Population Impact of Drug Interactions with Warfarin: A Real-World Data Approach.

OBJECTIVE: To investigate the population impact of previously reported interactions between warfarin and other drugs on international normalized ratio (INR) levels. METHODS: Using The Health Improvement Network (THIN), a United Kingdom primary care database, a cohort of warfarin users between 2005 and 2013 (N = 121,962) was followed until the first qualifying prescription for the potential interacting drugs was evaluated. Sixteen sub-cohorts, one for each study drug, and a control sub-cohort of warfarin were ascertained. Short-term changes in INR levels were assessed by comparing INR values measured before and after initiation of the interacting drug with paired Student's t-test. We also evaluated the proportion of patients with INR values outside the therapeutic range (INR: 2-3). RESULTS: Miconazole use was associated with the highest mean increase in INR (+3.35), followed by amiodarone (+1.28), fluconazole (+0.79), metronidazole (+0.75) and nystatin (+0.65). After subtracting the natural INR variation observed in the control sub-cohort, supra-therapeutic levels (INR > 3) were found in 53.2% (miconazole), 45.5% (amiodarone), 23.3% (metronidazole), 23.2% (fluconazole) and 17.6% (nystatin) of patients initiating treatment with these drugs. Carbamazepine use was associated with a mean INR decrease of -0.63 and infra-therapeutic levels (INR < 2) were observed in 46.2% of patients initiating carbamazepine. For all other drugs, the change was small to moderate, in absolute INR units (+0.23 to +0.55) and in the proportion of patients with INR levels out of therapeutic range (<16%). CONCLUSIONS: Clinically potentially important interactions were observed in several study drugs. The majority of them, although confirmed, had little impact after adjusting for standard INR variability in the general population of warfarin users.

Cardiovascular events and all-cause mortality in a cohort of 57,946 patients with type 2 diabetes: associations with renal function and cardiovascular risk factors.

BACKGROUND: Diabetes and chronic kidney disease (CKD) are independent predictors of death and cardiovascular events and their concomitant prevalence has increased in recent years. The aim of this study was to characterize the effect of the estimated glomerular filtration rate (eGFR) and other factors on the risk of death and cardiovascular events in patients with type 2 diabetes. METHODS: A cohort of 57,946 patients with type 2 diabetes who were aged 20-89 years in 2000-2005 was identified from The Health Improvement Network, a UK primary care database. Incidence rates of death, myocardial infarction (MI), and ischemic stroke or transient ischemic attack (IS/TIA) were calculated overall and by eGFR category at baseline. eGFR was calculated using the Modification of Diet in Renal Disease (MDRD) study equation. Death, MI and IS/TIA cases were detected using an automatic computer search and IS/TIA cases were further ascertained by manual review of medical records. Hazard ratios (HRs) and their corresponding 95% confidence intervals (CIs) for death, MI, and IS/TIA associated with eGFR category and other factors were estimated using Cox regression models adjusted for potential confounders. RESULTS: Overall incidence rates of death (mean follow-up time of 6.76 years), MI (6.64 years) and IS/TIA (6.56 years) were 43.65, 9.26 and 10.39 cases per 1000 person-years, respectively. A low eGFR (15-29 mL/min) was associated with an increased risk of death (HR: 2.79; 95% CI: 2.57-3.03), MI (HR: 2.33; 95% CI: 1.89-2.87) and IS/TIA (HR: 1.77; 95% CI: 1.43-2.18) relative to eGFR ≥ 60 mL/min. Other predictors of death, MI and IS/TIA included age, longer duration of diabetes, poor control of diabetes, hyperlipidemia, smoking and a history of cardiovascular events. CONCLUSIONS: In patients with type 2 diabetes, management of cardiovascular risk factors and careful monitoring of eGFR may represent opportunities to reduce the risks of death, MI and IS/TIA.

Patterns of Antiplatelet Therapy in Patients Who Have Experienced an Acute Coronary Event: A Descriptive Study in UK Primary Care.

BACKGROUND: Antiplatelet (AP) therapy is well established for the secondary prevention of acute coronary events. However, patients may discontinue treatment, often owing to gastrointestinal (GI) complications, leaving them at elevated risk of recurrent cardiovascular events. OBJECTIVES: This descriptive retrospective study assessed trends in prescription of AP agents and coprescription of gastroprotective therapy, after an acute coronary event. Discontinuation of AP therapy within 2 years of an event and factors predicting discontinuation were investigated. METHODS: The study was conducted in a UK primary care setting from 2000 to 2008; a total of 27, 351 patients aged 50 to 84 years were included in the analysis. Main outcome measures were exposures to low-dose acetylsalicylic acid (ASA), clopidogrel, and proton pump inhibitors (PPIs). RESULTS: At 90 days after an acute coronary event, 85.9% of patients had been prescribed some form of AP therapy and 33.6% of patients who were issued at least 1 ASA prescription in this period were also issued a PPI prescription. The use of dual antiplatelet therapy (DAT) 90 days after an event increased from 2% in 2000 to over 50% in 2008. An estimated 15.1% of patients on ASA monotherapy and 37.5% on DAT discontinued treatment within 1 year. A bleeding event during follow-up, including upper GI bleeding or hemorrhagic stroke, was the strongest predictor of discontinuation. CONCLUSION: Although most patients were prescribed AP therapy in the 90 days following an acute coronary event, a substantial proportion discontinued DAT or ASA monotherapy within 1 year. It is essential that physicians consider strategies to reduce the risk of discontinuation of AP therapy.

Risk of uncomplicated peptic ulcer disease in a cohort of new users of low-dose acetylsalicylic acid for secondary prevention of cardiovascular events.

BACKGROUND: The aim of this study was to analyse the risk of uncomplicated peptic ulcer disease (PUD) in a cohort of new users of low-dose acetylsalicylic acid (ASA) for secondary prevention of cardiovascular events in a UK primary care setting. METHODS: New users of low-dose ASA for secondary prevention of cardiovascular events, aged 50-84 years in 2000-2007, were identified from The Health Improvement Network. Among those 38,975 individuals, 309 patients were considered to be incident cases of uncomplicated PUD. Incidence of uncomplicated PUD was calculated and a nested case-control analysis adjusted for potential confounding factors was performed to calculate the odds ratios (ORs) for the association of potential risk factors with uncomplicated PUD. RESULTS: The crude incidence of uncomplicated PUD was 1.41 per 1000 person-years (95% confidence interval [CI], 1.26-1.58). Individuals with a history of PUD were more likely to develop uncomplicated PUD than those without such a history (hazard ratio [HR], 2.22, 95% CI, 1.60-3.09). In nested case-control analyses, the risk of uncomplicated PUD was associated with current use of non-steroidal anti-inflammatory drugs, oral steroids or acid suppressants. Other risk factors for developing uncomplicated PUD included smoking, stress, depression, anaemia and social deprivation. CONCLUSION: Our results indicate that several risk factors significantly increase the risk of development of uncomplicated PUD in new users of low-dose ASA. Therefore, physicians should monitor ASA users for gastrointestinal symptoms and signs of ulcer, particularly if they have additional risk factors.

Observational data for comparative effectiveness research: an emulation of randomised trials of statins and primary prevention of coronary heart disease.

This article reviews methods for comparative effectiveness research using observational data. The basic idea is using an observational study to emulate a hypothetical randomised trial by comparing initiators versus non-initiators of treatment. After adjustment for measured baseline confounders, one can then conduct the observational analogue of an intention-to-treat analysis. We also explain two approaches to conduct the analogues of per-protocol and as-treated analyses after further adjusting for measured time-varying confounding and selection bias using inverse-probability weighting. As an example, we implemented these methods to estimate the effect of statins for primary prevention of coronary heart disease (CHD) using data from electronic medical records in the UK. Despite strong confounding by indication, our approach detected a potential benefit of statin therapy. The analogue of the intention-to-treat hazard ratio (HR) of CHD was 0.89 (0.73, 1.09) for statin initiators versus non-initiators. The HR of CHD was 0.84 (0.54, 1.30) in the per-protocol analysis and 0.79 (0.41, 1.41) in the as-treated analysis for 2 years of use versus no use. In contrast, a conventional comparison of current users versus never users of statin therapy resulted in a HR of 1.31 (1.04, 1.66). We provide a flexible and annotated SAS program to implement the proposed analyses.

Antihypertensive drugs and risk of incident gout among patients with hypertension: population based case-control study.

OBJECTIVE: To determine the independent associations of antihypertensive drugs with the risk of incident gout among people with hypertension. DESIGN: Nested case-control study. SETTING: UK general practice database, 2000-7. PARTICIPANTS: All incident cases of gout (n = 24,768) among adults aged 20-79 and a random sample of 50,000 matched controls. MAIN OUTCOME MEASURE: Relative risk of incident gout associated with use of antihypertensive drugs. RESULTS: After adjusting for age, sex, body mass index, visits to the general practitioner, alcohol intake, and pertinent drugs and comorbidities, the multivariate relative risks of incident gout associated with current use of antihypertensive drugs among those with hypertension (n = 29,138) were 0.87 (95% confidence interval 0.82 to 0.93) for calcium channel blockers, 0.81 (0.70 to 0.94) for losartan, 2.36 (2.21 to 2.52) for diuretics, 1.48 (1.40 to 1.57) for ß blockers, 1.24 (1.17 to 1.32) for angiotensin converting enzyme inhibitors, and 1.29 (1.16 to 1.43) for non-losartan angiotensin II receptor blockers. Similar results were obtained among those without hypertension. The multivariate relative risks for the duration of use of calcium channel blockers among those with hypertension were 1.02 for less than one year, 0.88 for 1-1.9 years, and 0.75 for two or more years and for use of losartan they were 0.98, 0.87, and 0.71, respectively (both P<0.05 for trend). CONCLUSIONS: Compatible with their urate lowering properties, calcium channel blockers and losartan are associated with a lower risk of incident gout among people with hypertension. By contrast, diuretics, ß blockers, angiotensin converting enzyme inhibitors, and non-losartan angiotensin II receptor blockers are associated with an increased risk of gout.

Hormonal therapies and meningioma: is there a link?

BACKGROUND: The aetiology of meningiomas is largely unknown although hormones have been suggested to play a role. METHODS: A cohort study was performed to evaluate hormone-related factors associated with meningioma. Patients (12-89 years) with a first diagnosis of meningioma (January 1996-June 2008) were identified from The Health Improvement Network UK primary care database and age- and sex-matched to controls (n=10000) from the same cohort. Odds ratios (ORs) were calculated following a nested case control analysis using unconditional logistic regression. RESULTS: In total, 745 patients with meningioma were identified from a study population of 2171287. No significantly increased risk of meningioma was found among female users of oral contraceptives (OR: 1.15; CI: 0.67-1.98), hormone replacement therapy (OR: 0.99; CI: 0.73-1.35) or low-dose cyproterone acetate (CPA; OR: 1.51; CI: 0.33-6.86) compared with non-users. There was a significantly increased risk of meningioma among male users of androgen analogues (OR: 19.09; CI: 2.81-129.74) and among users of high-dose CPA (OR: 6.30; CI: 1.37-28.94) compared with non-users, however there were only three cases currently using these drugs. No significant association was found between meningioma and prostate, breast, or genital cancers. CONCLUSIONS: Our results do not support a role for exogenous hormone use by females in meningioma development. The risk in males was only observed with high-dose, short-term (<1 year) therapy. IMPACT: While hormonal cancers and therapies are not associated with meningioma in females, the risk in males requires further investigation.

Discontinuation of low dose aspirin and risk of myocardial infarction: case-control study in UK primary care.

OBJECTIVES: To evaluate the risk of myocardial infarction and death from coronary heart disease after discontinuation of low dose aspirin in primary care patients with a history of cardiovascular events. DESIGN: Nested case-control study. SETTING: The Health Improvement Network (THIN) database in the United Kingdom. PARTICIPANTS: Individuals aged 50-84 with a first prescription for aspirin (75-300 mg/day) for secondary prevention of cardiovascular outcomes in 2000-7 (n=39,513). MAIN OUTCOME MEASURES: Individuals were followed up for a mean of 3.2 years to identify cases of non-fatal myocardial infarction or death from coronary heart disease. A nested case-control analysis assessed the risk of these events in those who had stopped taking low dose aspirin compared with those who had continued treatment. RESULTS: There were 876 non-fatal myocardial infarctions and 346 deaths from coronary heart disease. Compared with current users, people who had recently stopped taking aspirin had a significantly increased risk of non-fatal myocardial infarction or death from coronary heart disease combined (rate ratio 1.43, 95% confidence interval 1.12 to 1.84) and non-fatal myocardial infarction alone (1.63, 1.23 to 2.14). There was no significant association between recently stopping low dose aspirin and the risk of death from coronary heart disease (1.07, 0.67 to 1.69). For every 1000 patients, over a period of one year there were about four more cases of non-fatal myocardial infarction among patients who discontinued treatment with low dose aspirin (recent discontinuers) compared with patients who continued treatment. CONCLUSIONS: Individuals with a history of cardiovascular events who stop taking low dose aspirin are at increased risk of non-fatal myocardial infarction compared with those who continue treatment.

Frequency and risk factors of gout flares in a large population-based cohort of incident gout.

OBJECTIVE: So far, few data are available to characterize the flare history of patients with gout. The objective of this study was to describe the frequency and risk factors of gout flares with special consideration of the comorbidity. METHODS: A cohort study was conducted in a U.K. general practice database (The Health Improvement Network) including all patients aged 20-89 years diagnosed with incident gout between the years 2000 and 2007. RESULTS: In this study, 23 857 incident gout patients (mean age 61.9 years) were included, overall incidence rate was 2.68 (95% CI 2.65, 2.72) per 1000 person-years. The proportion of patients with at least one flare during the follow-up period (mean 3.8 years) was 36.9% (n=8806). A history of ischaemic heart disease [hazard ratio (HR) 1.12 (95% CI 1.06, 1.19)], hypertension [HR 1.15 (95% CI 1.10, 1.20)] and renal failure [HR 1.33 (95% CI 1.20, 1.48)] were independently associated with a higher risk of a first gout flare. Use of allopurinol at initial gout diagnosis was associated with a lower risk [HR 0.80 (95% CI 0.75, 0.85)]. CONCLUSIONS: Gout flares are relatively common among patients with gout. Some of the underlying cardiometabolic comorbid conditions are themselves independent risk factors for flares, which further contribute to the complexity of treatment of gout flares.

Acute pancreatitis in association with type 2 diabetes and antidiabetic drugs: a population-based cohort study.

OBJECTIVE: Previous observational studies have found an increased risk of acute pancreatitis among type 2 diabetic patients. However, limited information is available on this association and specifically on the role of antidiabetic treatment. Our aim, therefore, was to further assess the risk of acute pancreatitis in adult patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: We performed a population-based case-control analysis nested in a cohort of 85,525 type 2 diabetic patients and 200,000 diabetes-free individuals from the general population using data from The Health Improvement Network database. Subjects were followed up to ascertain incident cases of acute pancreatitis. RESULTS: We identified 419 cases of acute pancreatitis, 243 in the general population and 176 in the diabetes cohort. Incidence rates were 30.1 and 54.0 per 100,000 person-years in the general population and the diabetes cohort, respectively. In the cohort analysis, the adjusted incidence rate ratio of acute pancreatitis in diabetic patients versus that in the general population was 1.77 (95% CI 1.46-2.15). The magnitude of this association decreased with adjustment for multiple factors in the nested case-control analysis (adjusted odds ratio 1.37 [95% CI 0.99-1.89]). Furthermore, we found that the risk of acute pancreatitis was decreased among insulin-treated diabetic patients (0.35 [0.20-0.61]). CONCLUSIONS: Type 2 diabetes may be associated with a slight increase in the risk of acute pancreatitis. We also found that insulin use in type 2 diabetes might decrease this risk. Further research is warranted to confirm these associations.

Heart failure, myocardial infarction, lung cancer and death in COPD patients: a UK primary care study.

BACKGROUND: The leading comorbidities and causes of death in patients with chronic obstructive pulmonary disease (COPD) are lung cancer and cardiovascular disease. The aim of this study was to establish the incidence of lung cancer, myocardial infarction and heart failure in patients with COPD in UK primary care. METHODS: The General Practice Research Database (GPRD) was used to identify a cohort of 1927 patients with a first recorded diagnosis of COPD. This cohort was followed for up to 5 years to identify new diagnoses of lung cancer, myocardial infarction and heart failure. Mortality was also assessed. The relative risk (RR) of each outcome in the COPD cohort was compared with that in a control cohort with no diagnosis of COPD. RESULTS: The risk of lung cancer was significantly increased in individuals with a diagnosis of COPD compared with those with no COPD diagnosis (RR: 3.33; 95% confidence interval [CI]: 2.33-4.75; adjusted for age, sex and smoking status). A diagnosis of COPD was also associated with a significant increase in the risk of heart failure (age- and sex-adjusted RR: 2.94; 95% CI: 2.46-3.51) and death (age- and sex-adjusted RR: 2.76; 95% CI: 2.45-3.12), but not myocardial infarction (age- and sex-adjusted RR: 1.18; 95% CI: 0.81-1.71). CONCLUSIONS: Patients with a diagnosis of COPD are at significantly increased risk of lung cancer, heart failure and death compared with the general population. They do not appear to be at increased risk of myocardial infarction.

Risk of Upper Gastrointestinal Bleeding in a Cohort of New Users of Low-Dose ASA for Secondary Prevention of Cardiovascular Outcomes.

The Health Improvement Network UK primary care database was used to identify a cohort of 38 077 individuals aged 50-84 years with a first prescription of low-dose acetylsalicylic acid (ASA; 75-300 mg/day) for secondary prevention of cardiovascular or cerebrovascular events during 2000-2007. From this cohort, 169 incident cases of upper gastrointestinal bleeding (UGIB) were identified. Controls with no UGIB (n = 2000) were frequency-matched to the cases by age, sex, and follow-up time. A nested case-control analysis was performed to determine risk factors associated with UGIB. The incidence of UGIB was 1.1 per 1000 person-years (95% CI, 1.0-1.3). Low-dose ASA users with a history of peptic ulcer disease had an increased risk of UGIB compared with those without (Relative Risk [RR], 4.59; 95% CI, 2.87-7.33). Concomitant use of ASA and clopidogrel (RR, 1.61; 95% CI, 0.85-3.05) or non-steroidal anti-inflammatory drugs (NSAIDs; RR, 2.92; 95% CI, 1.77-4.82) conferred an increased risk of UGIB compared with ASA monotherapy. Discontinuation of ASA therapy (RR: 0.71, 95% CI, 0.42-1.20) and PPI co-treatment given since the start of ASA therapy (RR, 0.56; 95% CI, 0.33-0.96) were associated with a reduced risk of UGIB. In conclusion, in a cohort of individuals receiving low-dose ASA for secondary prevention of cardiovascular or cerebrovascular events, patients with a history of peptic ulcer disease, or who were receiving clopidogrel or NSAIDs had an increased risk of UGIB. The prescription of PPI therapy at the initiation of low-dose ASA reduced the risk of UGIB by almost half.

Gastroesophageal reflux disease in children and adolescents in primary care.

OBJECTIVES: To determine the prevalence and incidence of a diagnosis of gastroesophageal reflux disease (GERD) in children and adolescents in UK primary care, and to assess comorbidities that are associated with a diagnosis of GERD. MATERIAL AND METHODS: Incident GERD cases during 2000-05 were identified from The Health Improvement Network (THIN) UK primary care database via a computer search for diagnostic codes for GERD, followed by manual review of the patient records. RESULTS: We identified 1700 children with a first diagnosis of GERD during 2000-05. The incidence of GERD was 0.84 per 1000 person-years. The incidence decreased with age from 1.48 per 1000 person-years among 1-year-old children until the age of 12 years, whereupon it increased to a maximum at 16-17 years of 2.26 per 1000 person-years for girls and 1.75 per 1000 person-years for boys. Pregnant adolescents were not included in the study. In addition to typical GERD symptoms (epigastric pain, heartburn, reflux, regurgitation), 21.2% of children reported nausea or vomiting. Children with neurological disorders were at increased risk of a GERD diagnosis. Hiatus hernia and congenital esophageal disorders were also associated with a diagnosis of GERD. Children and adolescents using antiepileptics, oral/inhaled steroids, beta-agonists and paracetamol had an increased risk of a GERD diagnosis. CONCLUSIONS: The incidence of a GERD diagnosis was age-dependent and was highest among very young children and older female adolescents. Children with neurological impairments and other comorbidities were at increased risk of a GERD diagnosis.

Risk of myocardial infarction and overall mortality in survivors of venous thromboembolism.

BACKGROUND: Venous thromboembolism (VTE) and thromboembolic arterial diseases are usually considered to be distinct entities, but there is evidence to suggest that these disorders may be linked. The aim of this study was to determine whether a diagnosis of VTE increases the long-term risk of myocardial infarction (MI). METHODS: The incidence rate (IR) and relative risk (RR) of MI in a cohort of patients with a diagnosis of VTE (n = 4890) compared with that of a control cohort without prior VTE (n = 43 382) were evaluated in the UK General Practice Research Database (GPRD). Death during follow-up was also determined. Patients were followed for up to 8 years (mean of 3 years). RESULTS: The IR of MI per 1000 person-years was 4.1 (95% CI: 3.1-5.3) for the VTE cohort and 3.5 (95% CI: 3.2-3.8) for the control cohort. The IR of MI was highest in the first year after the VTE episode, but overall differences between the two cohorts were not significant (RR of MI associated with VTE: 1.2; 95% CI: 0.9-1.6). The risk of death was higher in the VTE cohort than the control cohort, even after adjustment for cancer, heart failure and ischaemic heart disease (RR: 2.4; 95% CI: 2.2-2.6), particularly during the first year after VTE (RR: 3.8; 95% CI: 3.4-4.3). CONCLUSION: A VTE episode does not significantly increase the risk of MI, but does increase the risk of death, particularly in the first year following VTE diagnosis.

Incidence and risk factors for psoriasis in the general population.

OBJECTIVES: To study the clinical spectrum of psoriasis and the incidence in the general population and to identify risk factors associated with the occurrence of psoriasis. DESIGN: Prospective cohort study with nested case-control analysis. SETTING: The data source was the United Kingdom General Practice Research Database containing computerized clinical information entered by general practitioners (GPs). PATIENTS: The study population comprised patients receiving a first-ever diagnosis of psoriasis between January 1, 1996, and December 31, 1997, and free of cancer. INTERVENTIONS: Diagnosis of psoriasis was validated in a random sample of 14% of all ascertained cases requesting confirmation by the GPs. Nested case-control analysis included 3994 cases of psoriasis and a random sample of 10 000 controls frequency matched to cases by age, sex, and calendar year. MAIN OUTCOME MEASURES: Incidence rate of psoriasis and estimates of the odds ratio (OR) and 95% confidence interval (CI) for psoriasis as associated with selected risk factors. RESULTS: The incidence rate of psoriasis was 14 per 10 000 person-years. Patients with antecedents of skin disorders and skin infection within the last year carried the highest risk of developing psoriasis (OR, 3.6 [95% CI, 3.2-4.1], and OR, 2.1 [95% CI, 1.8-2.4], respectively). Also, smoking was found to be an independent risk factors for psoriasis (OR, 1.4 [95% CI, 1.3-1.6]). We did not find an association between risk of psoriasis and antecedents of stress, diabetes, hypertension, hyperlipidemia, cardiovascular disease, or rheumatoid arthritis. CONCLUSIONS: The incidence rate in our study was higher than those published in other studies, probably owing to our case definition that considered cases recorded by the GPs independently of a specialist confirmation. Our results confirm the association between psoriasis, skin disorders, and smoking.

Gout and risk of Parkinson disease: a prospective study.

BACKGROUND: Several reports suggest that higher levels of serum uric acid are associated with a lower risk of Parkinson disease (PD). None of these studies, however, evaluated the potential association between gout, a condition characterized by hyperuricemia, and the risk of PD. OBJECTIVE: To estimate prospectively the association between gout diagnosis and the risk of PD. METHODS: We conducted a case-control study nested in the General Practice Research Database, a computerized database that gathers information on more than 3 million Britons followed up by their general practitioners. PD cases occurring between January 1995 and December 2001 were identified, and matched with up to 10 controls by sex, age, practice, and start of follow-up. We obtained information on history of gout and use of anti-gout medication using the computerized medical records. RESULTS: During the study period, we identified 1,052 PD cases and 6,634 controls. Individuals with previous history of gout had a lower risk of developing PD (OR 0.69, 95% CI 0.48, 0.99). This association was evident among men (OR 0.60, 95% CI 0.40, 0.91) but not among women (OR 1.26, 95% CI 0.57, 2.81; p for interaction: 0.11). Initiation of anti-gout medication was associated with a lower risk of PD (OR 0.57, 95% CI 0.19, 1.70). CONCLUSION: Gout is associated with a lower risk of Parkinson disease (PD). Our findings provide additional support for a potential link between uric acid and PD. Further research is required to explore a potential effect modification by sex.

Use of antidepressants and risk of lung cancer.

OBJECTIVE: To evaluate the effect of antidepressant use on lung cancer risk. METHODS: We conducted a case-control study nested in a cohort of patients 40-84 year-old in 1995-2004, without a prior diagnosis of cancer using The Health Improvement Network (THIN) database in the UK. Cases comprised 4,336 patients with a first diagnosis of primary lung cancer. A sample of 10,000 controls was frequency-matched to the cases for age, sex, and the calendar year of diagnosis. The index date for exposure definition was one year before the diagnosis for cases and one year before a random date for controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using conditional logistic regression models adjusted for potential confounders. RESULTS: Selective serotonin reuptake inhibitor (SSRI) use during the year preceding the index date with treatment duration of at least one year had an OR of 0.59 (95% CI 0.41, 0.86). The corresponding OR was 1.23 (95% CI 0.96, 1.58) for tricyclic antidepressants (TCAs). CONCLUSIONS: SSRI use did not increase the lung cancer risk and might be associated with a reduced risk. However, residual confounding might explain the apparent protective effect found for SSRI use, as well as the marginally elevated risk observed among TCA users.

Rosuvastatin safety: a comprehensive, international pharmacoepidemiology programme.

Results from clinical trials and clinical practice have shown statins to be generally well tolerated with a low frequency of clinically relevant side effects. Nevertheless, there are rare occasions when adverse events (AEs), sometimes serious, may occur. Rosuvastatin is the newest statin to be approved in the USA and many other countries. As part of the continued assessment of the benefit-risk profile of rosuvastatin, AstraZeneca has developed a progressive, comprehensive pharmacoepidemiology programme to complement safety data obtained from randomised clinical trials and spontaneous reporting systems, which have demonstrated that rosuvastatin has a safety profile in line with comparator statins. This programme comprises nine studies conducted in recognised centres of excellence assessing over 50,000 patients treated with rosuvastatin. It consists of three components: patient characteristics studies (four studies), safety evaluation studies (four studies); and review of data generated from the Prescription-Event Monitoring (PEM) study, designed and run by an independent third party. Patient characteristics studies are designed to describe the characteristics and drug utilisation patterns of new users of rosuvastatin compared with new users of other statins in automated databases. Safety evaluation studies will examine the rates of specific AEs in different cohorts of statin users and determine risk factors for these events using data recorded prospectively in automated databases with case adjudication via medical record review. The independent PEM study will monitor any significant events recorded by general practitioners since starting rosuvastatin treatment. This article is an overview of the rationale and methodology of the rosuvastatin pharmacoepidemiology programme.

Upper gastrointestinal complications among users of paracetamol.

Non-steroidal anti-inflammatory drugs (NSAIDs) have been associated with upper gastrointestinal complications such as bleeding or perforation. Paracetamol has been traditionally considered a safer alternative to NSAIDs. In a previous case-control study we found that paracetamol at high doses increased the risk of upper gastrointestinal complications. We proposed to review all studies addressing the association between paracetamol and upper gastrointestinal complications and placed our results in the context of existing literature. We conducted a nested case-control study using the United Kingdom General Practice Research Database during the period between April 1993 and October 1998. Then we performed a systematic review of the literature indexed in MEDLINE published between 1980 and 2004. We identified a total of twelve studies that assessed the association between paracetamol and upper gastrointestinal complications. We used a fixed effects model to calculate a summary estimate of these studies. In the nested case control study, use of paracetamol was associated with a small elevated risk of upper gastrointestinal complications (relative risk (RR), 1.3; 95% confidence interval (CI), 1.1-1.5). The RR was 3.6 (95% CI, 2.6-5.1) among paracetamol users of more than 2 g daily, whereas smaller doses did not increase the risk. Among the twelve studies identified in the systematic review, estimates ranged from 0.2 through 2.0 with a summary estimate of 1.3 (95% CI, 1.2-1.5). Our findings indicate that use of paracetamol at the doses most commonly used confer little or no increased risk of upper gastrointestinal complications. More data are needed to confirm or refute the suggestion that high-dose paracetamol is associated with an increased risk of upper gastrointestinal complications of the same magnitude as the one observed with traditional NSAIDs.

Antidepressants and risk of upper gastrointestinal bleeding.

Selective serotonin reuptake inhibitors (SSRIs) are nowadays the most widely used antidepressants in the world, mainly because they have a better adverse reaction profile and a higher safety margin in overdoses, when compared to other antidepressants. These drugs recently have been the target of important debates concerning safety issues, among them the possibility that they may increase the risk of bleeding. Over the 1990s, an increasing number of individual cases of bleeding disorders were reported in the literature and to the pharmacovigilance programmes which prompted several epidemiological and pharmacological studies. In this review we have examined all available data. The whole evidence supports the hypothesis that antidepressants with a relevant blockade action on serotonin reuptake mechanism increase the risk of bleeding. Such disorders may have different degrees of severity and may be located anywhere in the body. The epidemiological evidence is, however, more robust for upper gastrointestinal bleeding. It has been estimated that upper gastrointestinal bleeding may occur at a frequency ranging from 1 in 100 to 1 in 1,000 patient-years of exposure to high-affinity drugs (the SSRIs), with the very old patients being in the highest part of the range. The increased risk may be of particular relevance when the SSRIs are associated with NSAIDs as well as low-dose aspirin.