A methodological comparison of two European primary care databases and replication in a US claims database: inhaled long-acting beta-2-agonists and the risk of acute myocardial infarction.

PURPOSE: Results from observational studies on inhaled long-acting beta-2-agonists (LABA) and acute myocardial infarction (AMI) risk are conflicting, presumably due to variation in methodology. We aimed to evaluate the impact of applying a common study protocol on consistency of results in three databases. METHODS: In the primary analysis, we included patients from two GP databases (Dutch-Mondriaan, UK-CPRD GOLD) with a diagnosis of asthma and/or COPD and at least one inhaled LABA or a "non-LABA inhaled bronchodilator medication" (short-acting beta-2-agonist or short-/long-acting muscarinic antagonist) prescription between 2002 and 2009. A claims database (USA-Clinformatics) was used for replication. LABA use was divided into current, recent (first 91 days following the end of a treatment episode), and past use (after more than 91 days following the end of a treatment episode). Adjusted hazard ratios (AMI-aHR) and 95 % confidence intervals (95 % CI) were estimated using time-dependent multivariable Cox regression models stratified by recorded diagnoses (asthma, COPD, or both asthma and COPD). RESULTS: For asthma or COPD patients, no statistically significant AMI-aHRs (age- and sex-adjusted) were found in the primary analysis. For patients with both diagnoses, a decreased AMI-aHR was found for current vs. recent LABA use in the CPRD GOLD (0.78; 95 % CI 0.68-0.90) and in Mondriaan (0.55; 95 % CI 0.28-1.08), too. The replication study yielded similar results. Adjusting for concomitant medication use and comorbidities, in addition to age and sex, had little impact on the results. CONCLUSIONS: By using a common protocol, we observed similar results in the primary analysis performed in two GP databases and in the replication study in a claims database. Regarding differences between databases, a common protocol facilitates interpreting results due to minimized methodological variations. However, results of multinational comparative observational studies might be affected by bias not fully addressed by a common protocol.

Ascertainment of acute liver injury in two European primary care databases.

PURPOSE: The purpose of this study was to ascertain acute liver injury (ALI) in primary care databases using different computer algorithms. The aim of this investigation was to study and compare the incidence of ALI in different primary care databases and using different definitions of ALI. METHODS: The Clinical Practice Research Datalink (CPRD) in UK and the Spanish "Base de datos para la Investigación Farmacoepidemiológica en Atención Primaria" (BIFAP) were used. Both are primary care databases from which we selected individuals of all ages registered between January 2004 and December 2009. We developed two case definitions of idiopathic ALI using computer algorithms: (i) restrictive definition (definite cases) and (ii) broad definition (definite and probable cases). Patients presenting prior liver conditions were excluded. Manual review of potential cases was performed to confirm diagnosis, in a sample in CPRD (21%) and all potential cases in BIFAP. Incidence rates of ALI by age, sex and calendar year were calculated. RESULTS: In BIFAP, all cases considered definite after manual review had been detected with the computer algorithm as potential cases, and none came from the non-cases group. The restrictive definition of ALI had a low sensitivity but a very high specificity (95% in BIFAP) and showed higher rates of agreement between computer search and manual review compared to the broad definition. Higher incidence rates of definite ALI in 2008 were observed in BIFAP (3.01 (95% confidence interval (CI) 2.13-4.25) per 100,000 person-years than CPRD (1.35 (95% CI 1.03-1.78)). CONCLUSIONS: This study shows that it is feasible to identify ALI cases if restrictive selection criteria are used and the possibility to review additional information to rule out differential diagnoses. Our results confirm that idiopathic ALI is a very rare disease in the general population. Finally, the construction of a standard definition with predefined criteria facilitates the timely comparison across databases.

Antidepressant prescribing in five European countries: application of common definitions to assess the prevalence, clinical observations, and methodological implications.

PURPOSE: Drug utilization studies have applied different methods to various data types to describe medication use, which hampers comparisons across populations. The aim of this study was to describe the time trends in antidepressant prescribing in the last decade and the variation in the prevalence, calculated in a uniform manner, in seven European electronic healthcare databases. METHODS: Annual prevalence per 10,000 person-years (PYs) was calculated for 2001-2009 in databases from Spain, Germany, Denmark, the United Kingdom (UK), and the Netherlands. Prevalence data were stratified according to age, sex, antidepressant type (selective serotonin re-uptake inhibitors [SSRIs] or tricyclic antidepressants [TCAs]) and major indications. RESULTS: The age- and sex-standardized prevalence was lowest in the two Dutch (391 and 429 users per 10,000 PYs) and highest in the two UK (913 and 936 users per 10,000 PYs) populations in 2008. The prevalence in the Danish, German, and Spanish populations was 637, 618, and 644 users per 10,000 PY respectively. Antidepressants were prescribed most often in 20- to 60-year-olds in the two UK populations compared with the others. SSRIs were prescribed more often than TCAs in all except the German population. In the majority of countries we observed an increasing trend of antidepressant prescribing over time. Two different methods identifying recorded indications yielded different ranges of proportions of patients recorded with the specific indication (15-57% and 39-69% for depression respectively). CONCLUSION: Despite applying uniform methods, variations in the prevalence of antidepressant prescribing were obvious in the different populations. Database characteristics and clinical factors may both explain these variations.

Incidence rates and trends of hip/femur fractures in five European countries: comparison using e-healthcare records databases.

Hip fractures represent a major public health challenge worldwide. Multinational studies using a common methodology are scarce. We aimed to estimate the incidence rates (IRs) and trends of hip/femur fractures over the period 2003-2009 in five European countries. The study was performed using seven electronic health-care records databases (DBs) from Denmark, The Netherlands, Germany, Spain, and the United Kingdom, based on the same protocol. Yearly IRs of hip/femur fractures were calculated for the general population and for those aged ≥50 years. Trends over time were evaluated using linear regression analysis for both crude and standardized IRs. Sex- and age-standardized IRs for the UK, Netherlands, and Spanish DBs varied from 9 to 11 per 10,000 person-years for the general population and from 22 to 26 for those ≥50 years old; the German DB showed slightly higher IRs (about 13 and 30, respectively), whereas the Danish DB yielded IRs twofold higher (19 and 52, respectively). IRs increased exponentially with age in both sexes. The ratio of females to males was ≥2 for patients aged ≥70-79 years in most DBs. Statistically significant trends over time were only shown for the UK DB (CPRD) (+0.7% per year, P < 0.01) and the Danish DB (-1.4% per year, P < 0.01). IRs of hip/femur fractures varied greatly across European countries. With the exception of Denmark, no decreasing trend was observed over the study period.

Incidence of and risk factors for severe hypoglycaemia in treated type 2 diabetes mellitus patients in the UK--a nested case-control analysis.

AIMS: To assess incidence rates (IRs) of and identify risk factors for incident severe hypoglycaemia in patients with type 2 diabetes newly treated with antidiabetic drugs. METHODS: Using the UK-based General Practice Research Database, we performed a retrospective cohort study between 1994 and 2011 and a nested case-control analysis. Ten controls from the population at risk were matched to each case with a recorded severe hypoglycaemia during follow-up on general practice, years of history in the database and calendar time. Using multivariate conditional logistic regression analyses, we adjusted for potential confounders. RESULTS: Of 130,761 patients with newly treated type 2 diabetes (mean age 61.7 ± 13.0 years), 690 (0.5%) had an incident episode of severe hypoglycaemia recorded [estimated IR 11.97 (95% confidence interval, CI, 11.11-12.90) per 10,000 person-years (PYs)]. The IR was markedly higher in insulin users [49.64 (95% CI, 44.08-55.89) per 10,000 PYs] than in patients not using insulin [8.03 (95% CI, 7.30-8.84) per 10,000 PYs]. Based on results of the nested case-control analysis increasing age [≥ 75 vs. 20-59 years; adjusted odds ratio (OR), 2.27; 95% CI, 1.65-3.12], cognitive impairment/dementia (adjusted OR, 2.00; 95% CI, 1.37-2.91), renal failure (adjusted OR, 1.34; 95% CI, 1.04-1.71), current use of sulphonylureas (adjusted OR, 4.45; 95% CI, 3.53-5.60) and current insulin use (adjusted OR, 11.83; 95% CI, 9.00-15.54) were all associated with an increased risk of severe hypoglycaemia. CONCLUSIONS: Severe hypoglycaemia was recorded in 12 cases per 10,000 PYs. Risk factors for severe hypoglycaemia included increasing age, renal failure, cognitive impairment/dementia, and current use of insulin or sulphonylureas.

Incidence of cancer in the general population and in patients with or without atopic dermatitis in the U.K.

BACKGROUND: Atopic dermatitis (AD) affects approximately 20% of children and 1-3% of adults in developed countries. OBJECTIVE: To study the incidence of cancer in patients with AD in the U.K. general population. METHODS: We conducted a follow-up study in the U.K. using The Health Improvement Network (THIN) database. We calculated the incidence rate (IR) of the first occurrence of overall cancer, lymphoma, melanoma and nonmelanoma skin cancer (NMSC) in the general population, in patients with AD and in individuals without AD. In addition we calculated the IR ratio (IRR) of overall cancer and subtypes of cancer in patients with AD vs. those without. RESULTS: The study population included 4,518,131 patients [2,336,230 (51·7%) female]. There were 129,972 subjects [68,688 (52·8%) female] with a diagnosis of cancer (excluding NMSC). The IR (per 10,000 person-years) of cancer (excluding NMSC) was 42·41 [95% confidence interval (CI) 42·18-42·64]; of lymphoma 1·70 (95% CI 1·65-1·74); of skin melanoma 1·71 (95% CI 1·67-1·76) and of NMSC 11·76 (95% CI 11·64-11·88). The age- and sex-adjusted IRR for cancer (excluding NMSC) was 1·49 (95% CI 1·39-1·61); for lymphoma 2·21 (95% CI 1·65-2·98); for melanoma 1·74 (95% CI 1·25-2·41); and for NMSC 1·46 (95% CI 1·27-1·69). CONCLUSIONS: Our results indicate an increased incidence of cancer overall as well as of specific cancer subtypes, including lymphoma, in patients with AD. Further studies are needed to disentangle the effects of treatment for AD from AD itself.

[Prevalence of potential drug-drug interactions in ambulatory patients with statin therapy]. / Prävalenz potentieller Arznei- mittelinteraktionen bei ambulanten Patienten unter Statin-Therapie.

AIM: To asses the prevalence of potentially critical drug-drug interactions (DDIs) in outpatients treated with a statin. PATIENTS/METHODS: Data of patients (e.g. age, sex, comorbidities, individual statin, number of drugs, number of diagnoses) were collected from 242 Swiss practitioners. The medication was screened electronically for potentially critical DDIs. RESULTS: We included 2742 statin-treated patients (mean age 65.1 +/- 11.2 [SD] years, 3.2 +/- 1.6 diagnoses, 4.9 +/- 2.4 drugs prescribed) from the German (53.3%), French (36%) or Italian speaking (10.7%) part of Switzerland. Of those, 401 (14.6%) had a total of 591 potentially severe DDIs; 190 patients (6.9%) had potential statin DDIs, 288 (10.5%) potential non-statin DDIs, mainly due to pharmacodynamic mechanisms. The prevalence of potential DDIs was similar between regions, except for a trend for a higher prevalence of drug-statin interactions in the French-speaking part. The number of drugs per patient and a diagnosis of arrhythmia or heart failure were identified as risk factors for DDIs. CONCLUSIONS: Drug combinations with potentially severe DDIs are common in patients treated with statins due to pharmacotherapy of their co-morbidities. Special attention in this specific population should be drawn on patients with polypharmacy and those with drug treatments for arrhythmia or heart failure.

[Recurrent acute pancreatitis during pravastatin-therapy]. / Wiederholte akute Pankreatitis unter Pravastatin-therapie.

Acute pancreatitis can rarely be caused also by drugs. Several substances from different drug classes have been associated with the occurrence of acute pancreatitis. Regarding the class of the hydroxymethylglutaryl-CoA-reductase-inhibitors (statins) case-reports have been published in the literature in association with each individual statin. We present a 60-years-old male who developed twice an acute pancreatitis while being treated with pravastatin. Because some case reports describe the reoccurrence of acute pancreatitis after exposure to a different statin, recommendations for further therapy remain complex. There are also case reports of pancreatitis associated with fibrates and information on rare adverse reactions associated with ezetimibe is sparse.

[Metformin-associated lactic acidosis in a patient with pre-existing risk factors]. / Laktatazidose in Assoziation mit Metformin bei einer Patientin mit vorbestehenden Risikofaktoren.

Lactic acidosis is a serious clinical situation associated with a high case fatality rate. Lactic acidosis is particularly found in conditions with an insufficient supply of oxigen in the tissue. Other causes for lactic acidosis can be hepatic or renal insufficiency. For the therapy of overweight patients with type 2 diabetes metformin is the first choice if diet and physical training have been ineffective. Metformin, however, has the potential to increase serumlactate. Therefore its ability to cause lactic acidosis is controversely discussed. We present a 64-year-old female patient with metformin-associated lactic acidosis. She had several pre-existing risk factors to develop a lactic acidosis. On her referral to the hospital she suffered from acute renal failure which is considered to be a contraindication for the use of metformin.

Risk of cataract in patients treated with statins.

BACKGROUND: Studies in dogs showed that some hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) are associated with cataract when administered in excessive doses. Clinical safety data of statins regarding cataract development in humans have been of limited value so far. OBJECTIVE: To determine whether long-term use of statins is associated with an increased risk of cataract. METHODS: We conducted a case-control analysis using data from the United Kingdom-based General Practice Research Database. The main outcome was a first-time diagnosis of cataract and/or cataract extraction in patients aged 40 to 79 years. Controls were matched to cases on age, sex, practice, calendar time, and duration of medical history in the database. Use of statins, fibrates, or other lipid-lowering drugs was compared with nonuse of any lipid-lowering drug, stratified by exposure duration and dose. RESULTS: We identified 7405 cases and 28 327 controls. Long-term use of statins (eg, > or =30 prescriptions) was not associated with an increased cataract risk (adjusted odds ratio [OR], 0.9; 95% confidence interval [CI], 0.5-1.6), nor was use of fibrates or of other lipid-lowering drugs (adjusted OR, 0.5; 95% CI, 0.3-1.1; and OR, 0.7; 95% CI, 0.1-5.6, respectively). We found evidence that concomitant use of simvastatin and erythromycin, a potent inhibitor of simvastatin metabolism, is associated with an increased cataract risk (adjusted odds ratio, 2.2; 95% confidence interval, 1.2-4.1). CONCLUSIONS: Our study provides evidence that long-term use of therapeutic statin doses does not increase the risk of developing cataract. Concomitant use of erythromycin and simvastatin may increase the cataract risk.