Scientific
publications

BACKGROUND: Acid suppression may increase the risk of community-acquired pneumonia. We investigated this association in the United Kingdom primary care system taking account of the potential for confounding by indication. METHODS: We identified patients aged 20-79 years in The Health Improvement Network database with a new diagnosis of pneumonia between 2000 and 2005 (n = 7297). Cases were validated by manual review and compared with age- and sex-matched controls (n = 9993). Using unconditional logistic regression, we estimated the relative risk (RR) of pneumonia associated with current use of acid-suppressive drugs compared to nonuse. RESULTS: Newly diagnosed community-acquired pneumonia was increased with current use of proton pump inhibitors (RR = 1.16 [95% confidence interval 1.03-1.31]) but not H2-receptor antagonists (0.98 [0.80-1.20]). An increased risk of pneumonia was evident only in the first 12 months of treatment with proton pump inhibitors. There was some evidence of a dose response. Among patients taking proton pump inhibitors for less than 1 year, the risk of community-acquired pneumonia was stronger when current use was for dyspepsia or peptic ulcer (1.73 [1.29-2.34]) than for gastroesophageal reflux disease or prevention of upper gastrointestinal injury associated with aspirin or nonsteroidal anti-inflammatory drugs (1.22 [0.97-1.52]). CONCLUSIONS: We observed a small increase in the risk of community-acquired pneumonia associated with current proton pump inhibitor use, particularly during the first 12 months of treatment and at higher doses. This may be due in part to the underlying indication.

BACKGROUND: Bullous pemphigoid is associated with poorly understood dramatically increased early mortality rates. OBJECTIVES: To assess the incidence of acute events predisposing to early mortality. METHODS: Computerized medical records from the Health Improvement Network, a large population-based U.K. general practice database, were used to conduct a cohort analysis. Outcome measures were incidence rates of myocardial infarction, pulmonary embolism, pneumonia and sepsis compared with a matched control population. RESULTS: People with bullous pemphigoid were three times as likely to develop pneumonia, adjusted rate ratio 2.94 [95% confidence interval (CI) 2.01-4.31] or pulmonary embolism, adjusted rate ratio 3.12 (95% CI 1.37-7.12) compared with matched controls. No statistically significant increase was seen for myocardial infarction, adjusted rate ratio 1.24 (95% CI 0.66-2.33), or sepsis, adjusted rate ratio 2.02 (95% CI 0.78-5.21). CONCLUSIONS: The risk of pulmonary embolism and pneumonia is increased following a diagnosis of bullous pemphigoid. It may be possible to reduce associated mortality through considering prophylaxis with either antithromboembolic measures or antibiotic therapy and vaccination.

BACKGROUND: Few studies have examined the incidence of uncomplicated peptic ulcer or the trends in factors affecting its incidence. AIM: To estimate the incidence rate of uncomplicated peptic ulcer in the UK from 1997 to 2005 and report temporal changes in the main known preventive and risk factors. METHODS: Population-based cohort study of 1 049 689 patients enrolled in The Health Improvement Network in the UK. We estimated the incidence rate of uncomplicated peptic ulcer and evaluated temporal trends in demographic characteristics and prescription patterns for various anti-inflammatory and gastroprotective agents. RESULTS: Overall uncomplicated peptic ulcer incidence was 0.75 cases per 1000 persons-years, declining from 1.1 to 0.52 cases per 1000 person-years between 1997 and 2005. Distributions of age, gender and alcohol habits were similar in 1997 and 2005. The proportion of documented Helicobacter pylori-negative cases increased from 5% to 12%. Monthly prevalence of subjects with prescriptions for traditional non-aspirin NSAIDs changed from 7.7% to 6.8%, Coxibs from 0% to 0.7%, and proton pump inhibitors (PPIs) from 2.4% to 7.4%. The proportion of subjects on prescription NSAIDs on PPIs increased continuously over time. CONCLUSION: A reduction in H. pylori-related peptic ulcers, changing patterns in NSAID use and increasing PPI use may have contributed to a decline in uncomplicated peptic ulcer incidence in the UK.

PURPOSE: We determined whether men treated with oral antimuscarinics are at increased risk for acute urinary retention. MATERIALS AND METHODS: In this population based, retrospective cohort study using a nested case-control design we analyzed data from a large primary care database containing patient information entered by general practitioners in the United Kingdom. Our study cohort comprised men 20 to 84 years old. Cases of acute urinary retention were identified by reviewing diagnostic codes and were confirmed in a random sample through questionnaires sent to the treating physician. RESULTS: The overall incidence of acute urinary retention in the study cohort (1,844) was 1.0 per 1,000 person-years, with the incidence rate increasing with age. The first 30 days (early treatment) of antimuscarinic use was associated with a relative risk of acute urinary retention of 8.3 (95% CI 4.8-14.2) and with longer term use (more than 30 days) the relative risk was 2.0 (95% CI 1.2-3.1). The relative risk of acute urinary retention was similar for low/medium and high antimuscarinic doses (relative risk 2.8 vs 3.0, 95% CI 2.1-3.8 and 1.3-6.8, respectively). The relative risk of acute urinary retention was highest during early treatment for a urogenital indication (relative risk 14.2, 95% CI 6.8-29.6). The risk of acute urinary retention was not increased when antimuscarinics were used as antispasmodics or for drug induced parkinsonism. CONCLUSIONS: Men prescribed antimuscarinics, particularly for a urogenital condition, should be closely monitored during the first 30 days of treatment for signs or symptoms of urinary retention.

PURPOSE: Computerized databases can be an efficient resource to study the epidemiology of peptic ulcer (PU) and upper gastrointestinal complications (UGIC) if we achieve a high positive predictive value (PPV) of outcome definitions. We assessed the PPV of diagnosis codes in THIN, a primary-care medical-record database, to ascertain individuals with uncomplicated PU, and to identify UGIC and Helicobacter pylori infection status (HPIS) among these patients. METHODS: We identified: (1) patients with codes suggesting a first episode of uncomplicated PU; (2) episodes of UGIC among them. The computerized profiles with free-text comments of these individuals were reviewed and classified as definite, possible, or excluded cases. Dates and HPIS were also ascertained. For a sample of definite and possible PU, and for all UGIC cases, primary care physicians were sent a questionnaire for confirmation. RESULTS: The 5296 individuals with codes suggesting PU were classified as definite (49%), possible (25%), and excluded (26%) cases. The PPV for definite/possible PU was 94% (99% for definite, 84% for possible cases). Of the questionnaires with information on HPIS (62%), the PPV and NPV were 100%. The 97 individuals with codes suggesting UGIC were classified as definite (48%), possible (27%), and excluded (22%) cases; the PPV for definite/possible was 95% (100% for definite, 88% for possible cases). Code dates were generally later than medical-record dates. CONCLUSION: The identification of PU cases and their HPIS and UGIC requires careful review of the computerized clinical information with free-text comments. The validation of a sample is needed to confirm the accuracy of the diagnoses.

BACKGROUND: A causal relationship of common streptococcal infections and childhood neuropsychiatric disorders has been postulated. OBJECTIVE: To test the hypothesis of an increased rate of streptococcal infections preceding the onset of neuropsychiatric disorders. METHODS: Case-control study of a large primary care database comparing the rate of possible streptococcal infections in patients aged 2-25 years with obsessive-compulsive disorder (OCD), Tourette syndrome (TS), and tics with that in controls matched for age, gender, and practice (20 per case). We also examined the influence of sociodemographic factors. RESULTS: There was no overall increased risk of prior possible streptococcal infection in patients with a diagnosis of OCD, TS, or tics. Subgroup analysis showed that patients with OCD had a slightly higher risk than controls of having had possible streptococcal infections without prescription of antibiotics in the 2 years prior to the onset of OCD (odds ratio 2.59, 95% confidence interval 1.18, 5.69; p = 0.02). Cases with TS or tics were not more likely to come from more affluent or urban areas, but more cases lived in areas with a greater proportion of white population (p value for trend = 0.05). CONCLUSIONS: The present study does not support a strong relationship between streptococcal infections and neuropsychiatric syndromes such as obsessive-compulsive disorder and Tourette syndrome. However, it is possible that a weak association (or a stronger association in a small susceptible subpopulation) was not detected due to nondifferential misclassification of exposure and limited statistical power. The data are consistent with previous reports of greater rates of diagnosis of Tourette syndrome or tics in white populations.

BACKGROUND: Recent public health efforts, including in the UK and US, have targeted decreasing unnecessary antibiotic use. In the US, prescribing for acute non-specific respiratory infections (ARIs) has decreased, but broad-spectrum antibacterial prescribing has soared. AIM: To assess recent trends in antibacterial prescribing for ARIs in the UK. DESIGN OF STUDY: Retrospective cohort. SETTING: The Health Improvement Network database. METHOD: Outpatient ARI visits from 1 January 1990 to 31 December 2004 were selected. Outcomes were antibacterial and broad-spectrum antibacterial prescriptions per thousand person-years, and the probability of receiving an antibacterial and broad-spectrum prescription conditional on an ARI visit. RESULTS: From 1990 to 2004, antibacterial prescribing rates for ARIs decreased from 55.0 to 30.3 prescriptions/1000 person-years for adults and from 124.8 to 46.3 prescriptions/1000 person-years for children (P=0.001). The probability of receiving an antibacterial prescription after an ARI visit decreased from 70.8% to 59.5% for adults and from 46.1% to 30.8% for children (P=0.003 and 0.007, respectively). Antibacterial prescribing declined faster for younger than for older adults. Broad-spectrum antibacterial prescribing rates decreased from 3.8 to 2.9 prescriptions/1000 person-years for adults and from 5.2 to 2.2 prescriptions/1000 person years for children (P=0.005 and 0.003, respectively). The probability of broad-spectrum prescribing did not demonstrate a significant linear trend for adults (P=0.16), and decreased for children (P=0.01). CONCLUSION: UK antibacterial prescribing for ARIs has declined, similar to US trends, but there was no concomitant increase in low broad-spectrum prescribing. The success of UK strategies for limiting antimicrobial use has implications for programmes in other countries.

BACKGROUND: Pneumonia is a common diagnosis in general practice in the United Kingdom and yet there is little known about the short- and long-term prognosis of people with a diagnosis of pneumonia in general practice. We investigated the short- and long-term survival of people with pneumonia diagnosed in general practice as compared to the general population for all ages. METHODS: This was a general population-based cohort study. Data was obtained from a comprehensive general practice database called The Health Improvement Network (THIN) database which has computerized medical records from 300 general practice surgeries in the United Kingdom. We used Cox regression for our analyses. RESULTS: For pneumonia cases the 30-day mortality was 18.5% and the 3-year mortality was 30.8%. The equivalent figures for the general population controls were 0.4% and 10.3% respectively. The adjusted hazard ratio (HR) for all-cause mortality (for total follow-up time) in pneumonia cases vs. general population was 4.64 (95% CI 4.35-4.95). For the first 30 days the risk of mortality in cases was 46 times more (adj. HR 45.90, 95% CI 36.80-55.20). Even in the period of follow-up 91 days after diagnosis cases were almost 20% more likely to die compared to general population (adj. HR 1.19, 95% CI 1.08-1.31). CONCLUSION: People in general practice who have a diagnosis of pneumonia have a markedly increased mortality in the short-term but some increase in mortality persists during longer-term follow-up.

PURPOSE: The use of non-steroidal anti-inflammatory drugs (NSAIDs) is associated with a reduced risk of developing colorectal and lung cancer. Studies suggesting similar associations in leukaemia have been small and underpowered. We have conducted a large population-based case-control study to determine whether the use of NSAIDs is associated with a reduced risk of acute and chronic leukaemias, and whether their use has any impact on survival in these patients. METHODS: We identified all the incident cases of leukaemia in 'The Health Improvement Network' (THIN) general practice dataset, along with at least four matched controls per case. We used conditional logistic regression to determine odds ratios for NSAID prescription rates and the risk of developing several leukaemia sub-types. We then used Cox regression to determine the association between NSAID prescription rate and risk of death in leukaemia. Hazard ratios were adjusted for gender, age at diagnosis, smoking status and Townsend Score. RESULTS: The risk of leukaemia overall appears to increase marginally with increased use of NSAIDs prior to diagnosis. This is not seen when individual leukaemia sub-types are examined, however, except perhaps in CLL where patients who had received 2-5 prescriptions/year are 34% more likely to be diagnosed with CLL than those who had not had any NSAID prescriptions (O.R. 1.34, p = 0.03, 95% C.I. 1.02-1.74). There was no statistically significant association between exposure to NSAIDs prior to leukaemia diagnosis and survival. CONCLUSION: The use of NSAIDs does not reduce the risk of developing leukaemia, nor do they improve survival.

PURPOSE: Before using computerized databases to study hepatitis C virus (HCV) epidemiology, the validity of the diagnosis must be assessed. We determined the accuracy of HCV diagnostic codes within The Health Improvement Network (THIN), an electronic database containing medical record data from general medical practices in the United Kingdom. METHODS: Patients with initial diagnostic codes for HCV infection and nonspecific viral hepatitis between 2000 and 2007 in the THIN database were identified. Questionnaires were mailed to general practitioners caring for a random sample of 150 of these patients (75 with an HCV code; 75 with a nonspecific viral hepatitis code) to collect information on HCV and other hepatitis diagnoses. We determined the positive predictive value of the database's HCV diagnostic codes and its ability to identify the date of a new HCV diagnosis. RESULTS: Usable surveys were returned for 146 (97%) patients. Among 74 patients with an HCV code and questionnaire data, HCV was confirmed in 64 (positive predictive value, 86%; 95%CI, 77-93%). In 40 (63%), the first recorded diagnosis in THIN was within 30 days of the date reported in the questionnaire (median difference, 11 days; interquartile range, 0-362 days). Among 72 patients with a nonspecific viral hepatitis code, 16 (22%) had HCV, but manual review of the database's electronic records correctly identified 12/16 (75%). CONCLUSIONS: In THIN, the HCV-specific diagnostic codes are highly predictive of HCV infection. After manual review, few patients with a nonspecific viral hepatitis code were misclassified as having HCV infection.

AIMS/HYPOTHESIS: The risk of developing a range of solid tumours is increased in type 2 diabetes, and may be influenced by glucose-lowering therapies. We examined the risk of development of solid tumours in relation to treatment with oral agents, human insulin and insulin analogues. METHODS: This was a retrospective cohort study of people treated in UK general practices. Those included in the analysis developed diabetes >40 years of age, and started treatment with oral agents or insulin after 2000. A total of 62,809 patients were divided into four groups according to whether they received monotherapy with metformin or sulfonylurea, combined therapy (metformin plus sulfonylurea), or insulin. Insulin users were grouped according to treatment with insulin glargine, long-acting human insulin, biphasic analogue and human biphasic insulin. The outcome measures were progression to any solid tumour, or cancer of the breast, colon, pancreas or prostate. Confounding factors were accounted for using Cox proportional hazards models. RESULTS: Metformin monotherapy carried the lowest risk of cancer. In comparison, the adjusted HR was 1.08 (95% CI 0.96-1.21) for metformin plus sulfonylurea, 1.36 (95% CI 1.19-1.54) for sulfonylurea monotherapy, and 1.42 (95% CI 1.27-1.60) for insulin-based regimens. Adding metformin to insulin reduced progression to cancer (HR 0.54, 95% CI 0.43-0.66). The risk for those on basal human insulin alone vs insulin glargine alone was 1.24 (95% CI 0.90-1.70). Compared with metformin, insulin therapy increased the risk of colorectal (HR 1.69, 95% CI 1.23-2.33) or pancreatic cancer (HR 4.63, 95% CI 2.64-8.10), but did not influence the risk of breast or prostate cancer. Sulfonylureas were associated with a similar pattern of risk as insulin. CONCLUSIONS/INTERPRETATION: Those on insulin or insulin secretagogues were more likely to develop solid cancers than those on metformin, and combination with metformin abolished most of this excess risk. Metformin use was associated with lower risk of cancer of the colon or pancreas, but did not affect the risk of breast or prostate cancer. Use of insulin analogues was not associated with increased cancer risk as compared with human insulin.

BACKGROUND: The utility of electronic medical record databases for clinical research relies on the validity and completeness of the recorded medical diagnoses. This study assessed whether the recorded incidence of cancer among patients in The Health Improvement Network (THIN) database is comparable to that expected in the UK based on national cancer registry data. METHODS: We examined incidence rates of any cancer other than non-melanoma skin cancer and the specific cancers colorectal, lung, pancreas, and lymphoma from 1992 to 2007. Indirect standardization was used to calculate standardized incidence ratios (SIR) using age- and sex-specific rates from the UK cancer registry for England and Wales for the corresponding years. RESULTS: Recording of the incidence of all cancers combined in THIN was very close to the expected rates from 2001 to 2007, that is, SIR within 10% of unity. Recording of the solid cancers was less than the expected based on cancer registry data, but with SIRs > 0.80 in 2007 for each cancer. Recording of lymphoma was close to the expected rate for the entire follow-up period. Time and experience with Vision software emerged as important factors in reported incidence rates for all cancers. CONCLUSIONS: For all cancers combined and for lymphoma the observed rates in THIN are very close to those reported in cancer registry data for the years 2001-2007. However, for solid cancers the observed rates in THIN are below those reported in cancer registry data. This may reflect the use of non-specific codes to record solid cancers.