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Mortality study of 18 000 patients treated with

D N Bateman, D Colin-Jones, S Hartz, M Langman, R F Logan, J Mant, MMurphy, K R Paterson, R Rowsell, S Thomas and M Vessey Updated information and services can be found at: References
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Articles on similar topics can be found in the following collections To order reprints of this article go to: Mortality study of 18 000 patients treated withomeprazole D N Bateman, D Colin-Jones, S Hartz, M Langman, R F Logan, J Mant, M Murphy,K R Paterson, R Rowsell, S Thomas, M Vessey, for the SURVEIL (Study of UndetectedReactions. Vigilance Enquiry into Links) Group. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Background: The long term safety of potent gastric acid suppressive therapy has yet to be established.
Method: General practice record review at a median interval of 26 months followed by retrieval ofdetails of all deaths within four years using the UK National Health Service Central Registers in 17 936patients prescribed omeprazole in 1993–1995. Death rates were compared with general populationrates.
Results: Records of 17 489 patients (97.5%) were examined. A total of 12 703 patients received fur-ther scripts for antisecretory drugs, 8097 for omeprazole only (65.6%): 3097 patients have died. Allcause mortality was higher in the first year (observed/expected (O/E) 1.44 (95% confidence intervals(CI) 1.34–1.55); p<0.0001) but had fallen to population expectation by the fourth year. There weresignificant mortality increases in the first year, falling to or below population expectation by the fourthyear, for deaths ascribed to neoplasms (1.82 (95% CI 1.58–2.08); p<0.0001), circulatory diseases(1.27 (95% CI 1.13–1.43); p<0.0001), and respiratory diseases (1.37 (95% CI 1.12–1.64);p<0.001). Increased mortality ascribed to digestive diseases (2.56 (95% CI 1.87–3.43); p<0.0001)persisted, although reduced. Increased mortality rates for cancers of the stomach (4.06 (95% CI 2.60– 6.04); p<0.0001), colon and rectum (1.40 (95% CI 0.84–2.18); p=0.075), and trachea, bronchus, and lung (1.64 (95% CI 1.19–2.19); p<0.01) seen in the first year had disappeared by the fourth year . . . . . . . . . . . . . . . . . . . . . . .
but that for cancer of the oesophagus had not (O/E 7.35 (95% CI 5.20–10.09) (p<0.0001) in year 1; 2.88 (95% CI 1.62–4.79) (p<0.001) in year 4). Forty of 78 patients dying of oesophageal cancer had the disease present at registration. Twenty seven of those remaining cases had clinical evidence of Barrett’s disease, stricture, ulcer, or oesophagitis at registration (O/E 3.30 (95% CI 2.17–4.80)). Six deaths occurred in patients with hiatal hernia or reflux only (O/E 1.02 (95% CI 0.37–2.22)) and five in patients without oesophageal disease (O/E 0.77 (95% CI 0.25–1.80)). No relationships were detected with numbers of omeprazole scripts received.
Conclusions: Increases in mortality associated with treatment are due to pre- existing illness, includ- Accepted for publication:20 February 2002 ing pre-existing severe oesophageal disease. There was no evidence of an increased risk of oesopha- . . . . . . . . . . . . . . . . . . . . . . .
geal adenocarcinoma in those without oesophageal mucosal damage recorded at registration.
Theintroductionofanynewclassofdrugs,suchasthe METHOD proton pump inhibitors (PPIs), where usage is likely to be We sought to register a cohort of 18 000 patients prescribed widespread and prolonged, requires that safety during omeprazole in the six UK conurbations of or surrounding Bir- chronic treatment is assured. The need for such assessment is mingham, Glasgow, Newcastle, Nottingham, Oxford, and emphasised by claims that omeprazole treatment might Portsmouth. Using the computerised registers of cooperating adversely affect the management of upper gastrointestinal general practitioners, we identified takers of omeprazole in the period 1993–1995. Records of patients who were still alive andwho had received at least one prescription for omeprazole epithelialisation of the cancer might be promoted, so hinder- were examined and details taken of, inter alia, the patient’s ing disease recognition.1 It has also been suggested that raised age, sex, and NHS number, prescription data, and the reasons serum gastrin concentrations in response to reduced acidity for any prescription, together with details of any prior diagno- might act as growth promoters,2 or that treatment might sis of malignant disease, any previous upper abdominal surgi- accelerate the onset of atrophic gastritis, so predisposing to cal procedures, and any other recorded antisecretory drug use gastric cancer.3 Moreover, as omeprazole is commonly used to in the previous 12 months. We excluded from consideration all treat gastro-oesophageal reflux disease, it is important to those dying prior to the registration date.
determine whether treatment influences the frequency of Clinical diagnoses were those recorded in individual case oesophageal adenocarcinoma, a tumour known to complicate notes and were not re- interpreted, but details of investiga- oesophageal metaplasia (Barrett’s disease), which occurs in tions were recorded. Individual diagnoses of ulcer, oesoph- association with oesophageal reflux associated damage.
agitis, Barrett’s oesophagus, hiatal hernia or reflux, and cancer We examined mortality rates from any cause over a four required specific mention of these following investigation.
year period during or after treatment with omeprazole in sixcities in England and Scotland. Death rates were compared . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
with those expected nationally. Data have strength in relating Abbreviations: O/E, observed/expected; PPI, proton pump inhibitor; risks to those observed in the general population, as done pre- NHSCR, National Health Service Central Register; ICD, International Major diagnostic groups of patients prescribed omeprazole Diagnostic figures add up to more than 100% because some patients had more than one diagnosis.
*A single script is equivalent to one month of treatment at a standard dosage.
Records of patients registered were re-examined after two years, and new diagnoses of oesophageal cancer at hospital A total of 17 936 patients had been registered by December attendance and details of subsequent omeprazole and other 1995 when entry was completed, and clinical follow up data antisecretory drug prescribing were recorded. Patients trans- were available after two years in 17 489 (97.5%) patients.
ferring to another general practitioner were followed by post Mean age of the patients at registration was 59.6 years or visit to the practice if nearby. The records of cohort (median 61.5; range 7–105) with 46.9% being men. In the members were also flagged at the National Health Service year prior to registration, 38% had received 1–2 omeprazole Central Register (NHSCR) in England and Scotland, providing prescriptions while 25% had received six or more. Table 1 data on all causes of death and confirmation of cancer shows the major diagnostic groupings in patients prescribed omeprazole. Oesophageal disease and gastrointestinal symp- Observed death rates, classified according to the ninth revis- toms of uncertain cause formed the bulk of the indications.
ion of the International Classification of Disease (ICD), were There were 12 501 diagnoses of oesophageal disease recorded.
compared with expected population rates in England and Oesophagitis (3664), reflux not otherwise specified (3842), Scotland using published data from the Office of National and hiatal hernia (3142) were the commonest recorded but Statistics. For this purpose, rates were based on those with substantial numbers of patients with stricture (791), individuals dying in 1996, the approximate midpoint of the ulcer (441), or Barrett’s disease (417) of the oesophagus.
study period, taking account of age, within five year groups, Oesophageal disease was pre-existing cancer in 40 and was and sex. In addition, death rates were examined in relation to not clearly specified in the remaining 164.
the number of scripts received by patients for omeprazole, as We found that 2096 patients (11.7%) had undergone a total of 2477 upper abdominal procedures in the past. Commoner noted at the time of registration. Relative risks presented are procedures were cholecystectomy (1014 (5.3%)), oesophageal the ratios of observed to expected deaths, together with their surgery (489 (2.7%)) and elective ulcer surgery (439 (2.4%)).
95% confidence intervals (CI) throughout, alongside the Further prescriptions for antisecretory treatments had been observed and expected numbers of deaths.
received by 12 703 (72.6%) of 17 489 patients with two year The study was approved by local ethics committees and by follow up data; 10 929 (62.5%) had received at least one the Office of National Statistics. It was also constructed to further prescription for omeprazole with 8097 having omepra- conform to the guidelines for safety assessment of marketed medicines (SAMM guidelines),7 and was registered with the Table 2 shows that observed mortality tended to be higher in the first year after registration and then fell overall to population Observed (O) deaths from all causes and observed deaths divided by deaths expected* (O/E) in each study *Expected deaths based on national (England and Wales) rates for 1996, except for Glasgow which is based on Scottish rates for 1996, and total rateswhich are based on pooled Scotland, England, and Wales expected deaths. Calculations made for each sex separately within five year age groupings.
Observed and expected number of deaths for individual ICD (International Classification of Disease) chapters Observed/expected (O/E) ratios in parentheses.
*O/E significantly >1.0, p<0.05.
expectation, with similar trends in the six conurbations. Table 3 To examine results for oesophageal cancer in more detail, we shows the mortality observed for individual ICD chapters by stratified data in those without oesophageal cancer at year, together with their associated relative risks (observed/ registration according to whether patients were recorded ini- expected (O/E)). Mortality was initially higher than expected tially as having Barrett’s disease, oesophageal ulcer, stricture, for neoplasms (observed 217, expected 119; O/E 1.82; 95% CI or oesophagitis (categorised as severe disease), or whether 1.58–2.08; p<0.0001) and also for diseases of the circulatory they had reflux or hiatal hernia without Barrett’s disease, (observed 284, expected 224; O/E 1.27; 95% CI 1.13–1.43; ulcer, stricture, or oesophagitis (categorised as mild disease).
p<0.0001), respiratory (observed 112, expected 82; O/E 1.37; Table 5 shows the types of non- malignant oesophageal disease 95% CI 1.12–1.64; p<0.001), and digestive (observed 45, present in the 38 patients diagnosed as having oesophageal expected 18; O/E 2.56; 95% CI 1.87–3.43; p<0.0001) systems.
cancer after registration. Among those with severe oesopha- Death rates from neoplasms fell to population expectation by geal disease, 27 died of oesophageal cancer (expectation 8.2 in year 4, as did those for the circulatory and respiratory systems.
four years; O/E 3.30; 95% CI 2.17–4.80). In contrast, of those Greater mortality than expected was also initially recorded for with mild oesophageal disease, evidenced by clinical diag- infectious and parasitic disease (O/E 3.09; 95% CI 1.33–6.08; noses of reflux or hiatal hernia, only six died of oesophageal p<0.01), falling to population expectation by the fourth year of cancer (expectation 5.9; O/E 1.02; 95% CI 0.37–2.22). In those the study. Initially increased mortality from musculoskeletal without initial clinical diagnoses of oesophageal disease, five disorders, upper gastrointestinal disorders, and chronic liver patients died (against expectation 6.5; O/E 0.77; 95% CI 0.25– disease, although falling with time towards population expecta- 1.80). Of the 417 who had Barrett’s disease identified at some tion, still tended to remain raised.
time and recorded at registration, nine had died of oesopha- Table 4 shows the observed and expected deaths for selected geal cancer (O/E 11.25; 95% CI 5.14–21.36).
ICD rubrics, including major gut epithelial cancers and cancer In those with severe oesophageal disease, the risk of devel- of the lung, breast, and blood forming tissues, ischaemic and oping oesophageal cancer was slightly lower (observed 8, cerebrovascular disease, and upper gastrointestinal causes. For expected 2.8; O/E 2.86; 95% CI 1.23–5.63) in those who had all selected causes, initial increases in mortality declined received six or more scripts in the year before registration than towards or below population expectation, except for oesopha- in those who had received fewer (observed 19, expected 5.2; geal cancer and liver disease which remained significantly O/E 3.65; 95% CI 2.20–5.71). Examination of mortality from all other neoplasms, and from all other (non-neoplastic) Observed and expected number of deaths for selected ICD (International Classification of Disease) rubrics Observed/expected (O/E) ratios in parentheses.
*O/E significantly >1.0, p<0.05.
Observed and expected deaths from cancer of the oesophagus in successive years according to initial oesophageal disease diagnosis in those cancer free at registration Barrett’s disease/ulcer/stricture/oesophagitis (n=5517) (Barrett’s disease cases only)* (n=417) O/E, observed/expected.
*Includes all diagnoses of the condition, irrespective of date of diagnosis.
causes, likewise showed no relationship with the intensity of oesophageal cancer in the first year after registration. This treatment. Clear histological diagnoses were available in 29 of almost certainly represents confounding by indication rather 38 oesophageal cancer cases diagnosed after the study enrol- than an adverse drug effect, or masking of disease by ment date. Fifteen (83%) of 18 patients with adenocarcino- treatment. The patterns are similar to those seen with cimeti- mata had initial clinical diagnoses of oesophagitis, oesopha- dine; no dose relationship was seen with treatment, and death geal ulcer, stricture, and/or Barrett’s oesophagus. In contrast, rates fell progressively with time. Persisting increases into the only five (45%) of 11 patients with squamous cancers had fourth year were only seen for oesophageal cancer. The major- such initial diagnoses (p=0.086, Fisher’s exact test).
ity of those dying with oesophageal cancer had initialdiagnoses suggesting severe oesophageal disease, namely Bar-rett’s disease, stricture, ulcer, or oesophagitis. Observed mortality was more than three times as great as expected in By registering patients with the NHSCR, we systematically these patients whereas it was not increased in those with ini- collected information on the causes of death over four years in tial diagnoses of hiatal hernia or reflux, or in those initially nearly 18 000 patients prescribed omeprazole. Mortality was considered to have disease outside the oesophagus as the rea- significantly greater than population expectation in the first son for omeprazole prescription. Patients with adenocarcino- year after registration, falling progressively to that expectation mata were six times as likely to have initial clinical diagnoses by the fourth year. Increased mortality in the first year is suggesting severe underlying oesophageal disease as those unlikely to reflect drug effects because it was detectable for a with squamous tumours. Observed mortality was more than wide variety of causes and was unrelated to the duration of 10 times as high in patients in whom Barrett’s disease had initial treatment. Furthermore, very similar patterns were been detected at some time in their clinical course whether or observed in our previous studies of cimetidine takers not found at registration. However, findings of high propor- conducted in the same way.5 6 We deduce therefore that tions of Barrett’s disease in this group may reflect the results confounding by indication for treatment explains the general of differences in intensity of surveillance in those with and patterns observed. Thus treatment of chest pain attributed to reflux, but actually anginal in origin, could well explain Although in the long term follow up of approximately increased cardiovascular disease mortality. Use of omeprazole 10 000 patients prescribed cimetidine we found no evidence in those perceived to be at high risk of ulcer complications is that treatment was likely to cause gastric or other varieties of also likely to explain raised risks of death from peptic ulcer gastrointestinal cancer,4–6 it has recently been suggested that disease and musculoskeletal disease.8 This finding should not histamine receptor antagonist treatment might predispose to be taken to imply that such treatment fails in its objectives: cardio-oesophageal adenocarcinoma .18 That claim was based there is strong evidence from controlled trials to indicate that on comparing prior drug intake in cardio-oesophageal cancer treatment is appropriate and successful.9–11 In the same way, patients with that in individuals with myocardial infarction.
increased mortality from musculoskeletal diseases seems The nature of the control would seem to make sensible deduc- likely to reflect use of omeprazole in those perceived as at risk tions about causation impossible. Our findings indicate of ulcer complications.12 The increased mortality observed strongly that the nature of the underlying oesophageal disease from infectious and parasitic disease in the first two years of is the major, and probably sole, cause of the raised risk of observation lacks a plausible explanation but may represent oesophageal cancer death in our omeprazole takers. This con- the play of chance in small numbers. PPI use is known to be clusion is reinforced by evidence that death rates were associated with an increased frequency of dysenteric infec- unrelated to the number of omeprazole scripts received at tions but not with death from this cause.13 14 Persistently registration. This finding is consonant with findings that the increased mortality from chronic liver disease in our cohort proportions of patients receiving acid suppressant therapy for seems likely to represent deaths in patients with upper Barrett’s oesophagus, and oesophagitis without Barrett’s gastrointestinal symptoms coincident liver disease, and disease, did not differ significantly.19 The data in our study suggest strongly that underlying oesophageal disease explains drinking.15 16 Scrutiny of our cases revealed none where a the increased risk of oesophageal cancer but it should be noted causal relationship with antisecretory treatment seemed that classification depended upon reports available to us in likely. Prescribing of omeprazole to attendees at general prac- practice case records, these not being produced to standard- titioner surgeries with other main complaints, a form of Berk- ised criteria. The actual strength of risk is therefore uncertain.
son’s bias,17 would be expected to lead to increases in mortality Systematic study has suggested that there may be publication from a broad range of complaints, particularly in the early bias in the reporting of cancer risks in Barrett’s oesophagus.20 period after prescription, a phenomenon seen in our previous Our data show, compared with the findings of others, rather moderate increases in the risk of oesophageal cancer. Our set Examination of the data for neoplastic diseases showed that has particular strengths. Firstly, patients for study were mortality increases were particularly high for gastric and selected prior to the outcomes being known. Secondly, the population studied was large, and the follow up prolonged and complete. Thirdly, the number of incident oesophageal 1 Bramble MG, Suvakovic Z, Hungin APS. Detection of upper tumours diagnosed after enrolment (38) was large.
gastrointestinal cancer in patients taking antisecretory therapy prior togastroscopy. Gut 2000;46:464–7.
It has been suggested that, based on symptoms alone, 2 Thorburn CM, Friedman GD, Dickinson CJ, et al. Gastrin and colorectal patients with oesophageal reflux are at nearly eight fold cancer: a prospective study. Gastroenterology 1998;115:275–80.
increased risk of adenocarcinoma.21 Our data indicate that in 3 Pounder RE, Williams MP. Omeprazole and accelerated onset of atrophic gastritis. Gastroenterology 2000;118:238–9.
our population, any increase in oesophageal cancer risk may 4 Colin-Jones DG, Langman MJS, Lawson DH, et al. Post-marketing be confined to those with evidence of mucosal structural surveillance of the safety of cimetidine: 12 month mortality report. BMJ damage, and that simple symptomatic reflux may not pose 5 Colin-Jones DG, Langman MJS, Lawson DH, et al. Post-marketing significant risks. This conclusion is consonant with that of surveillance of the safety of cimetidine: mortality during second, third and Cohen and Parkman22 that structural damage, and Barrett’s fourth year of follow-up. BMJ 1985;291:1084–8.
oesophagus in particular, are the critical factors. Our data 6 Colin-Jones DG, Langman MJS, Lawson DH, et al. Post-marketing surveillance of the safety of cimetidine: 10 year mortality report. Gut showing a fall in gastric cancer death rates by the fourth year of the study to slightly below population expectation suggest 7 Medicines Control Agency, Committee of Safety of Medicines, Royal that gastric cancer risk is neither intrinsically raised in the College of General Practitioners, British Medical Association andAssociation of the British Pharmaceutical Industry. Guidelines for population studied nor influenced in the period under review company sponsored Safety Assessment of Marketed Medicines (SAMM by omeprazole or other antisecretory drug prescribing. Our Guidelines). Br J Clin Pharmacol 1994;38:95–7.
results are reassuring given concern that treatment might 8 Fries JF, Miller SR, Spitz PW, et al. Towards an epidemiology of gastropathy associated with nonsteroidal anti-inflammatory drug use.
cause early gastric atrophy,23 24 although any increased Gastroenterology 1989;96:647–55.
incidence of gastric atrophy associated with antisecretory 9 Hawkey CJ, Karrasch JA, Szcepanski L, et al, for the Omeprazole vs treatment might take longer than the period under review to Misoprostol for NSAID-induced Ulcer Management (OMNIUM) StudyGroup. Omeprazole compared with misoprostol for ulcers associated influence mortality from gastric cancer. We conclude that with non-steroidal anti-inflammatory drugs. N Engl J Med treatment with omeprazole per se did not increase the risks of dying from general or neoplastic disease. Our data also suggest 10 Ekstrom P, Carling L, Wetterhus S, et al. Prevention of peptic ulcer and dyspeptic symptoms with omeprazole in patients receiving continuous that raised risks of oesophageal malignancy are associated non-steroidal anti-inflammatory drug therapy. A Nordic multicentre study.
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11 Cullen D, Bardhan KD, Eisner M, et al. Primary gastroduodenal prophylaxis with omeprazole for non-steroidal anti-inflammatory drugusers. Aliment Pharmacol Ther 1998;12:135–40.
12 Yeomans ND, Tulassey Z, Juhasz L, et al, for the ASTRONAUT study group. A comparison of omeprazole and ranitidine for treating and Group members: S Thomas, D N Bateman, Judy Bland, Fiona Ander- preventing ulcers associated with non-steroidal anti-inflammatory drugs.
son, Elizabeth Wray, Wolfson Unit of Clinical Pharmacology, N Engl J Med 1998;338:719–26.
University of Newcastle upon Tyne, UK; D Colin Jones, Shirley Wood, 13 Nwokolo CU, Loft DE, Holder R, et al. Increased incidence of bacterial Vivienne Barrett, Department of Gastroenterology, Queen Alexandra diarrhoea in patients taking gastric antisecretory drugs. Eur J Hospital, Portsmouth, UK; M Langman, J Mant, P Brettle, Theresa Gastroenterol Hepatol 1994;6:697–9.
Grimley, Madeleine Rowsby, Ros Salter, Departments of Medicine and 14 Neale KR, Brij SO, Slack RCB, et al. Recent treatment with H2 antagonists and antibiotics and gastric surgery as risk factors for General Practice, University of Birmingham, Birmingham, UK; R F Salmonella infection. BMJ 1994;310:176.
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Murphy, M Vessey, Pauline Marshall, Division of Public Health and 16 McCormack TT, Sims I, Eyre-Brook I, et al. Gastric lesions in portal Primary Health Care, Institute of Health Sciences, Oxford University, hypertension: inflammatory gastritis or congestive gastropathy? Gut Oxford, UK; K R Paterson, Gill Paice, Department of Clinical Pharma- cology, Royal Infirmary, Glasgow, UK; S Hartz, Sue West, Innovative 17 Berkson J. Limitations of the application of 4 fold tables to hospital data.
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D N Bateman, S Thomas, Wolfson Unit of Clinical Pharmacology, 20 Shaheen NJ, Crosby MA, Bozymski EM, et al. Is there publication bias in the reporting of cancer risk in Barrett’s oesophagus? Gastroenterology D Colin-Jones, Department of Gastroenterology, Queen Alexandra 21 Lagergren J, Bergstrom R, Lindgren A, et al. Symptomatic S Hartz, Innovative Clinical Solutions Ltd, UK gastro-oesophageal reflux as a risk factor for oesophagealadenocarcinoma. N Engl J Med 1999; M Langman, J Mant, Departments of Medicine and General Practice, Cohen S, Parkman HP. Heartburn—a serious symptom. N Engl J Med1999;340:878–79.
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R Rowsell, AstraZeneca UK Ltd, Luton, Beds, UK


Benjamin arbel ph

Benjamin Arbel Ph.D. Professor of Early Modern History Incumbent of the Chair for the History and Culture of the Jewry of Salonika and Greece Department of History Tel Aviv University List of Publications June 2009 A. BOOKS AND MONOGRAPHS 1. Trading Nations. Jews and Venetians in the Early Modern Eastern Mediterranean (Leiden, 1995), xi+237 pp. 2. Cyprus, the Franks and Venice (13t

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