Publications
scientifiques

PURPOSE: Data on cardiovascular outcomes among treated diabetics have been inconsistent. Our goal was to compare cardiovascular outcomes associated with different treatments for diabetes. METHODS: This is a retrospective cohort study of diabetic patients at least 40 years of age treated in general practices participating in The Health Information Network (THIN) data system between 2002 and 2006. Our primary outcome was serious atherosclerotic vascular disease of the heart. RESULTS: Among all diabetics (N = 63 579), the fully adjusted hazard ratios of association with our outcome were 1.2 (1.1, 1.3) for insulin, 1.03 (0.97, 1.09) for sulfonylureas, 0.8 (0.7, 0.8) for biguanide, 1.2 (0.99, 1.5) for meglitinide, 0.5 (0.5, 0.6) for thiazolidinediones, and individually 0.6 (0.5, 0.6) for rosiglitazone, and 0.5 (0.4, 0.7) for pioglitazone. Among those individuals newly diagnosed and treated for diabetes after 2002 (N = 13 576), the adjusted hazard ratios of association with our outcome were 2.4 (2.0, 2.9) for insulin, 1.4 (1.2, 1.7) for sulfonylureas, 0.5 (0.4, 0.5) for biguanide, 0.9 (0.4, 2.1) for meglitinide, 0.8 (0.7, 1.0) for thiazolidinediones, and individually 0.8 (0.6, 1.0) for rosiglitazone, and 0.9 (0.6, 1.4) for pioglitazone. Risk increased as total duration of therapy increased for insulin, sulfonylureas, and biguanide, but decreased with duration for rosiglitazone and pioglitazone. CONCLUSIONS: Overall, insulin was associated with an increased risk of myocardial infarction. Its risk increased with longer use, and risk emerged with longer use of sulfonylureas and biguanide. Conversely, a protective effect emerged with longer use of rosiglitazone or pioglitazone.

OBJECTIVE: To estimate the cost-effectiveness of macrogol 4000 compared to lactulose in the treatment of chronic functional constipation, from the perspective of the National Health Service (NHS) in the UK. METHODS: A decision model depicting the management of chronic functional constipation was constructed using clinical outcomes and resource use values derived from patients suffering from chronic functional constipation in The Health Improvement Network (THIN) Database. The model was used to estimate the cost-effectiveness of a general practitioner (GP) prescribing macrogol 4000 relative to lactulose to treat adults >/=18 years of age suffering from chronic functional constipation. RESULTS: Forty-two per cent (95% confidence interval [CI]: 38%; 46%) of macrogol 4000-treated patients are expected to be successfully treated within 3 months after starting treatment, compared to 31% (95% CI: 27%; 37%) of lactulose-treated patients. Patients' health status at 3 months was estimated to be 0.213 (95% CI: 0.200; 0.223) and 0.210 (95% CI: 0.197; 0.220) quality-adjusted life years (QALYs) in the macrogol 4000 and lactulose groups, respectively. The total 3-monthly NHS cost of treating patients with macrogol 4000 or lactulose was estimated to be pound115 (95% CI: pound98; pound132) and pound102 (95% CI: pound86; pound119), respectively. Hence, the cost per QALY gained with macrogol 4000 was estimated to be pound4333. CONCLUSION: Within the limitations of the model, treatment with macrogol 4000 relative to lactulose is expected to increase the probability of being successfully treated by 35% at 3 months (p<0.0001), although this yields only a 1% improvement in health gain. Nevertheless, macrogol 4000 affords a cost-effective addition to the range of laxatives available for this potentially resource-intensive condition, since it is clinically more effective than lactulose and the cost-effective strategy from the perspective of the NHS.

CONTEXT: Selective serotonin reuptake inhibitors have been reported to increase the risk of upper gastrointestinal tract bleeding. The wide use of these drugs makes such potential risk a public health concern, and identification of factors that may increase or minimize such risk is necessary. OBJECTIVES: To test the association of selective serotonin reuptake inhibitors and venlafaxine hydrochloride therapy with upper gastrointestinal tract bleeding, to identify subgroups of patients at particularly increased risk, and to explore whether acid-suppressing agents may be effective in minimizing risk. DESIGN: Nested case-control study. SETTING: General practice database from the United Kingdom. PARTICIPANTS: One thousand three hundred twenty-one patients with upper gastrointestinal tract bleeding referred to a consultant or hospital and 10 000 control subjects matched for age, sex, and calendar year of the index date. Main Outcome Measure Risk of bleeding associated with selective serotonin reuptake inhibitors and effect of acid-suppressing agents. RESULTS: The percentage of current users of selective serotonin reuptake inhibitors (5.3%) or venlafaxine (1.1%) among case subjects was significantly higher than in matched control subjects (3.0% and 0.3%; adjusted odds ratio [OR], 1.6; 95% confidence interval [CI], 1.2-2.1, and OR, 2.9; 95% CI, 1.5-5.6, respectively). An interaction with nonsteroidal anti-inflammatory drugs (OR, 4.8; 95% CI, 2.8-8.3) was observed, in particular among those not using acid-suppressing agents (OR, 9.1; 95% CI, 4.8-17.3) compared with users of these drugs (OR, 1.3; 95% CI, 0.5-3.3). In addition, an interaction with antiplatelet drugs in nonusers of acid-suppressing agents was suggested (OR, 4.7; 95% CI, 2.6-8.3) compared with users of these drugs (OR, 0.8; 95% CI, 0.3-2.5). CONCLUSIONS: Antidepressants with a relevant blockade action on the serotonin reuptake mechanism increase the risk of upper gastrointestinal tract bleeding. The increased risk may be of particular relevance when these drugs are associated with nonsteroidal anti-inflammatory drugs. Our study findings also provide evidence that use of acid-suppressing agents limits such increased risk.

We hypothesized that digoxin toxicity has declined in recent years, and that the decline is accompanied by reductions in overall utilization and dose. To analyze trends in digoxin toxicity and utilization from 1991 to 2004, we used surveys from the National Center for Health Statistics and Medicaid data in the United States and The Health Improvement Network (THIN) database in the United Kingdom. There was a significant decline in digoxin toxicity hospitalizations in the United States and a decline in ambulatory digoxin toxicity in the United Kingdom. The study demonstrated a reduction in the use of digoxin in the United States, but found no change in digoxin use in the United Kingdom. Finally, the number of prescriptions written for at least 250 microg decreased in the United States and the United Kingdom. The public health burden of digoxin toxicity declined dramatically from 1991 to 2004 in the United Kingdom and the United States.

OBJECTIVE: To determine the incidence of and mortality from bullous pemphigoid and pemphigus vulgaris in the United Kingdom. DESIGN: Retrospective historical cohort study. SETTING: Computerised medical records from the health improvement network, a large population based UK general practice database. PARTICIPANTS: Patients with pemphigus vulgaris and bullous pemphigoid diagnostic codes and age, sex, and practice matched controls. MAIN OUTCOME MEASURES: Incidence and mortality compared with the control population by calendar period, age group, sex, geographical region, and degree of social deprivation. RESULTS: 869 people with bullous pemphigoid and 138 people with pemphigus vulgaris were identified. The median age at presentation for bullous pemphigoid was 80 (range 23-102) years, and 534 (61%) patients were female. The median age at presentation for pemphigus vulgaris was 71 (21-102) years, and 91 (66%) patients were female. Incidences of bullous pemphigoid and pemphigus vulgaris were 4.3 (95% confidence interval 4.0 to 4.6) and 0.7 (0.6 to 0.8) per 100 000 person years. The incidence of bullous pemphigoid increased over time; the average yearly increase was 17% (incidence rate ratio=1.2, 95% confidence interval 1.1 to 1.2). An average yearly increase in incidence of pemphigus vulgaris of 11% (incidence rate ratio=1.1, 1.0 to 1.2) occurred. The risk of death for patients with bullous pemphigoid was twice as great as for controls (adjusted hazard ratio=2.3, 95% confidence interval 2.0 to 2.7). For pemphigus vulgaris, the risk of death was three times greater than for controls (adjusted hazard ratio=3.3, 2.2 to 5.2). CONCLUSIONS: Incidences of bullous pemphigoid and pemphigus vulgaris are increasing. The reasons for the changes in incidence are not clearly understood but have implications for identifying causative factors. Both disorders are associated with a high risk of death. Previous estimates may have underestimated the risk of death associated with these diseases.

OBJECTIVE: The objective of this study was to evaluate the association between foot ulcers (DFU) and lower-extremity amputation (LEA) and chronic kidney disease (CKD) in patients with diabetes. RESARCH DESIGN AND METHODS: This was a retrospective cohort study of individuals enrolled between 2002 and 2006 who were aged > or =35 years, had a history of diabetes, and were cared for in general practice. The physicians participated in The Health Information Network of the U.K. RESULTS: The presence of DFU or LEA and estimated glomerular filtration rate (eGFR) were evaluated in 90,617 individuals with a median time of observation of 2.4 years. Of these individuals 378 had an LEA and 2,619 had a DFU. CKD (eGFR <60 ml/min per 1.73 m(2)) was noted in 23,350 (26%) individuals in our cohort. For the development of DFU compared with our reference group (group 1 [eGFR > or =60 ml/min per 1.73 m(2)]), the hazard ratio (HR) for group 2 (eGFR > or =30 and <60 ml/min per 1.73 m(2)) was 1.85 (95% CI 1.71-2.01) and for group 3 (eGFR <30 ml/min per 1.73 m(2)) was 3.92 (3.23-4.75) (all P < 0.001). For LEA, the HR for group 2 was 2.08 (1.68-2.58) and for group 3 was 7.71 (5.29-11.26) (all P < 0.001). CONCLUSIONS: In this observational study, there is a strong association between stage of CKD and DFU or LEA that is probably not just related to the presence of peripheral arterial disease. Individuals with even moderate CKD (eGFR <60 ml/min per 1.73 m(2)) have an increased risk for DFU and LEA.

BACKGROUND: Statins are widely used as a cholesterol lowering medication, reduce cardiovascular mortality and morbidity in high risk patients; and only rarely cause serious adverse drug reactions (ADRs). UK primary care databases of morbidity and prescription data, which now cover several million people, have potential for more powerful analytical approaches to study ADRs including adjusting for confounders and examining temporal effects. METHODS: Case-crossover design in detecting statin associated myopathy ADR in 93, 831 patients, using two independent primary care databases (1991-2006). We analysed risk by drug class, by disease code and cumulative year, exploring different cut-off exposure times and confounding by temporality. RESULTS: Using a 12 and 26 week exposure period, large risk ratios (RR) are associated with all classes of statins and fibrates for myopathy: RR 10.6 (9.8-11.4) and 19.9 (17.6-22.6) respectively. At 26 weeks, the largest risks are with fluvastatin RR 33.3 (95% CI 16.8-66.0) and ciprofibrate (with previous statin use) RR 40.5 (95% CI 13.4-122.0). AT 12 weeks the differences between cerivastatin and atorvastatin RR for myopathy were found to be significant, RR 2.05 (95% CI 1.2-3.5), and for rosuvastatin and fluvastatin RR 3.0 (95% CI 1.6-5.7). After 12 months of statin initiation, the relative risk for myopathy for all statins and fibrates increased to 25.7 (95% CI 21.8-30.3). Furthermore, this signal was detected within 2 years of first events being recorded. Our data suggests an annual incidence of statin induced myopathy or myalgia of around 11.4 for 16, 591 patients or 689 per million per year. CONCLUSION: There may be differential risks associated with some classes of statin and fibrate. Myopathy related to statin or fibrate use may persist after a long exposure time (12 months or more). These methods could be applied for early detection of harmful drug side effects, using similar primary care diagnostic and prescribing data.

Antibiotic use has been associated with an increased risk of cancer in epidemiologic studies. We evaluated the association between antibiotic use and the risk of primary lung cancer by conducting a prospective case-control study nested in a cohort of subjects who were 40 to 84 years old in 1995 to 2004, with at least 2 years of enrollment in The Health Improvement Network. There were 4,336 cases of primary lung cancer. A random sample of 10,000 controls was frequency matched to the cases for age, sex, and calendar year of diagnosis. Antibiotic exposure was measured by the total number of antibiotic prescriptions and the cumulative number of days on antibiotics since enrollment. We discounted exposure 1 year before the date of cancer diagnosis. Relative risks (RR) and 95% confidence intervals (95% CI) were estimated using conditional logistic regression. Smoking, chronic obstructive pulmonary disease, respiratory infections, body mass index, and health care utilization were introduced in the model. Compared with subjects with no prescription of antibiotics before the index date, the crude RR of lung cancer was 2.52 (95% CI, 2.25-2.83) among those who received 10 or more prescriptions. The corresponding RR was 1.31 (95% CI, 1.10-1.57) upon adjustment for confounders. We used directed acyclic graphs to illustrate that the observed higher risk of lung cancer among antibiotic users may be due to the increased frequency of infections in patients with subclinical cancer and to shared causes between cancer and infections. Current evidence is insufficient to support or refute a carcinogenic effect of antibiotics.

OBJECTIVE: To assess the epidemiology and treatment of storage symptoms suggestive of overactive bladder (OAB) and voiding symptoms suggestive of bladder outlet obstruction (BOO) because of benign prostatic hyperplasia in UK general practice. PATIENTS AND METHODS: This was a retrospective analysis of data collected between 2000 and 2006 and entered in The Health Improvement Network general practice database, containing medical records for > 1 million men (aged >or= 18 years) in the UK. Using Read codes, we analysed the prevalence of storage and voiding lower urinary tract symptoms (LUTS) as well as prescribing trends for 5alpha-reductase inhibitors (5ARIs) and alpha-blockers for LUTS secondary to BOO and antimuscarinics for OAB. RESULTS: In 2006, the prevalence of diagnosed LUTS/OAB was only 0.3% and the recorded prevalence of LUTS/BOO was only 2.2%. Treatment rates also remained low throughout the study period. In the 12 months before 1 January 2006, only 25% of men diagnosed with OAB and 6-7% of men with storage LUTS received antimuscarinics, whereas 36% of men with a record of LUTS/BOO received alpha-blockers and/or 5ARIs. Alpha-blockers were prescribed to approximately 10% of men diagnosed with OAB or storage LUTS who did not have any recorded BOO diagnosis or symptoms. CONCLUSION: Diagnosis of both storage and voiding LUTS occurs at much lower rates than indicated by prevalence estimates. Despite the availability of effective prescription therapies, many men with storage and/or voiding LUTS may not be receiving appropriate treatment in UK general practice.