rockall | Incidence of and mortality from acute upper gastrointestinal haemorrhage in the United Kingdom[END_REF][START_REF] Berry | Upper gastrointestinal haemorrhage in Oxford. A prospective study[END_REF] Upper GI bleeding has been associated with high levels of social deprivation in one study of the west of Scotland, [START_REF] Blatchford | Acute upper gastrointestinal haemorrhage in west of Scotland: case ascertainment study[END_REF] although little else has been reported on the relationship between upper GI bleeding and social inequality, particularly on a national scale. Local studies indicate that as the incidence of upper GI bleeding has increased over time, there has been little recent improvement in case fatality, which remains at about 10%. [START_REF] Williams | Gastroenterology services in the UK. The burden of disease, and the organisation and delivery of services for gastrointestinal and liver disorders: a review of the evidence[END_REF][START_REF] Hearnshaw | Use of endoscopy for management of acute upper gastrointestinal bleeding in the UK: results of a nationwide audit[END_REF] There is also current interest in whether prognosis for emergency disorders varies according to the day of admission, [START_REF] Ananthakrishnan | Outcomes of weekend admissions for upper gastrointestinal hemorrhage: a nationwide analysis[END_REF][START_REF] Shaheen | Weekend versus weekday admission and mortality from gastrointestinal hemorrhage caused by peptic ulcer disease[END_REF] the size of hospital, [START_REF] Coyne | Hospital cost and efficiency: do hospital size and ownership type really matter?[END_REF] and the distance travelled to hospital, [START_REF] Nicholl | The relationship between distance to hospital and patient mortality in emergencies: an observational study[END_REF] although little has been reported about these for upper GI bleeding.

The main objectives of this study were to establish the incidence of hospital admissions for upper GI bleeding in Wales and case fatality at 30 days following admission, and to Further objectives were to assess trends over time in incidence and case fatality, and whether they are associated with factors including social deprivation, distance from hospital and hospital size.

Our main study hypotheses are that the incidence of upper GI bleed is associated strongly with social deprivation and that case fatality is increased for people who are admitted on weekends and public holidays -rather than on weekdays -and may be lower for people admitted to 'medium' size rather than to small or large hospitals. Administrative Registrar, [START_REF]NHS Administrative Register[END_REF] and has been used as the basis of previous published studies. [START_REF] Lyons | Socioeconomic variation in injury in children and older people: a population based study[END_REF][START_REF] Polinder | International variation in clinical injury incidence: exploring the performance of indicators based on health care, anatomical and outcome criteria[END_REF][START_REF] Lyons | Using multiple datasets to understand trends in serious road traffic casualties[END_REF][START_REF] Button | Hospitalised prevalence and 5 year mortality for IBD: record linkage study[END_REF] The systematic record linkage of inpatient and mortality data enables all repeat hospital admissions to be identified for the same patients, and deaths following discharge from hospital to be included with in-hospital deaths.

We included adult patients who were admitted as an emergency for upper GI bleeding (where upper GI bleeding was recorded as the principal diagnosis on the first episode during the admission). Some upper GI bleeds occur as 'inpatient bleeds' following an admission for another disorder, for surgery or for maternity care. We therefore also included emergency, elective and maternity admissions for all other causes (when recorded as the principal diagnosis on the first episode) but where upper GI bleeding occurred subsequently (when recorded as the principal diagnosis of a subsequent episode during the admission).

The International Classification of Diseases, 10th edition (ICD-10) codes used for upper GI bleeding categories are listed in the Appendix.

We included each person's first admission for upper GI bleeding after the start of the study period in April 1 st 1999. Subsequent hospitalisations for upper GI bleeding in each patient were also included up to the study end in March 31 st 2007, providing they occurred more than 30 days after the preceding admission. We investigated the aetiology/diagnoses for the upper GI bleeds using diagnoses recorded in any of the diagnostic fields during the admission.

Social deprivation scores were assigned anonymously using residential postcodes at the Lower Super Output Areas (LSOA; average population size of each LSOA = ~1500) using the Welsh Index of Multiple Deprivation (WIMD) 2005. [START_REF]Welsh Index of Multiple Deprivation (WIMD)[END_REF] The WIMD 2005 is based on seven by size based on the number of beds; as small (less than 400 beds), medium (400-599) and large (600+). We compared case fatality for those who were admitted on weekdays (Monday to Friday), weekends (Saturdays and Sundays) and public holidays. We also investigated whether diagnostic endoscopy of the upper gastrointestinal tract had been performed (using the OPCS-4 surgical procedure code G45, when recorded in any procedure field).

Hospitalised incidence rates for upper GI bleeding were calculated using the numbers of hospitalised cases as the numerators and the Welsh adult residential populations as the denominators, expressed per 100 000 population. To standardise incidence rates, we used the direct method and the total Welsh population during the study period as the standard.

Case fatality at 30 day follow up was calculated using the numbers of deaths (from all causes) as the numerators and the numbers of hospitalised cases as the denominators, and were expressed as percentages. To standardise case fatality, we used the direct method and the total population of people admitted with upper GI bleeding. When investigating case fatality, we adjusted for major co-morbidities (circulatory diseases, all malignancies except upper GI, liver disease, COPD, diabetes and renal failure) that were recorded in any of the other diagnostic fields during the admission (see notes to Table 3 for ICD-10 codes).

Urban/rural residences were measured using five categories, based on 'settlement sizes' of <2500, 2500-9999 up to 100 000 people. [START_REF]A statistical focus on rural Wales: 2008 Edition. Statistics for Wales[END_REF] Distances from patients' residences to the hospital of admission were calculated using ArcGIS Geographical Information System (GIS) software and were measured in five categories from <3 kilometres (km), 3-9.99

Incidence of upper GI bleeding

The overall hospitalised incidence rate of upper GI bleeding was 134 per 100 000 population (Table 1). Incidence was significantly higher in men (153 per 100 000) than in women (117) and it increased sharply with age (Table 1) with highest incidence in the oldest age group (85+ years) for both men (864 per 100 000 population) and women (739). Table 2 and Figure 1 show large geographical variation in the incidence of upper GI bleeding across Wales. Incidence was by far the highest in the local authority with the highest social deprivation, Merthyr Tydfil (268 per 100 000) followed by other local authorities with high levels of deprivation (Table 2). Figure 2a shows a significant association between the incidence of upper GI bleeding and social deprivation. Incidence was 2.0 times higher (95% CI = 1.9-2.1) in the most deprived quintile V (189 per 100 000 population) than in the least deprived quintile I (94).

Diagnostic endoscopy of the upper GI tract

Diagnostic endoscopy was recorded in 10 594 (43.4%) of the 24 421 admissions. Recorded endoscopy varied from 31.7% to 60.5% across hospitals and was higher (p<0.001) in small (51.5%) than in medium (41.9%) or large (40.6%) hospitals. 1733 (16.4%) of the patients were scoped on the day of admission, 3321 (31.3%) on the following day, 1452 (13.7%) on the second day and 4078 (38.5%) after 3+ days. Recorded endoscopy was significantly lower (p<0.001) for admissions on Fridays (37.1%) and Saturdays (38.8%) than on other days (which varied between 44.3% for Sundays to 47.8% for Tuesdays). Rates of endoscopy on the day of admission were lower (p<0.001) for admissions on Saturdays (8.5%) and Sundays (7.4%) than on weekdays (17.5% to 20.9%). The median time to endoscopy was higher (p<0.001) for admissions on Fridays and Saturdays (both 3 days) and on Sundays (2 days) than for other days of the week (one day).

Case fatality at 30 days following hospital admission

There were 2452 deaths at 30 days, with overall case fatality of 10.0%. Age-specific case fatality increased sharply from <1% among people aged 18-34 years to 21% for people aged 85+ years (Table 3). Overall, age adjusted case fatality was significantly lower among females than among males (odds ratio = 0.89; 95% CI = 0.81-0.97), while age-specific case fatality was higher among males than among females in most age groups.

There was large variation in case fatality across local authorities, ranging from 7.7% to 13.7% (Table 2). Local authorities with lowest case fatality often had the highest incidence.

Although case fatality was slightly higher in the most deprived quintiles (IV and V both = 10.5%) than in the most affluent (I = 9.6% and II = 9.4%) this was not significant (Figure 2b).

Age and sex adjusted mortality for weekend admissions was 13% higher than for weekdays (odds ratio = 1.13; 95% CI = 1.02-1.25) while mortality for admissions on public holidays was 41% higher (odds ratio = 1.41; 1.04-1.91; Table 3). After adjusting also for major comorbidities, the increased mortality for weekend and public holiday admissions was largely unaffected (odds ratio = 1.11; 1.00-1.23 and 1.42; 1.05-1.92 respectively). The hospital admission rate was lower on weekends and public holidays (109 and 113 per 100 000 respectively) than during the week (145 per 100 000; Table 3). However, people admitted on weekends and public holidays were slightly but significantly younger (63.4 vs 64.4 years; p=0.020), were discharged slightly sooner (overall median length of stay = 4 days for both; but p=0.022) and had similar levels of co-morbidities recorded compared with patients who were admitted during the week (see notes to Table 3).

Case fatality was slightly lower in medium size hospitals (9.3%) than in small or large hospitals (11.1% and 10.8%) but after adjusting for age and sex, these differences were not significant (Table 3). Patients resident in the most urban locations had slightly higher mortality than those in the most rural locations (odds ratio = 1.14; 95% CI = 1.00-1.31), although after adjusting for social deprivation, this risk was not significant (1.06; 0.91-1.23).

There was little variation in case fatality according to distance from hospital (Table 3).

Case fatality varied strongly according to aetiology/diagnoses, with significantly increased age and sex adjusted mortality for upper GI malignancies, varices and duodenal ulcer, and significantly reduced mortality for Mallory Weiss tear, oesophagitis, gastritis & duodenitis, gastric ulcer, other specific diseases of the stomach & duodenum (including gastric antral vascular ectasia) and complications of analgesics, antipyretics and anti-inflammatory drugs (Table 3). Of the major co-morbidities, age and sex adjusted mortality was significantly increased for liver disease (odds ratio = 4.90), renal failure (3.75), non-upper GI malignancies (3.64), circulatory diseases (1.73) and COPD (1.55), but not for diabetes (1.12; Table 3).

Over the study period, out of hours endoscopy services was provided in three study hospitals, which had overall case fatality of 12.2%, 7.7% and 9.2% respectively. Age and sex adjusted case fatality for admissions on weekends and public holidays for these three hospitals was similar to that for all other hospitals (odds ratio=0.98; 95% CI=0.80-1.21; p=0.88). Corresponding mortality for weekday admissions was similar (0.91; 0.82-1.03; p=0.12).

Discussion

We found a very strong association between the incidence of upper GI bleeding and social deprivation, with highest incidence among the most deprived groups. Mortality was increased among people who were admitted on weekends and public holidays compared with those admitted during the week. We also found a stable incidence of upper GI bleeding from 1999 to 2007, but a significant reduction over time in mortality.

A major strength of this study is that it is one of the largest investigations of upper GI bleeding, covering more than 24 000 cases in a defined population. It investigated the influence of several factors on upper GI bleed mortality, including week day of admission, size of hospital, distance from hospital and social deprivation. Little has been reported on these factors -particularly on a large scale -so that our findings are quite novel. The study is more than three times larger than the recent national audit of upper GI bleeding across the UK, [START_REF] Hearnshaw | Use of endoscopy for management of acute upper gastrointestinal bleeding in the UK: results of a nationwide audit[END_REF] and six times larger than the major audit in the south east of England and the Midlands during the mid 1990s. [START_REF] Rockall | Incidence of and mortality from acute upper gastrointestinal haemorrhage in the United Kingdom[END_REF] Importantly, our study is based on systematic record linkage of abstracts from inpatient records and death certificates, which enables deaths that occur following discharge from hospital to be included with deaths in hospital.

There are several limitations of this study. Firstly, it was restricted to NHS hospitals. However, the private sector is small in Wales and rarely receives acutely ill patients, which would have minimal effect on the study findings. As upper GI bleeding is frequently a symptom of various aetiologies, rather than a defined disorder, it was necessary to use a series of ICD codes. It is possible that we may have missed some upper GI bleeds through the limitations of hospital and ICD coding, and may have included some lower GI bleeds. However, our high incidence of 134 per 100 000 adult population and case fatality of 10% (as expected from the literature) suggests that these discrepancies are small. Our study lacked information on the aetiology/diagnoses for some bleeds, although this can also be quite common in clinical audits and case series. Our administrative inpatient data also lacked detailed information about disease history, pathology, severity of bleeding and treatment, and the recording of diagnostic endoscopy and major co-morbidities was also incomplete. Our hospitalised incidence of upper GI bleeding (134 per 100 000) is higher than incidence rates previously reported in most regional or local studies across the UK, although lower than in the west of Scotland study (172 per 100 000). [START_REF] Blatchford | Acute upper gastrointestinal haemorrhage in west of Scotland: case ascertainment study[END_REF] Lower rates of about 50 to 120 per 100 000 have been reported more typically in the UK, 2,[START_REF] Holman | Value of a centralised approach in the management of haematemesis and melaena: experience in a district general hospital[END_REF][START_REF] Masson | Upper gastrointestinal bleeding in an open-access dedicated unit[END_REF][START_REF] Rockall | Incidence of and mortality from acute upper gastrointestinal haemorrhage in the United Kingdom[END_REF][START_REF] Berry | Upper gastrointestinal haemorrhage in Oxford. A prospective study[END_REF][START_REF] Madden | Management of upper gastrointestinal bleeding in a district general hospital[END_REF] and across Europe, [START_REF] Longstreth | Epidemiology of hospitalization for acute upper gastrointestinal haemorrhage: a population-based study[END_REF][START_REF] Van Leerdam | Acute upper GI bleeding: did anything change? Time trend analysis of incidence and outcome of acute upper GI bleeding between 1993/1994 and 2000[END_REF] during the last 30 years. Factors which may have contributed to our high incidence of upper GI bleeding include high levels of social deprivation and alcohol consumption in some areas of Wales, [START_REF]Alcohol and health in Wales: a major public health issue[END_REF] our criteria of including adults rather than patients of all ages, and a slightly high proportion of mild bleeds: 10% of patients were discharged on the day of admission compared with 7% in the recent UK upper GI bleeding audit. [START_REF] Hearnshaw | Use of endoscopy for management of acute upper gastrointestinal bleeding in the UK: results of a nationwide audit[END_REF] We found very high risks of upper GI bleeding among elderly people. Among both men and women aged 85+ years, the risk of hospitalisation with upper GI bleeding was almost 1% per year. We found that socioeconomic deprivation was associated strongly with incidence. In the west of Scotland a 2.2 fold increased risk was identified for the most deprived quarter of patients compared with the least deprived quarter. [START_REF] Blatchford | Acute upper gastrointestinal haemorrhage in west of Scotland: case ascertainment study[END_REF] We found a similar 2.0 fold increased risk between the most and least deprived quintiles. Like the Scottish study, we found little association between social deprivation and case fatality.

Our overall case fatality of 10.0% in Wales is about average in the UK. Rates of 6% to 15% have been reported typically in local or regional studies across the UK, 2,[START_REF] Blatchford | Acute upper gastrointestinal haemorrhage in west of Scotland: case ascertainment study[END_REF][START_REF] Johnston | Epidemiology and course of gastrointestinal haemorrhage in North-east Scotland[END_REF][START_REF] Rockall | Incidence of and mortality from acute upper gastrointestinal haemorrhage in the United Kingdom[END_REF][START_REF] Berry | Upper gastrointestinal haemorrhage in Oxford. A prospective study[END_REF][START_REF] Schiller | Haematemesis and melaena, with special reference to factors influencing the outcome[END_REF][START_REF] Sanders | Effectiveness of an upper-gastrointestinal haemorrhage unit: a prospective analysis of 900 concecutive cases using the Rockall score as a method of risk standardisation[END_REF][START_REF] Mayberry | Mortality in acute upper gastrointestinal haemorrhage: a six-year survey from the University Hospital of Wales[END_REF][START_REF] Sanderson | Sepcialized gastrointestinal units for the management of upper gastrointestinal haemorrhage[END_REF][START_REF] Clements | Acute upper gastrointestinal haemorrhage in a district general hospital: audit of an agreed management policy[END_REF] although some single centre studies have reported lower case fatality of 3% to 4%. [START_REF] Holman | Value of a centralised approach in the management of haematemesis and melaena: experience in a district general hospital[END_REF][START_REF] Masson | Upper gastrointestinal bleeding in an open-access dedicated unit[END_REF] We found a stable incidence of upper GI bleeding from 1999 to 2007, but a significant reduction over time in case fatality. Case fatality varied strongly according to the aetiology/diagnoses -with highest mortality for upper GI malignancies and varices and lowest mortality for Mallory Weiss tear -and was affected adversely by major co-morbidities, most importantly liver disease and renal failure.

Case fatality was slightly worse among people resident in the most urban compared with the most rural residences. Although case fatality was slightly lower for medium than for 13 small or large hospitals, this was not significant. We also found little evidence that the distance travelled to hospital affected prognosis adversely. There were large differences in both incidence and case fatality across local authorities.

Those with highest incidence of upper GI bleeding often had lowest case fatality. As well as case mix differences, this may indicate lower thresholds for admitting less severe cases and possibly less effective GP out of hours services in some areas. It is known that many patients presenting to general hospitals with low risk upper GI bleeding could be managed safely without hospital admission. [START_REF] Stanley | Outpatient management of patients with low-risk upper-gastrointestinal haemorrhage: multicentre validation and prospective evaluation[END_REF] Case fatality was 13% higher for people admitted on weekends and public holidays compared with weekdays. Although admission rates for upper GI bleed were lower on weekends and public holidays than during the week, the increased mortality could not be explained by differences in case mix measures. Compared with patients admitted during the week, patients admitted on weekends and public holidays were significantly younger and had shorter lengths of stay -indicating less severe bleeds -and had similar levels of comorbidities recorded. These findings are consistent with North American studies that have reported increased mortality for admissions at weekends for acute MI, [START_REF] Kostis | Weekend versus weekday admission and mortality from myocardial infarction[END_REF] stroke, [START_REF] Saposnik | Weekends: a dangerous time for having a stroke?[END_REF] peptic ulcer bleeding, [START_REF] Ananthakrishnan | Outcomes of weekend admissions for upper gastrointestinal hemorrhage: a nationwide analysis[END_REF] upper GI bleeding, [START_REF] Shaheen | Weekend versus weekday admission and mortality from gastrointestinal hemorrhage caused by peptic ulcer disease[END_REF] abdominal aortic aneurysm, 39 pulmonary embolism, 39 and acute epiglottis. 39 Interestingly, we found that mortality was even more increased (by 41%) for admissions on public holidays.

We found no difference in mortality among patients admitted to hospitals with out of hours endoscopy services on weekends and public holidays, compared with those that had no formal services. This finding is inconclusive, particularly as informal services are provided on an ad hoc basis in most other hospitals.

Possible explanations for the increased mortality at weekends and on public holidays include reduced staffing levels that may lead to less thorough assessment, lack of specialist or senior consultant cover, less application of multidisciplinary team care, poor communication at handover and possible delays to investigation such as endoscopy in some

Notes

The ages of five patients were not known

F o r P e e r R e v i e w

  fatality is higher for admissions on weekends and public holidays.

  MethodsWe used systematic record linkage of hospital inpatient and mortality data from the Patient Episode Database for Wales (PEDW) for 1999-2007. PEDW is a comprehensive administrative database covering inpatient and day case admissions to all NHS hospitals in Wales, incorporating systematic linkage to death certificate data from the Welsh

  deprivation including income, housing, employment, environment, health, access to services, and education. The LSOAs were ranked according to their WIMD 2005 score and were categorised into quintiles, with quintile I representing the 20% of least deprived LSOAs and quintile V the 20% of most deprived LSOAs. Hospitals were classified

10

 10 Trends in the incidence of upper GI bleeding and case fatalityThere was no change over time in the incidence of upper GI bleeding over the eight year study period from 1999/2000 to 2006/07 (p=0.74;

  of hours services. The efforts of the British Society of Gastroenterology to extend out of hours endoscopy are welcome but further studies are required to understand deficiencies in care at weekends and on public holidays.

  6), oesophagitis (K20, K21.1, K22.1), varices -oesophageal (I85), varices -gastric (I86.4), ulcer -duodenal (K26), ulcer -gastric (K25), ulcer -peptic, unspecified (K27), ulcer -jejunal (K28), malignancy -oesophageal (C15), malignancy -gastric/duodenal (C16, C17.0), gastritis & duodenitis (K29), other specific diseases of stomach & duodenum, including gastric antral vascular ectasia (K31.8), complications of analgesics, antipyretics & anti-inflammatory drugs (Y45). ICD-10 codes used for the co-morbidities were as follows; circulatory diseases (ICD-10 = I00-I99), all malignancies except upper GI (C00-C15, C17.2-C97), liver disease (K70-K77), COPD (J40-J44), diabetes (E10-E14) and renal failure (N17-N19). Ref = reference category

Figure 1

 1 Figure 1Hospitalised incidence of upper GI bleeding across Wales

Table 4

 4

	). However, case fatality fell

Table 1 Hospitalised incidence rates for upper GI bleeding according to age group and sex, 1999-2007 Hospitalised incidence of upper GI bleeding No. of cases Incidence rate per 100 000 (95% CI) Age group (years) by sex

 1

	Male	All cases	13 288	153	(150-156)
		18-24	662	63.6	(58.9-68.6)
		25-34	1173	87.1	(82.2-92.2)
		35-44	1494	91.7	(87.1-96.4)
		45-54	1517	101	(96-106)
		55-64	1871	131	(126-138)
		65-74	2499	247	(237-257)
		75-84	2952	488	(471-506)
		85+	1120	864	(815-916)
	Female	All cases	11 128	117	(115-119)
		18-24	411	40.1	(36.3-44.2)
		25-34	513	36.4	(33.3-39.7)
		35-44	803	47.0	(43.8-50.3)
		45-54	931	60.0	(56.2-63.9)
		55-64	1097	75.0	(70.6-79.5)
		65-74	1795	159	(152-167)
		75-84	3078	344	(332-356)
		85+	2500	739	(710-768)
	All cases		24 421	134	(133-136)

Table 2 Hospitalised incidence of upper GI bleeding and case fatality at 30 days, with age of patients, length of hospital stay, and social deprivation levels across local authorities, 1999-2007 Hospitalised incidence of upper GI bleeding 30 day follow-up Patient and local authority characteristics: age, length of stay and social deprivation

 2 Notes* For geographical details of each local authority, see Figure1. ‡ The mortality odds ratios for local authorities are adjusted for age group and sex. Odds ratios were obtained through multiple logistic regression.

								Median length	Mean social
				No. of	Case	Adjusted mortality	Mean age of	of hospital stay	deprivation score
		No. of	Incidence rate per	deaths within	fatality	odds ratio	patients admitted	in days (IQ	in local authority
	Local authority *	cases	100 000 (95% CI)	30 days	(30 days)	(95% CI) ‡	(95% CI)	Range)	(95% CI)
	Blaenau Gwent	827	194 (181-208)	68	8.2%	Ref.	63.7 (62.4-65.0)	5 (2-10)	33.8 (30.2-37.4)
	Bridgend	1304	162 (153-171)	112	8.6%	1.08 (0.78-1.49)	62.6 (61.5-63.7)	4 (1-8)	23.2 (20.4-26.0)
	Caerphilly	1701	164 (156-172)	165	9.7%	1.28 (0.95-1.73)	61.8 (60.8-62.8)	4 (1-9)	27.0 (24.4-29.6)
	Cardiff	2263	119 (114.-124)	190	8.4%	1.05 (0.78-1.41)	62.8 (62.0-63.6)	5 (2-10)	21.3 (18.8-23.8)
	Carmarthenshire	1594	145 (138-152)	183	11.5%	1.29 (0.96-1.74)	67.3 (66.4-68.2)	5 (2-12)	22.0 (20.1-23.9)
	Ceredigion	676	138 (128-149)	75	11.1%	1.16 (0.81-1.65)	68.8 (67.4-70.2)	5 (2-12)	15.0 (13.2-16.8)
	Conwy	849	120 (112-129)	116	13.7%	1.58 (1.14-2.18)	67.0 (65.6-68.4)	4 (2-8)	18.0 (15.4-20.6)
	Denbighshire	682	115 (106-124)	67	9.8%	1.09 (0.76-1.57)	65.8 (64.3-67.4)	4 (2-8)	20.4 (16.4-24.4)
	Flintshire	895	96.9 (90.7-104)	100	11.2%	1.42 (1.02-1.97)	63.3 (62.0-64.6)	4 (2-9)	15.0 (12.9-17.1)
	Gwynedd	772	105 (98.0-113)	70	9.1%	0.98 (0.67-1.40)	66.5 (65.1-67.9)	5 (2-9)	17.3 (15.6-19.0)
	Isle of Anglesey	441	103 (93.4-113)	38	8.6%	0.96 (0.63-1.47)	65.5 (63.6-67.4)	5 (2-9)	20.7 (18.1-23.3)
	Merthyr Tydfil	917	268 (251-286)	71	7.7%	1.14 (0.80-1.62)	58.7 (57.4-60.0)	3 (0-9)	37.2 (31.7-42.8)
	Monmouthshire	726	135 (125-145)	78	10.7%	1.14 (0.80-1.61)	68.3 (66.9-69.7)	5 (2-10)	12.2 (10.7-13.7)
	Neath Port Talbot	1083	127 (120-135)	120	11.1%	1.36 (0.98-1.87)	64.1 (62.9-65.3)	5 (2-10)	28.2 (25.2-31.2)
	Newport	1267	150 (142-159)	166	13.1%	1.76 (1.30-2.39)	63.1 (62.0-64.2)	4 (2-8)	22.0 (18.9-25.1)
	Pembrokeshire	1167	162 (153-172)	114	9.8%	1.12 (0.81-1.55)	65.9 (64.8-67.0)	5 (2-11)	19.4 (17.3-21.5)
	Powys	887	109 (102-117)	101	11.4%	1.21 (0.87-1.68)	68.4 (67.2-69.6)	5 (2-9)	14.3 (13.0-15.6)
	Rhondda Cynon Taff	1855	130 (124-136)	162	8.7%	1.21 (0.90-1.64)	60.5 (59.6-61.4)	4 (1-9)	29.2 (26.8-31.7)
	Swansea	1856	132 (126-138)	189	10.2%	1.24 (0.92-1.67)	64.0 (63.1-64.9)	4 (2-10)	22.6 (19.7-25.5)
	Torfaen	905	162 (152-173)	90	9.9%	1.23 (0.88-1.73)	63.7 (62.4-65.0)	5 (2-10)	21.3 (18.6-24.0)
	Vale of Glamorgan	1002	136 (128-145)	95	9.5%	1.11 (0.79-1.55)	64.7 (63.4-66.0)	5 (2-9)	15.0 (12.7-17.3)
	Wrexham	752	93.3 (86.8-100)	82	10.9%	1.35 (0.95-1.90)	63.5 (62.0-65.0)	4 (2-9)	19.9 (17.0-22.8)
	All Wales	24 421	134 (133-136)	2452	10.0%		64.1 (63.9-64.4)	4 (2-9)	21.7 (21.1-22.3)

Table 3 Case fatality at 30 days and adjusted odds ratios for prognostic and sociodemographic factors following hospital admission for upper GI bleeding, 1999-2007 30 day follow-up

 3

				Unadjusted	Adjusted mortality
			No. of deaths	case fatality	odds ratio
		No. of cases	within 30 days	(30 days)	(95% CI) * ‡
	All cases †	24 421	2452	10.0%
	All
	Age group (years) and sex
	Male -all	13 288	1215	9.1%
	18-24	662	2	0.3%
	25-34	1173	10	0.9%
	35-44	1494	28	1.9%
	45-54	1517	71	4.7%
	55-64	1871	142	7.6%
	65-74	2499	279	11.2%
	75-84	2952	442	15.0%
	85+	1120	241	21.5%
	Female -all	11 128	1237	11.1%
	18-24	411	1	0.2%
	25-34	513	4	0.8%
	35-44	803	25	3.1%
	45-54	931	31	3.3%
	55-64	1097	59	5.4%
	65-74	1795	163	9.1%
	75-84	3078	437	14.2%
	85+	2500	517	20.7%
	Sex
	Male	13 288	1215	9.1%	Ref.
	Female	11 128	1237	11.1%	0.89 (0.81-0.97)
	Social deprivation
	I (least deprived)	3499	380	10.9%	Ref.
	II	4296	434	10.1%	0.96 (0.83-1.12)
	III	4933	529	10.7%	1.09 (0.94-1.26)
	IV	5462	554	10.1%	1.12 (0.97-1.29)
	V (most deprived)	6231	555	8.9%	1.11 (0.97-1.28)
	Urban/rural residence
	Under 2,500 people	4497	471	10.5%	Ref.
	2,500 -9,999	3935	376	9.6%	0.98 (0.85-1.13)
	10,000 -24,999	5880	595	10.1%	1.08 (0.95-1.23)
	25,000 -99,999	5355	524	9.8%	1.09 (0.96-1.25)
	At least 100,000	4754	486	10.2%	1.14 (1.00-1.31)
	Distance from hospital
	Less than 3 km	4133	442	10.7%	Ref.
	3 to 9.99 km	8511	792	9.3%	0.88 (0.77-1.01)
	10 to 19.99 km	6548	660	10.1%	0.96 (0.84-1.10)
	20 to 29.99 km	1846	197	10.7%	0.99 (0.82-1.20)
	At least 30 km	2089	222	10.6%	0.98 (0.81-1.17)
	Hospital size (beds)
	Small (0-399)	4428	488	11.1%	Ref.
	Medium (400-599)	11 658	1084	9.3%	0.97 (0.86-1.09)
	Large (600+)	7400	798	10.8%	1.10 (0.97-1.24)
	Day of admission ‡
	Weekday	18 285	1792	9.8%	Ref.
	Weekend Public holiday	5686 450	602 58	10.6% 12.9%	1.13 (1.02-1.25) c 1.13 (1.0()2-1.26) 1.41 (1.04-1.91) c 1.40 (1.03-1.90)

Table 3 cont'd 30 day follow-up

 3 The mortality odds ratio for sex is adjusted for age group. The odds ratios for social deprivation, urban/rural residence, distance from hospital, hospital size, day of admission, main diagnoses/aetiology and co-morbidities are adjusted for age group and sex. Odds ratios were obtained through multiple logistic regression. ‡ After adjusting for major co-morbidities (malignancies, circulatory diseases, renal failure, diabetes, COPD and liver disease), the increased mortality for weekend and public holiday admissions was largely unaffected (odds ratio=1.ICD-10 codes used for the main diagnoses/aetiology were as follows: Mallory Weiss tear (K22.

					Unadjusted	Adjusted mortality
				No. of deaths	case fatality	odds ratio
		No. of cases (%)	within 30 days	(30 days)	(95% CI) * ‡
	Main diagnoses/aetiology **
	Mallory Weiss tear	1485 (6.1%)	24	1.6%	0.26 (0.18-0.40)
	Oesophagitis	2459 (10.1%)	202	8.2%	0.73 (0.63-0.86)
	Varices -oesophageal	(11.2%) 656 (2.7%)	107	16.3%	2.69 (2.15-3.56)
	Varices -gastric	66	(0.3%)	12	18.2%	3.15 (1.63-6.06)
	Ulcer -duodenal	2661 (10.9%)	355	13.3%	1.25 (1.10-1.41)
	Ulcer -gastric	2485 (10.2%)	259	10.4%	0.86 (0.75-0.99)
	Ulcer -peptic, unspecified	291 (1.2%)	49	16.8%	1.59 (1.16-2.19)
	Ulcer -jejunal	34	(0.1%)	4	11.8%	1.03 (0.36-2.99)
	Malignancy -oesophageal	112 (0.5%)	40	35.7%	4.40 (2.95-6.56)
	Malignancy -gastric/duodenal	197 (0.8%)	48	24.4%	2.24 (1.61-3.14)
	Gastritis & duodenitis	3377 (13.8%)	198	5.9%	0.52 (0.44-0.60)
	Other specific diseases of stomach &
	duodenum, including gastric antral
	vascular ectasia	273 (1.1%)	23	8.4%	0.62 (0.40-0.96)
	Complications of analgesics,
	antipyretics & anti-inflammatory drugs	729 (3.0%)	46	6.3%	0.47 (0.35-0.64)
	Major co-morbidities **
	Circulatory diseases	9276 (38.0%)	1439	15.5%	1.73 (1.59-1.89)
	Malignancies (all except upper GI))	1147 (4.7%)	351	30.6%	3.64 (3.17-4.17)
	Liver disease	1366 (5.6%)	254	18.6%	4.90 (4.15-5.79)
	COPD	982 (4.0%)	182	18.5%	1.55 (1.31-1.84)
	Diabetes	2565 (10.5%)	328	12.8%	1.12 (0.99-1.27)
	Renal failure	812 (3.3%)	271	33.4%	3.75 (3.21-4.39)
	Notes:
					11; 95% CI=1.00-1.23
	and 1.42; 1.05-1.92 respectively). The prevalence of co-morbidities across the three patient groups (admitted on weekdays,
	weekends and public holidays respectively) were as follows: circulatory diseases = 6931 (37.9%), 2162 (38.0%) and 183 (40.7%);
	respectively; malignancies = 1105 of 18 285 (6.0%), 323 of 5686 (5.7%) and 24 of 450 (5.3%); liver disease = 1003 (5.5%), 341
	(6.0%), 22 (4.9%); COPD = 735 (4.0%), 229 (4.0%), 18 (4.0%); diabetes=1921 (10.5%), 599 (10.5%), 45 (10.0%); renal failure =
	589 (3.2%), 204 (3.65) and 19 (4.2%). Hence, the prevalence of major co-morbidities was very similar across the three groups of
	patients.
	† For non-variceal bleeds, case fatality was 9.8% overall, based on 23 742 admissions: adjusted case fatality was higher among
	women than men (OR = 1.11; 95% CI = 1.02-1.22), higher in large than small hospitals (1.11; 1.01-1.30) and highest in the most
	urban than rural residences (1.16; 1.01-1.34), higher for weekend (1.13; 1.02-1.25), and public holiday (1.48; 1.10-1.98) admissions
	but it was not associated with distance travelled to hospital
	**

*

Table 4 Trends in hospitalised incidence, case fatality and length of stay for upper GI bleeding, 1999-2007 Hospitalised incidence of upper GI bleeding 30 day follow-up Length of hospital stay Year No. of cases

 4

	Incidence rate
	per 100 000	No. of	Case fatality	Median
	(95% CI)	deaths	(95% CI)	(IQ range)

Alimentary Pharmacology & Therapeutic

Acknowledgements

The authors are grateful to Caroline Brooks and Sarah Rodgers for help with the GIS analyses. The authors are also grateful to the Health Information Research Unit (HIRU), School of Medicine, Swansea University, for preparing and providing access to the project specific linked datasets from the Secure Anonymised Information Linkage (SAIL) system, which is funded by the Wales Office of Research and Development.

Declaration of personal interests:

No conflict of interests declared.

Declaration of funding interests:

The study was funded by The Health Foundation [Grant no: 5091]. The views expressed in this paper are those of the authors and not necessarily those of the funding body.

Conflict of interest

None declared