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PURPOSE Our objective was to calculate the positive predictive value (PPV) of the ICD-9 diagnosis code for angioedema when physicians adjudicate the events by electronic health record review. Our secondary objective was to evaluate the inter-rater reliability of physician adjudication. METHODS Patients from the Cardiovascular Research Network previously diagnosed with heart failure who were started on angiotensin-converting enzyme inhibitors (ACEI) during the study period (July 1, 2006 through September 30, 2015) were included. A team of two physicians per participating site adjudicated possible events using electronic health records for all patients coded for angioedema for a total of five sites. The PPV was calculated as the number of physician-adjudicated cases divided by all cases with the diagnosis code of angioedema (ICD-9-CM code 995.1) meeting the inclusion criteria. The inter-rater reliability of physician teams, or kappa statistic, was also calculated. RESULTS There were 38 061 adults with heart failure initiating ACEI in the study (21 489 patient-years). Of 114 coded events that were adjudicated by physicians, 98 angioedema events were confirmed for a PPV of 86% (95% CI: 80%, 92%). The kappa statistic based on physician inter-rater reliability was 0.65 (95% CI: 0.47, 0.82). CONCLUSIONS ICD-9 diagnosis code of 995.1 (angioneurotic edema, not elsewhere classified) is highly predictive of angioedema in adults with heart failure exposed to ACEI.

Purpose: The purpose of this study was to examine the trends in heart failure (HF) epidemiology and diagnostic work-up in Sweden.Methods: Adults with incident HF (>= 2 ICD-10 diagnostic codes) w ...

Background: The clinical development program of sacubitril/valsartan (sac/val) for heart failure with reduced ejection fraction (HFrEF) only included a very limited number of patients being naive to prior angiotensin converting enzyme inhibitors (ACEis) or angiotensin II receptor antagonists (ARBs). Recent studies support the use of sac/val in hospitalised HF patients without prior ACEis/ARBs. This study aims to compare HF patients newly prescribed either sac/val or ACEis/ARBs. Methods: Retrospective non-interventional cohort study describing two mutually exclusive adult patient cohorts diagnosed with HFrEF either initiating sac/val or ACEis/ARBs. All patients were naive to both sac/val and ACEis/ARBs for 12 months prior to the first prescription. All patients had a left ventricular ejection fraction (LVEF) ≤40%. Patients were identified any time between 1 st July 2015 and 31 st Dec 2018 in the Optum® de-identified EHR dataset from providers across the continuum of care. Results: 2,414 patients were initiated on sac/val, 36,563 on ACEis/ARBs. Mean age was 66.1 (SD 12.9) and 67.2 years (SD 13.7) for sac/val and ACEis/ARBs users, respectively. Sac/val patients were more likely to be male: 70.8% vs 67.2% (p Conclusions: This real-world study indicates that sac/val tends to be newly prescribed to younger, male HFrEF patients with lower LVEF and a higher proportion of cardio resynchronization therapy devices compared with patients newly initiated on ACEis/ARBs. The prevalence of ischemic heart disease is similar between the groups.

Background and purpose Sacubitril/valsartan (sac/val), an angiotensin receptor neprilysin inhibitor, reduces the risk for cardiovascular (CV) death or hospitalization for heart failure (HF) in HF with reduced ejection fraction (HFrEF). Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are approved in patients with type 2 diabetes (T2D) and have shown to reduce the CV risk in T2D patients with established CV or at risk of CV disease. The SGLT2i dapagliflozin has shown to improve outcomes in patients with chronic HFrEF, with or without T2D, when used in addition to standard of care including sac/val. As the use of SGLT2i in HF evolves, and given the large overlap of HF and T2D populations, it is of interest to understand the population with concomitant use of sac/val and SGLT2i. This study describes the clinical characteristics of patients treated concomitantly with sac/val and SGLT2i or concomitantly with sac/val and dipeptidyl peptidase-4 inhibitors (DPP4i) or glucagon-like peptide-1 receptor agonists (GLP1), two comparable second line anti-diabetic drug classes. Methods This retrospective non-interventional study describes two mutually exclusive adult patient cohorts diagnosed with HF and T2D concomitantly prescribed sac/val and SGLT2i (cohort 1), or concomitantly prescribed sac/val and DDP4i/GLP1 (cohort 2). The index date was defined as the first date of concomitant use with prescriptions overlapping a minimum of 21 days. Patients were identified any time between 1/1/2015 and 30/6/2019 in the Optum® de-identified electronic health record (EHR) data from providers across the continuum of care. Results 2.3 million HF patients were identified, and 41.6% had a T2D diagnosis. 560 patients were concomitantly prescribed sac/val and SGLT2i (cohort 1) and 1,566 concomitantly sac/val and DDP4/GLP1 (cohort 2). There was a higher proportion of females in cohort 2 (35.0% vs 27.9%). Mean age was higher in cohort 2 (66.4 vs 61.4 years). The mean estimated glomerular filtration rate was 85.93 (SD 23.43) ml/min/1.73m2 (cohort 1) and 72.10 (Std. 27.11) ml/min/1.73m2 (cohort 2). The proportion of stage 3 CKD (30 ml/min/1.73m2) was 11.8% (cohort 1) and 24.4% (cohort 2). Mean systolic blood pressure was similar, 120 mmHg (cohort 1) and 122 mmHg (cohort 2). Mean hemoglobin was 13.60 g/dl (cohort 1) and 12.43 g/dl (cohort 2). Median (IQR) NT-proBNP differed between the two cohorts, 914 (2154) pg/ml (cohort 1) and 2,290 (5,301) pg/ml (cohort 2) but with complete values available in only 17.7 and 19.0% of each cohort. Conclusions This descriptive analysis of concomitant prescription of sac/val and SGLT2i or DPP4/GLP1 highlights differences in the clinical characteristics between the two cohorts. The patients treated with sac/val and SGLT2i start with a more favorable clinical profile compared to the patients treated with sac/val and DPP4/GLP1. Further analyses are needed to determine if these differences are driven by age, gender or other factors. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Novartis Pharma AG

Aim: We examined characteristics of early sacubitril/valsartan users in a large US electronic health records database. Patients & methods: We identified three cohorts of patients with heart failure (HF): sacubitril/valsartan patients with a prior HF diagnosis; patients with HF with reduced ejection fraction; and patients with HF treated with an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker and a β-blocker. Results: Sacubitril/valsartan patients were younger than patients in the other cohorts; the mean age of sacubitril/valsartan patients increased by 2 years in the first 15 months of marketing. Most sacubitril/valsartan patients had prior use of HF treatment. Conclusion: Overall, sacubitril/valsartan patients resembled those in the HF with reduced ejection fraction cohort, and commonly used other drugs for HF.

PURPOSE: Results from observational studies on the same exposure-outcome association may be inconsistent because of variations in methodological factors, clinical factors or health care systems. We evaluated the consistency of results assessing the association between antidepressant use and the risk of hip/femur fractures in three European primary care databases using two different study designs. METHODS: Cohort and nested case control studies were conducted in three European primary care databases (Spanish BIFAP, Dutch Mondriaan and UK THIN) to assess the association between use of antidepressants and hip/femur fracture. A common protocol and statistical analysis plan was applied to harmonize study design and conduct between data sources. RESULTS: Current use of antidepressants was consistently associated with a 1.5 to 2.5-fold increased risk of hip/femur fractures in all data sources with both designs, with estimates for SSRIs generally higher than those for TCAs. In general, risk estimates in Mondriaan, the smallest data source, were higher compared to the other data sources. This difference may be partially explained by an interaction between SSRI and age in Mondriaan. Adjustment for GP-recorded lifestyle factors and matching on general practice had negligible impact on adjusted relative risk estimates. CONCLUSION: We found a consistent increased risk of hip/femur fracture with current use of antidepressants across different databases and different designs. Applying similar pharmacoepidemiological study methods resulted in similar risks for TCA use and some variation for SSRI use. Some of these differences may express real (or natural) variance in the exposure-outcome co-occurrences. Copyright © 2016 John Wiley & Sons, Ltd.

The purpose of this study is to evaluate the performance and validity of the case-crossover (CCO) and self-controlled case-series (SCCS) designs when studying the association between hip/femur fracture (HF) and antidepressant (AD) use in general practitioner databases. In addition, comparability with cohort and case-control designs is discussed. Adult patients with HF and who received an AD prescription during 2001-2009 were identified from UK's The Health Improvement Network (THIN) and the Dutch Mondriaan databases. AD exposure was classified into current, recent and past/non-use (reference). In the CCO, for each patient, a case moment (date of HF) and four prior control moments at -91, -182, -273 and -365 days were defined. In SCCS, incidence of HF was compared between exposure states. Conditional logistic regression was used in the CCO and Poisson regression in the SCCS to compute odds ratios and incidence rate ratios, respectively. In CCO, we adjusted for time-varying co-medication and in SCCS for age. Adjusted estimates for the effect of current AD exposure on HF were higher in the CCO (co-medication-adjusted odds ratio, THIN: 2.24, 95% confidence interval [CI]: 2.04-2.47; Mondriaan: 2.57, 95%CI [1.50, 4.43]) than in the SCCS (age-adjusted incidence rate ratio, THIN: 1.41, 95%CI [1.32, 1.49]; Mondriaan: 2.14, 95%CI [1.51, 3.03]). The latter were comparable with the traditional designs. Case-only designs confirmed the association between AD and HF. The CCO design violated assumptions in this study with regard to exchangeability and length of exposure, and transient effects on outcome. The SCCS seems to be an appropriate design for assessing AD-HF association. Copyright © 2016 John Wiley & Sons, Ltd.

AIMS: To analyse real-world treatment patterns of sacubitril/valsartan (sac/val) using data from a pharmacy database in Germany. METHODS AND RESULTS: A retrospective cohort study of 26 191 adult patients (aged ≥ 18 years) in the IMS® longitudinal prescriptions database in Germany who were dispensed sac/val from January 2016 to June 2017 was conducted. The analysis included sac/val dose titration assessed in the 6 months from first sac/val prescription; prescriptions of concomitant cardiovascular medications in the 6 months pre- and post-index and compliance and persistence during 12 months post-index. Two-thirds of patients were prescribed the lowest sac/val dose of 50 mg twice daily (b.i.d.) at index and up-titration during the first 6 months was attempted in 41% of these patients. Ten percent of patients prescribed 200 mg b.i.d. at index had to be stably down-titrated; among patients prescribed 50 or 100 mg b.i.d. at index that were up-titrated, > 80% remained on the higher dose. Overall, the mean daily diuretic dose decreased by 25% after initiation of sac/val. High compliance and persistence rates were observed across sac/val doses, increasing with higher sac/val dose at index. Prior dose of angiotensin-converting enzyme inhibitor or angiotensin receptor blocker had only minor impact on first sac/val dose, compliance and persistence. CONCLUSIONS: Most patients prescribed sac/val are not initiated on the recommended dose nor up-titrated as recommended by the EU Summary of Product Characteristics. Initiation of sac/val was associated with high persistence and compliance and a dose reduction of diuretics. Barriers to up-titration must be explored. peerReviewed

Since the introduction of DPP-4 inhibitors, vildagliptin has accumulated extensive efficacy/effectiveness and safety data from various meta-analyses of clinical trials, large randomized controlled trials, non-interventional studies, and post-authorization safety studies. In this non-interventional post-authorization study, we explored if vildagliptin is associated with an increased risk of hepatic events vs. other non-insulin antidiabetic drugs (NIADs) in a real-world setting. A cohort study was performed in adult T2DM patients with a vildagliptin or NIAD prescription between January 20and June 2014 with data from five European electronic healthcare databases from the UK (CPRD), Germany and France (IMS), Denmark (OPED) and Sweden (National Registers). Patients with cancer, HIV/AIDS or insulin prior to the index date (date of first vildagliptin or NIAD prescription in the study period) were excluded. Age- and sex-adjusted incidence rate ratios (aIRRs) were estimated in current vildagliptin vs. current other NIAD users using negative binomial regression. We included 738,054 patients, of which 20,973 received vildagliptin (mean follow-up 1.4 years, 28,330 cumulative vildagliptin patient-years). The database-specific aIRR estimates for serious hepatic events were not suggestive of an increased risk with vildagliptin (range of individual aIRR: 0.29-0.55), with two data sources having an upper limit of the 95% confidence interval (CI) 3-times upper limit of normal (ULN) together with bilirubin >2-times ULN (only assessed in CPRD) was 0.72 (95% CI: 0.42-1.25). In this real-world setting there was no evidence of an increased risk of hepatic toxicity with vildagliptin exposure compared to other NIADs across five European databases. Disclosure R. Williams: Employee; Self; Clinical Practice Research Datalink, London, UK. W. Kothny: Employee; Self; Novartis AG. Stock/Shareholder; Self; Novartis AG. C. Serban: Employee; Self; Novartis AG. Stock/Shareholder; Self; Novartis AG. P.M. Paldánius: Employee; Self; Novartis AG. Stock/Shareholder; Self; Novartis AG. R. Schlienger: Employee; Self; Novartis AG. Stock/Shareholder; Self; Novartis AG.

PURPOSE: Studies on drug utilization usually do not allow direct cross-national comparisons because of differences in the respective applied methods. This study aimed to compare time trends in BZDs prescribing by applying a common protocol and analyses plan in seven European electronic healthcare databases. METHODS: Crude and standardized prevalence rates of drug prescribing from 2001-2009 were calculated in databases from Spain, United Kingdon (UK), The Netherlands, Germany and Denmark. Prevalence was stratified by age, sex, BZD type [(using ATC codes), i.e. BZD-anxiolytics BZD-hypnotics, BZD-related drugs and clomethiazole], indication and number of prescription. RESULTS: Crude prevalence rates of BZDs prescribing ranged from 570 to 1700 per 10 000 person-years over the study period. Standardization by age and sex did not substantially change the differences. Standardized prevalence rates increased in the Spanish (+13%) and UK databases (+2% and +8%) over the study period, while they decreased in the Dutch databases (-4% and -22%), the German (-12%) and Danish (-26%) database. Prevalence of anxiolytics outweighed that of hypnotics in the Spanish, Dutch and Bavarian databases, but the reverse was shown in the UK and Danish databases. Prevalence rates consistently increased with age and were two-fold higher in women than in men in all databases. A median of 18% of users received 10 or more prescriptions in 2008. CONCLUSION: Although similar methods were applied, the prevalence of BZD prescribing varied considerably across different populations. Clinical factors related to BZDs and characteristics of the databases may explain these differences. Copyright © 2015 John Wiley & Sons, Ltd. Language: en

BACKGROUND: Results from observational studies may be inconsistent because of variations in methodological and clinical factors that may be intrinsically related to the database (DB) where the study is performed. OBJECTIVES: The objectives of this paper were to evaluate the impact of applying a common study protocol to study benzodiazepines (BZDs) (anxiolytics, hypnotics, and related drugs) and the risk of hip/femur fracture (HFF) across three European primary care DBs and to investigate any resulting discrepancies. METHODS: To measure the risk of HFF among adult users of BZDs during 2001-2009, three cohort and nested case control (NCC) studies were performed in Base de datos para la Investigacion Farmacoepidemiologica en Atencion Primaria (BIFAP) (Spain), Clinical Practice Research Datalink (CPRD) (UK), and Mondriaan (The Netherlands). Four different models (A-D) with increasing levels of adjustment were analyzed. The risk according to duration and type of BZD was also explored. Adjusted hazard ratios (cohort), odds ratios (NCC), and their 95% confidence intervals were estimated. RESULTS: Adjusted hazard ratios (Model C) were 1.34 (1.23-1.47) in BIFAP, 1.66 (1.54-1.78) in CPRD, and 2.22 (1.55-3.29) in Mondriaan in cohort studies. Adjusted odds ratios (Model C) were 1.28 (1.16-1.42) in BIFAP, 1.60 (1.49-1.72) in CPRD, and 1.48 (0.89-2.48) in Mondriaan in NCC studies. A short-term effect was suggested in Mondriaan, but not in CPRD or BIFAP. All DBs showed an increased risk with the concomitant use of anxiolytic and hypnotic drugs. CONCLUSIONS: Applying similar study methods to different populations and DBs showed an increased risk of HFF in BZDs users but differed in the magnitude of the risk, which may be because of inherent differences between DBs. Copyright © 2015 John Wiley & Sons, Ltd.

This study aimed to provide early insights into sacubitril/valsartan (sac/val) prescription patterns and the demographic and clinical characteristics of patients prescribed sac/val in primary care and cardiology settings in Germany.The study used electronic medical records from the German IMS® Disease Analyzer database. Patients with ≥1 prescription for sac/val during 1 January-31 December 2016 (n = 1643) were identified and followed up for ≤12 months from first prescription. Patients with ≥1 heart failure (HF) diagnosis during the study period, ≥1 additional HF diagnosis in the full history of the database, and ≥1 prescription for an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker and a β-blocker during the study period, without a prescription for sac/val (n = 25,264), were included as a reference cohort. Changes in clinical parameters in the 12 months before and after sac/val initiation were investigated and compared with those from the PARADIGM-HF study.The characteristics of patients prescribed sac/val more closely resembled those of patients enrolled in PARADIGM-HF (e.g. younger age, higher proportion of men than women, lower systolic blood pressure) than patients in the reference cohort. Most patients were initiated on the lowest dose of sac/val irrespective of clinical setting. Significant decreases (p 0.001) in NT-proBNP and glycated haemoglobin levels were observed following sac/val initiation.Patients prescribed sac/val had similar baseline demographics and clinical characteristics to those from PARADIGM-HF, and most patients were initiated on the lowest dose. Changes in clinical parameters before and after initiation mirrored findings from the PARADIGM-HF study.

Real-world evidence on the risk of angioedema associated with angiotensin-converting enzyme inhibitors (ACEIs) in patients with heart failure (HF) is scarce. This non-interventional study aimed to estimate the incidence of and risk factors for angioedema in patients with HF initiating an ACEI in real-world practice. This was a retrospective cohort study using claims data from the PharMetrics Plus database, supplemented with consumer health data, from 1 January 2007 to 31 March 2015. Patients with HF initiating an ACEI were followed up for a maximum of 1 year, until the first occurrence of angioedema or until cohort exit. Angioedema incidence rates were estimated and stratified by potential risk factors such as race, age, sex, and time from initiation of ACEI therapy. For each risk factor, the unadjusted and adjusted hazard ratio (HR) was calculated; exploratory analyses were carried out to account for all potential confounders. We identified 21,639 patients with HF initiating an ACEI (mean age 58 years; 35.6% women; mean follow-up 205 days). The 1-year incidence of angioedema per 1000 patient-years was 3.3 [95% confidence interval (CI) 2.4–4.5]. The incidence was higher in Black [6.2 (95% CI 3.1–12.5)] than in non-black [2.9 (95% CI 2.1–4.1)] patients, higher in women [5.2 (95% CI 3.4–7.9)] than in men [2.3 (95% CI 1.5–3.6)], and greatest in the first 30 days of ACEI therapy. The risk of angioedema in patients with HF initiating an ACEI observed in this study is in line with published estimates for the general patient population treated with ACEIs.

The aim of this non-interventional, multi-database, analytical cohort study was to assess the cardiovascular (CV) safety of vildagliptin vs other non-insulin antidiabetic drugs (NIADs) using real-world data from 5 European electronic healthcare databases. Patients with type 2 diabetes aged >= 18 years on NIAD treatment were enrolled. Adjusted incidence rate ratios (IRRs) and 95% confidence intervals (CIs) for the outcomes of interest (myocardial infarction [MI], acute coronary syndrome [ACS], stroke, congestive heart failure [CHF], individually and as a composite) were estimated using negative binomial regression. Approximately 2.8% of the enrolled patients (n = 738 054) used vildagliptin at any time during the study, with an average followup time of 1.4 years, resulting in a cumulative current vildagliptin exposure of 28 330 person-years. The adjusted IRRs (vildagliptin [+other NIADs] vs other NIADs) were in the range of 0.61 to 0.97 (MI), 0.55 to 1.60 (ACS), 0.02 to 0.77 (stroke), 0.49 to 1.03 (CHF), and 0.22 to 1.02 (composite CV outcomes). The IRRs and their 95% CIs were close to 1, demonstrating no increased risk of adverse CV events, including the risk of CHF, with vildagliptin vs other NIADs in real-world conditions.

A non-interventional study suggested that use of angiotensin-converting enzyme inhibitors (ACEIs) or aliskiren was associated with an angioedema risk three times that of beta-blockers (BBs). The aim was to assess angioedema incidence rates (IRs) and the relative angioedema risk of aliskiren compared to other antihypertensive drugs (AHDs). A cohort study in hypertensive patients with an AHD prescription between 2007 and 2012 was conducted using data from the US PharMetrics Plus™ claims database. Angioedema was identified using the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9CM) code 995.1. Additionally, a nested case–control analysis was conducted to assess the relative angioedema risk of aliskiren or other AHDs versus BBs. A total of 3,090,114 patients were included (aliskiren n = 30,720). There were 15,744 angioedema events (IR 2.28/1000 person-years; 95% confidence interval (CI) 2.24–2.32). Aliskiren IRs were: any aliskiren 2.58 (2.08–3.17), aliskiren monotherapy 1.71 (0.74–3.37), aliskiren fixed-dose combination (FDC) 1.27 (0.41–2.96), and aliskiren free-standing combination (FSC) 2.93 (2.31–3.66). The case–control analysis included 15,100 angioedema cases and 60,400 controls; the angioedema risk for both aliskiren monotherapy and FDC was not significantly different from BBs [adjusted odds ratio (adjOR) 0.99 (95% CI 0.45–2.20) and 1.06 (0.40–2.76)]; aliskiren FSC was associated with an increased angioedema risk [adjOR 3.29 (2.42–4.48)], mainly driven by concomitant ACEI use [adjOR 7.03 (4.10–12.05)]. The IR and risk of angioedema in patients with aliskiren monotherapy or FDC are comparable to BBs. The higher IR and risk of angioedema identified in the aliskiren FSC group may largely be driven by the concomitant use of ACEIs.

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.; 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.; 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.; 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.

PURPOSE: The purpose of this study is to quantify the impact of the different outcomes and definitions of suicidality on the association between antiepileptic drugs (AEDs) and suicidality.METHODS: Retrospective cohort studies of selected AEDs (carbamazepine, gabapentin, lamotrigine, phenytoin, pregabalin, topiramate and valproate) using data from UK Clinical Practice Research Datalink (CPRD) alone and linked to UK Hospital Episode Statistics (HES) and UK Office of National Statistics (ONS), and from Danish national registries (DNR). Follow-up started at initiation of one of the study AEDs, divided into exposure periods, a maximum 90-day post-exposure period, and the reference period starting the day after the 90-day post-exposure period ended. Primary outcomes were completed suicide (SUI)/suicide attempt (SA) for CPRD and SUI/deliberate self-harm (DSH) for DNR. We applied adjusted Cox regression analyses and sensitivity analyses with varying outcome definitions.RESULTS: We analyzed 84 524 AED users from CPRD-HES-ONS (1188 SUI/SA; 96 SUI) and 258 180 users from DNR (7561 SUI/DSH; 781 SUI). The adjusted hazard ratios (HRs) on SUI/SA ranged between 1.3 (95% confidence interval (CI): 0.84-2.00) for lamotrigine and 2.7 (1.24-5.81) for phenytoin in CPRD-HES-ONS, and between 0.9 (0.78-1.00) for valproate and 1.8 (1.10-3.07) for phenytoin on SUI/DSH in DNR. HRs for the primary outcomes varied consistently across exposure periods and data sources. HRs for SUI were in general lower, more stable and similar for periods of exposure and the 90-day post-exposure period.CONCLUSION: Applying different outcomes and definitions of suicidality had an impact on the relative risks of suicidality associated with the investigated AEDs with results for SUI being most consistent and reliable. Copyright © 2016 John Wiley & Sons, Ltd.

This cohort study assessed the pancreatic safety of vildagliptin versus other noninsulin antidiabetic drugs (NIADs) based on data from five European electronic health care databases. Patients with type 2 diabetes aged ≥18 years on NIAD treatment were enrolled. Adjusted incidence rate ratios (IRRs) and 95% confidence intervals (CIs) were estimated separately for acute pancreatitis and pancreatic cancer for vildagliptin (± other NIADs) compared with other NIADs using negative binomial regression. Approximately 2.8% of the enrolled patients (n = 738 054) used vildagliptin during the study, with an average follow‐up time of 1.4 years. For acute pancreatitis, adjusted IRRs ranged between 0.89 andt 2.58 with all corresponding 95% CIs crossing 1. For pancreatic cancer adjusted IRRs ranged from 0.56 to 3.64, with the lower limit of 95% CIs >1 in some analyses. Post hoc sensitivity analyses taking latency time into account markedly lowered the risk estimates with corresponding 95% CIs crossing 1. Overall, the results do not suggest an increased pancreatitis risk with vildagliptin, while the observation for pancreatic cancer have to be interpreted carefully as this study was not designed to assess pancreatic cancer and rather be explained by certain underlying limitations including latency ‐time, chance findings and/or bias and confounding.

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.

Summary 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.

PURPOSE: Results from observational studies on the same exposure-outcome association may be inconsistent because of variations in methodological factors, clinical factors or health care systems. We evaluated the consistency of results assessing the association between antidepressant use and the risk of hip/femur fractures in three European primary care databases using two different study designs. METHODS: Cohort and nested case control studies were conducted in three European primary care databases (Spanish BIFAP, Dutch Mondriaan and UK THIN) to assess the association between use of antidepressants and hip/femur fracture. A common protocol and statistical analysis plan was applied to harmonize study design and conduct between data sources. RESULTS: Current use of antidepressants was consistently associated with a 1.5 to 2.5-fold increased risk of hip/femur fractures in all data sources with both designs, with estimates for SSRIs generally higher than those for TCAs. In general, risk estimates in Mondriaan, the smallest data source, were higher compared to the other data sources. This difference may be partially explained by an interaction between SSRI and age in Mondriaan. Adjustment for GP-recorded lifestyle factors and matching on general practice had negligible impact on adjusted relative risk estimates. CONCLUSION: We found a consistent increased risk of hip/femur fracture with current use of antidepressants across different databases and different designs. Applying similar pharmacoepidemiological study methods resulted in similar risks for TCA use and some variation for SSRI use. Some of these differences may express real (or natural) variance in the exposure-outcome co-occurrences. Copyright © 2016 John Wiley & Sons, Ltd.

Study objective To determine if the use of statins affects pneumonia-related outpatient visits, hospitalizations with survival, and deaths. Design Population-based, retrospective, nested case-control analysis. Data source United Kingdom-based General Practice Research Database. Participants The study population (134,262 patients aged > or = 30 yrs) consisted of 55,118 patients who took statins and/or fibrates, 29,144 patients with hyperlipidemia not taking lipid-lowering agents, and 50,000 randomly selected patients without hyperlipidemia and without lipid-lowering treatment. Measurements and main results We identified 1253 patients with pneumonia and matched them with 4838 control subjects based on age, sex, general practice, and index date. After adjusting for comorbidity and frequency of visits to general practitioners, we calculated the risks (odds ratios with 95% confidence intervals) of uncomplicated pneumonia, hospitalization for pneumonia with survival, and fatal pneumonia in participants who used statins compared with those who did not. Current statin users had a significantly reduced risk of fatal pneumonia (adjusted odds ratio 0.47, 95% confidence interval 0.25-0.88) and slightly but not significantly reduced risks of uncomplicated pneumonia and pneumonia hospitalization with survival. Recent or past statin use and fibrate use at any time were not associated with a reduced risk of pneumonia. Conclusion Current use of statins was associated with a reduced risk of pneumonia. The risk reduction was particularly strong in the subgroup of patients with fatal pneumonias.

Problems associated with pharmacotherapy (in particular, medication errors and adverse drug events) are frequent and are associated with increased costs for treatment. Analysis of original publications published between 1990 and 2005 on the topics of medication errors and/or adverse drug events in hospitalised patients, focusing on the frequency of, risk factors for and avoidance of such problems associated with pharmacotherapy, indicated that medication errors occurred in a mean of 5.7% of all episodes of drug administration, but with a high variability among the 35 studies retrieved. This variability was explained by the methods by which medication errors were detected (systematic screening of patients versus chart review or spontaneous reporting) and by the way drugs were administered (intravenously administered drugs are associated with the highest error frequencies). Errors occurred throughout the whole medication process, with administration errors accounting for more than half of all errors. Important risk factors included insufficient pharmacological knowledge of health professionals, errors in the patient charts or documentation by nurses and inadequate pharmacy services. Adverse events or reactions, on the other hand, affected 6.1 patients per 100 hospitalised and also showed a high variability among the 46 studies retrieved. This variability could also be explained by the different methods of assessment of the frequency of adverse drug events or reactions, as well as by the different wards on which the studies were performed. Important risk factors for adverse drug events or reactions included polypharmacy, female sex, drugs with a narrow therapeutic range, renal elimination of drugs, age >65 years and use of anticoagulants or diuretics. Since medication errors are strong risk factors for preventable adverse drug events or reactions, strategies have to be put in place for their reduction. Such strategies include ensuring that all persons involved in the medication process (nurses, pharmacists and physicians) have good pharmacological knowledge, computerisation of the entire medication process, and the engagement of a sufficient number of clinical pharmacists on the wards.

To assess the impact of a variety of methodological parameters on the association between six drug classes and five key adverse events in multiple databases.The selection of Drug-Adverse Event pairs was based on public health impact, regulatory relevance, and the possibility to study a broad range of methodological issues. Common protocols and data analytical specifications were jointly developed and independently and blindly executed in different databases in Europe with replications in the same and different databases.The association between antibiotics and acute liver injury, benzodiazepines and hip fracture, antidepressants and hip fracture, inhaled long-acting beta2-agonists and acute myocardial infarction was consistent in direction across multiple designs, databases and methods to control for confounding. Some variation in magnitude of the associations was observed depending on design, exposure and outcome definitions, but none of the differences were statistically significant. The association between anti-epileptics and suicidality was inconsistent across the UK CPRD, Danish National registries and the French PGRx system. Calcium channel blockers were not associated with the risk of cancer in the UK CPRD, and this was consistent across different classes of calcium channel blockers, cumulative durations of use up to10 years and different types of cancer.A network for observational drug effect studies allowing the execution of common protocols in multiple databases was created. Increased consistency of findings across multiple designs and databases in different countries will increase confidence in findings from observational drug research and benefit/risk assessment of medicines.

The Pharmacoepidemiological Research on Outcomes of Therapeutics by a European ConsorTium (PROTECT) initiative was a collaborative European project that sought to address limitations of current methods in the field of pharmacoepidemiology and pharmacovigilance. Initiated in 2009 and ending in 2015, PROTECT was part of the Innovative Medicines Initiative, a joint undertaking by the European Union and pharmaceutical industry. Thirty-five partners including academics, regulators, small and medium enterprises, and European Federation of Pharmaceuticals Industries and Associations companies contributed to PROTECT. Two work packages within PROTECT implemented research examining the extent to which differences in the study design, methodology, and choice of data source can contribute to producing discrepant results from observational studies on drug safety. To evaluate the effect of these differences, the project applied different designs and analytic methodology for six drug-adverse event pairs across several electronic healthcare databases and registries. This papers introduces the organizational structure and procedures of PROTECT, including how drug-adverse event and data sources were selected, study design and analyses documents were developed, and results managed centrally.

Studienziel: Ziel der vorliegenden Studie war, die Prävalenz von potentiell kritischen Arzneimittelinterkationen (AMI) bei ambulanten Patienten unter Statin-Therapie zu bestimmen. Methoden: Die Daten (Alter, Geschlecht, Statin, Komorbiditäten, Anzahl verschriebener Medikamente, Anzahl Diagnosen) wurden von 242 niedergelassenen Ärzten unterschiedlicher Fachausrichtung erfasst. Die Medikation wurde mittels eines computerisierten AMI-Programms auf potentiell kritische AMI gescreent. Resultate: Es wurden 2742 Patienten, die mit einem Statin therapiert wurden, in die Studie eingeschlossen. Das Durchschnittsalter lag bei 65.1+/-11.2 (Standardabweichung) Jahren, die Patienten hatte durchschnittlich 3.2+/-1.6 Diagnosen und 4.9+/-2.4 verschriebene Arzneimittel. Sie stammten zu 53.3% aus der Deutschschweiz, 36.0% kamen aus der Romandie und 10.7% aus der italienisch-sprechenden Schweiz. Von 2742 Patienten hatten 401 (14.6%) insgesamt 591 potentiell kritische AMI; 190 Patienten (6.9%) hatten eine potentiell kritische Statin-Interaktion, 288 (10.5%) eine potentiell kritische Nicht-Statin-Interaktion. Die Prävalenz der AMI war in den verschiedenen Sprachregionen vergleichbar und zeigte keine Unterschiede bezüglich jeweiligem Fachgebiet des verschreibenden Arztes. Wichtige Risikofaktoren für potentiell kritische AMI waren die Anzahl verschriebener Arzneimittel sowie eine Diagnose einer Herzinsuffizienz oder Arrhythmie. Schlussfolgerung: Potentiell kritische AMI bei Patienten unter Statin-Therapie sind – aufgrund der Pharmakotherapie anderer Komorbiditäten – häufig. Ein spezielles Augenmerk sollte in dieser Population auf Patienten mit Polypharmazie sowie einer Pharmakotherapie für Arrhythmien respektive Herzinsuffizienz gerichtet sein.

Als Auslöser für eine akute Pankreatitis kommen selten auch Medikamente in Frage. Dabei gehören die Wirkstoffe, die mit solch einem Ereignis in Verbindung gebracht werden, einer Vielzahl unterschiedlicher Wirkstoffgruppen an. Für die Hydroxymethylglutaryl-CoA-Reduktase-Hemmer (HMG-CoA-Reduktase-Hemmer oder auch Statine) liegen mittlerweile Fallberichte zu allen Einzelsub-stanzen vor.Wir berichten von einem 60-jährigen Patienten, der zweimal unter einer Pravastatin-Therapie eine akute Pankreatitis entwickelte. Da bei einigen Patienten in den publizierten Fallberichten nach dem Wechsel auf ein anderes Statin erneut eine Pankreatitis auftrat, gestaltet sich eine Therapieempfehlung nach einer Statin-induzierten Pankreatitis schwierig. Während auch unter Fibrat-Therapie bereits Pankreatitiden beschrieben wurden, sind für den neuen Wirkstoff Ezetimib selten auftretende unerwünschte Arzneimittelwirkungen noch nicht ausreichend bekannt.

Inappropriate drug use is one of the risk factors for adverse drug reactions in the elderly. We hypothesised that, in elderly patients, geriatricians are more aware of potentially inappropriate medications (PIMs) and may replace or stop PIMs more frequently compared with internists. We therefore evaluated and compared the prevalence of PIMs as well as anticholinergic drug use throughout hospital stay in elderly patients admitted to a medical or geriatric ward. In this retrospective cross-sectional study, 800 patients aged ≥65 years admitted to a general medical or geriatric ward of a 700-bed teaching hospital in Switzerland during 2004 were included. PIMs were identified using the Beers criteria published in 2003. The prevalence of anticholinergic drug use was assessed based on drug lists published in the literature. The prevalence of use of PIMs that should generally be avoided was similar in medical and geriatric inpatients both at admission (16.0% vs 20.8%, respectively; p = 0.08) and at discharge (13.3% vs 15.9%, respectively; p = 0.31). In contrast to medical patients, the reduction in the prevalence of use of PIMs between admission and discharge in geriatric patients reached statistical significance (p < 0.05). Overall, the three most prevalent inappropriate drugs/drug classes were amiodarone, long-acting benzodiazepines and anticholinergic antispasmodics. At admission, the prevalence of use of PIMs related to a specific diagnosis was not significantly different between patients hospitalised to a medical or a geriatric ward (14.0% vs 17.5%, respectively; p = 0.17), as compared with the significant difference evident at hospital discharge (11.7% vs 23.7%, respectively; p < 0.001). This was largely because of ahigher prescription rate of platelet aggregation inhibitors in combination with low-molecular-weight heparins and benzodiazepines in patients with a history of falls and syncope. The proportions of patients taking anticholinergic drugs in medical and geriatric patients at admission (13.0% vs 17.5%, respectively; p = 0.08) and discharge (12.2% vs 16.5%, respectively; p = 0.10) were similar. Inappropriate drug use as defined by the Beers criteria was common in both medical and geriatric inpatients. Compared with internists, geriatricians appear to be more aware of PIMs that should generally be avoided, but less aware of PIMs related to a specific diagnosis, and of the need to avoid anticholinergic drug use. However, the results of this study should be interpreted with caution because some of the drugs identified as potentially inappropriate may in fact be beneficial when the patient’s clinical condition is taken into consideration.

Pharmacotherapy for heart failure is complex and, due to polypharmacy, is associated with a large risk of potential drug-drug interactions (DDIs). The objective of the present study was to assess the prevalence of potential DDIs in the medication of hospitalised heart failure patients and to evaluate their clinical relevance.The medication of 400 patients was retrospectively analysed for potential DDIs at hospital admission and discharge using a computerised drug interaction program. Main inclusion criteria were the diagnosis of heart failure and a minimum of two drug prescriptions at discharge.In the study population of 400 heart failure patients (median age 79 years, 55.5% men), the median number of drugs per patient was lower at admission than at discharge (6 [interquartile range {IQR} 4-9] vs 8 [IQR 6-10]; p0.001). At hospital admission, a total of 863 potential DDIs were detected in 272 patients (68.0%; 95% CI 63.4, 72.6). At discharge, 1171 potential DDIs were detected in 355 patients (88.8%; 95% CI 85.7, 91.8). This corresponds with a significant increase in the median number of potential DDIs per patient from admission to discharge (1.5 [IQR 0-3] vs 3 [IQR 1-4]; p0.001). Of the 1171 potential DDIs at discharge, 432 (36.9%) were prevalent at admission and 739 (63.1%) resulted from a medication change during the hospital stay. Of these 739 new potential DDIs, the severity of the potential adverse effect was rated as 'major' in 190 (25.7%) patients, 'moderate' in 482 (65.2%) and 'minor' in 67 (9.1%). The 190 potential DDIs with major severity were recorded in a total of 145 patients (36.3%; 95% CI 31.5, 41.0%). Hyperkalaemia was the most prevalent potential adverse effect of major severity (n = 93) and the combination of an ACE inhibitor with a potassium-sparing diuretic was recorded in 64 (16.0%) patients.The study shows that hospitalisation of patients with heart failure results in an increase in the number of drugs prescribed per patient and, thereby, also in the number of potentially interacting drug combinations per patient. Although electronic drug interaction programs are a valuable tool to check for potential DDIs, the clinical relevance of most potential DDIs can only be judged by assessment of the individual patient.

Study Objective. To evaluate the risk of acute myocardial infarction during current exposure to nonsteroidal antiinflammatory drugs (NSAIDs). Design. Retrospective case-control analysis. Setting. General practice offices. Subjects. A total of 8688 case patients, aged 89 years or younger, with a first-time acute myocardial infarction and 33,923 control subjects matched on age, sex, calendar time, and general practice attended. Intervention. The United Kingdom General Practice Research Database was searched for potential cases of first-time acute myocardial infarction between January 1995 and April 2001. Control subjects without acute myocardial infarction were identified at random. Measurements and Main Results. Exposure to NSAIDs was assessed, and 650 case patients and 2339 control subjects were found to be currently taking NSAIDs. After adjusting for various risk factors for acute myocardial infarction (e.g., hypertension, hyperlipidemia, diabetes mellitus, ischemic heart disease, body mass index, smoking), the relative risk (expressed as odds ratio [OR]) of acute myocardial infarction was 1.07 (95% confidence interval [CI] 0.96–1.19) for subjects with current NSAID exposure compared with those not taking NSAIDs. The adjusted OR for current diclofenac use was 1.23 (95% CI 1.00–1.51), for current ibuprofen use 1.16 (95% CI 0.92–1.46), and for current naproxen use 0.96 (95% CI 0.66–1.38) compared with those not taking NSAIDs. Current aspirin use combined with current NSAID use was associated with a statistically significant risk reduction (adjusted OR 0.74, 95% CI 0.57–0.97), compared with nonuse of NSAIDs and aspirin. Current use of aspirin together with current use of ibuprofen yielded an adjusted OR of 0.69 (95% CI 0.42–1.15). Conclusions. Our results provide additional evidence that the risk of first-time acute myocardial infarction during current use of NSAIDs is not materially altered. We found no evidence for a reduced cardioprotective effect of aspirin with concomitant NSAID use.

Introduction and objective: Corticosteroids may cause tendinopathies, an adverse effect that is not well known and characterised, although it was initially described more than 40 years ago. This study was conducted in order to characterise the important aspects of this adverse reaction, such as the role played by routes of corticosteroid administration, therapy duration, comedication, cumulative corticosteroid dose and underlying disease. Study design and methods: Published case reports of tendinopathies that were associated with corticosteroid use were identified by a comprehensive literature search using the databases MEDLINE, Pharm-line, EMBASE, ToxFile, Adis Inpharma, International Pharmaceutical Abstracts, Drug Information Fulltext and PASCAL. The reference lists of all pertinent articles were cross-referenced to retrieve additional cases. Spontaneous reports were requested from the Uppsala Monitoring Centre (the WHO Collaborating Centre for International Drug Monitoring). Information of published and spontaneous reports was analysed with regard to age, sex, underlying disease, individual corticosteroids, equivalent corticosteroid dose, latency time, cumulative dose, route of administration, comedication and type of tendinopathy. Results: We included and analysed 73 published case reports and case series involving 133 patients and 191 spontaneous reports of corticosteroid-associated tendinopathies. The proportion of women with tendinopathies was 50.8% and 41.0%, respectively. The mean age (± standard deviation) of patients with a tendinopathy was 50 ± 17 years and 61 ± 16 years, respectively. The predominant routes of administration were oral (33% of published cases and 47% of spontaneous cases) and intra-articular (35% of the published cases or parenteral (7% of the spontaneous cases). There were isolated cases of tendinopathy after inhaled or topical (i.e. ocular, cutaneous, nasal) corticosteroid use. Tendinopathies that were reported in the literature cases consisted mainly of tendon ruptures (93%), predominantly of the Achilles tendon. Of the spontaneous cases, 31% had a rupture and the remaining cases had a tendinitis or an unspecified tendon disorder. Conclusion: Oral and parenteral applications, especially intra-articular use, were the most prevalent routes of administration in cases with corticosteroid-associated tendinopathies. However, topical application has also been rarely associated with tendinopathies. Future pharmacoepidemiological studies should further address this issue to quantify the risk of corticosteroid-associated tendinopathies.

Background: Drug-drug interactions (DDIs) are a well known risk factor for adverse drug reactions. HMG-CoA reductase inhibitors (‘statins’) are a cornerstone in the treatment of dyslipidaemia and patients with dyslipidaemia are concomitantly treated with a variety of additional drugs. Since DDIs are associated with adverse reactions, we performed a cross-sectional study to assess the prevalence of potentially critical drug-drug and drug-statin interactions in an outpatient adult population with dyslipidaemia. Methods: Data from patients with dyslipidaemia treated with a statin were collected from 242 practitioners from different parts of Switzerland. The medication list was screened for potentially harmful DDIs with statins or other drugs using an interactive electronic drug interaction program. Results: We included 2742 ambulatory statin-treated patients (mean age ± SD 65.1 ± 11.1 years; 61.6% males) with (mean ± SD) 3.2 ± 1.6 diagnoses and 4.9 ± 2.4 drugs prescribed. Of those, 190 patients (6.9%) had a total of 198 potentially harmful drug-statin interactions. Interacting drugs were fibrates or nicotinic acid (9.5% of patients with drug-statin interactions), cytochrome P450 (CYP) 3A4 inhibitors (70.5%), digoxin (22.6%) or ciclosporin (cyclosporine) [1.6%]. The proportion of patients with a potential drug-statin interaction was 12.1% for simvastatin, 10.0% for atorvastatin, 3.8% for fluvastatin and 0.3% for pravastatin. Additionally, the program identified 393 potentially critical non-statin DDIs in 288 patients. Conclusions: CYP3A4 inhibitors are the most frequent cause of potential drug interactions with statins. As the risk for developing rhabdomyolysis is increased in patients with drug-statin interactions, clinicians should be aware of the most frequently observed drug-statin interactions and how these interactions can be avoided.

Objective. To determine whether children or adolescents who are exposed to inhaled corticosteroids (ie, beclomethasone, budesonide, fluticasone) are at a higher risk of having bone fractures compared with nonexposed individuals. Methods. We performed a population-based nested case-control analysis using data from the United Kingdom–based General Practice Research Database. Within a base population of 273 456 individuals aged 5 to 79 years, we identified by International Classification of Diseases codes children or adolescents who were aged 5 to 17 years with a fracture diagnosis and up to 6 control subjects per case matched to cases on age, gender, general practice attended, calendar time, and years of history in the GPRD. We compared use of inhaled steroids before the index date between fracture cases and control patients. Results. We identified 3744 cases and 21 757 matched control subjects aged 5 to 17 years. Current exposure to inhaled steroids did not reveal a substantially altered fracture risk compared with nonusers, even in individuals with current longer term exposure (ie, ≥20 prescriptions; adjusted odds ratio 1.15; 95% confidence interval: 0.89–1.48). In individuals with current or previous exposure to oral steroids, the adjusted odds ratio for current long-term inhaled steroid use compared with nonusers was 1.21 (95% confidence interval: 0.99–1.49). Conclusions. Exposure to inhaled steroids does not materially increase the fracture risk in children or adolescents compared with nonexposed individuals.

The United Kingdom General Practice Research Database (GPRD) is an office-based, computer-generated, medical resource designed from its inception to be used for epidemiologic research. A distinct version of the GPRD is maintained by the Boston Collaborative Drug Surveillance Program and has been the source of more than 130 scientific articles primarily addressing drug safety issues. We reviewed evidence related to the validity of the GPRD. Specifically, with our extensive experience with this automated database, we evaluated the quality and completeness of the data that it contains.

Ischemic colitis (IC) incidence rates (IRs) among treated hypertensive patients are poorly understood, and existing literature on the subject is sparse. Antihypertensive drugs may raise the risk of developing IC. Novel antihypertensive agents—such as the direct renin inhibitor aliskiren—have not been assessed for IC risk. The aims of this study were to evaluate (1) the IRs of probable IC (pIC) in treated hypertensive adults, with a focus on aliskiren-treated patients; (2) the antihypertensive therapies used; and (3) the IRs of pIC in non-hypertensive adults. This study selected hypertensive and non-hypertensive patients (N = 2,356,226 each) from a US health plan claims database. pIC was defined as diagnosis of IC within 3 months after colonoscopy, recto-sigmoidoscopy, or colectomy. IRs were calculated per 100,000 person-years (PYs) with 95 % confidence intervals (CIs) and stratified by antihypertensive regimen. IRs of pIC in hypertensive and non-hypertensive subjects were 18.6 (95 % CI 17.6–19.8) and 4.0 (95 % CI 3.4–4.7), respectively. The non-hypertensive cohort consisted of younger patients who may have been less prone to developing IC. The overall (i.e., all antihypertensive regimens combined) monotherapy IR per 100,000 PYs was 17.5 (95 % CI 16.2–18.8), the overall dual-combination regimen IR per 100,000 PYs was 19.5 (95 % CI 17.37–21.83), and the overall triple-plus combination regimen IR per 100,000 PYs was 27.7 (95 % CI 22.72–33.38). Study results indicate that the treated hypertensive patients may have a higher risk of pIC compared with non-hypertensive populations. The quantity of antihypertensive agents prescribed may contribute to IC more than treatment duration.

Aims Aspirin decreases the risk of clinical manifestations of atherothrombosis. This effect is mainly due to inhibition of platelet aggregation and potentially due to antiinflammatory properties of aspirin. To evaluate whether use of non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) may also be associated with a decreased risk of first-time acute myocardial infarction (AMI), we performed a populationbased case-control analysis using the United Kingdom-based General Practice Research Database (GPRD) Methods We identified first-time AMI-patients free of preexisting diagnosed cardiovascular or metabolic diseases. We compared use of NSAIDs prior to the index date between cases and control patients who were matched to cases on age, gender, practice and calendar time. Results A total of 3319 cases ( ≤ 75 years) with a diagnosis of first-time AMI between 1992 and 1997 and 13 139 controls (matched to cases on age, sex, general practice attended, calendar time, years of prior history in the GPRD) were included. Overall, the relative risk estimate of AMI (adjusted for smoking, body mass index, hormone replacement therapy and aspirin) in current NSAID users was 1.17 (95% CI 0.99, 1.37). Long-term current NSAID use ( ≥ 30 prescriptions) yielded an adjusted odds ratio (OR) of 1.20 (95% CI 0.94, 1.55). Stratification by age ( < 65 years vs ≥ 65 years) and sex did not materially change the results. Conclusions Our findings indicate that current NSAID exposure in patients free of diagnosed cardiovascular or metabolic conditions predisposing to cardiovascular diseases does not decrease the risk of AMI.

The purpose of this study is to evaluate the performance and validity of the case-crossover (CCO) and self-controlled case-series (SCCS) designs when studying the association between hip/femur fracture (HF) and antidepressant (AD) use in general practitioner databases. In addition, comparability with cohort and case-control designs is discussed.Adult patients with HF and who received an AD prescription during 2001-2009 were identified from UK's The Health Improvement Network (THIN) and the Dutch Mondriaan databases. AD exposure was classified into current, recent and past/non-use (reference). In the CCO, for each patient, a case moment (date of HF) and four prior control moments at -91, -182, -273 and -365 days were defined. In SCCS, incidence of HF was compared between exposure states. Conditional logistic regression was used in the CCO and Poisson regression in the SCCS to compute odds ratios and incidence rate ratios, respectively. In CCO, we adjusted for time-varying co-medication and in SCCS for age.Adjusted estimates for the effect of current AD exposure on HF were higher in the CCO (co-medication-adjusted odds ratio, THIN: 2.24, 95% confidence interval [CI]: 2.04-2.47; Mondriaan: 2.57, 95%CI [1.50, 4.43]) than in the SCCS (age-adjusted incidence rate ratio, THIN: 1.41, 95%CI [1.32, 1.49]; Mondriaan: 2.14, 95%CI [1.51, 3.03]). The latter were comparable with the traditional designs.Case-only designs confirmed the association between AD and HF. The CCO design violated assumptions in this study with regard to exchangeability and length of exposure, and transient effects on outcome. The SCCS seems to be an appropriate design for assessing AD-HF association.

Aims Selective serotonin reuptake inhibitors (SSRIs) have been associated with serotonin depletion in platelets, potentially leading to abnormal aggregation and prolonged bleeding time. In view of the importance of serotonin in coronary thrombosis, and decreased platelet serotonin concentrations associated with SSRIs, the present study was performed to test the hypothesis of a decreased risk of acute myocardial infarction (AMI) associated with SSRIs. Methods We conducted a population-based case-control analysis using the UK General Practice Research Database (GPRD). A total of 3319 patients aged 75 years or younger free of clinical conditions predisposing to ischaemic heart disease, with a firsttime diagnosis of AMI between 1992 and 1997, and 13 139 controls without AMI matched to cases for age, sex, general practice attended, and calendar time were included. Conditional logistic regression was used to estimate relative risks. Results Adjusted odds ratios (with 95% CI) for current use of SSRIs, non-SSRIs, or other antidepressants, compared to the group of nonusers of antidepressants were 0.9 (95% CI 0.5,1.8), 0.9 (95% CI 0.7,1.2), and 1.3 (95% CI 0.6,2.8), respectively. As compared with nonuse of SSRIs, current use (regardless of any other antidepressants used) resulted in an adjusted OR of 1.1 (95% CI 0.7,1.6). Conclusions The current analysis provides evidence that SSRI exposure does not substantially decrease the risk of developing first-time AMI in patients free of factors predisposing to ischaemic heart disease. However, due to relatively small numbers of exposed subjects and the resulting wide confidence intervals, further studies may be needed to document a lack of effect of SSRIs in subjects without pre-existing diseases predisposing to AMI.

OBJECTIVE: To report a patient having a first-time seizure after receiving venlafaxine and trimipramine for depression. CASE SUMMARY: A 25-year-old white woman with chronic depression was treated with venlafaxine 150 mg/d and trimipramine 50 mg/d. Eleven days after increase of the trimipramine dosage to 100 mg/d, she was hospitalized because of seizures suggesting a secondary generalized grandmal episode. The electroencephalogram showed a pathologic pattern with several generalized epileptiform discharges. Because of suspected drug-induced seizures, both antidepressants were stopped. After antidepressant drug cessation, the patient was symptom free and had no further seizure episodes within the following 12 months of follow-up. No other potential cause for the seizure episode could be identified. DISCUSSION: Both venlafaxine and trimipramine have been associated with seizures, mainly after overdose. Venlafaxine-associated seizures at therapeutic doses have not been reported in the literature. We hypothesize that a pharmacodynamic or pharmacokinetic drug interaction between venlafaxine and trimipramine involving the CYP2D6 isoenzyme may have played a role in inducing the seizures. CONCLUSIONS: Clinicians should be aware of the proepileptogenic effect of venlafaxine and trimipramine at therapeutic doses and that this combination may eventually increase the risk of seizures.

Background: Minocycline has increasingly been associated with different adverse auto-immune reactions including drug-induced lupus. Objective: To identify the scope of minocycline-induced lupus and to characterise its typical features. Methods: Comprehensive Medline and Embase search of the English and non-English literature for case reports of minocycline-induced lupus. Results: We included 57 cases of minocycline-induced lupus (mean age ± SD at onset: 21.6 ± 8.6 years, median time of exposure: 19 months, range 3 days to 6 years). All patients showed the clinical features of polyarthralgia/polyarthritis often accompanied by liver abnormalities. Twelve patients had evidence of dermatological manifestations (i.e rash, livedo reticularis, oral ulceration, subcutaneous nodules, alopecia). The ANA test was positive in all patients. Conclusion: Long-term exposure to minocycline may be associated with drug-induced lupus. Baseline and periodic liver function and ANA tests accompanied by appropriate clinical monitoring are suggested for patients receiving long-term minocycline therapy.

Clomethiazole, a sedative-hypnotic and anticonvulsant drug, has been successfully administered orally and intravenously, but in cases where either of these methods presents complications, rectal administration may represent a practical alternative. We sought to compare the single-dose pharmacokinetics and pharmacodynamics of clomethiazole after oral and rectal administration. Ten healthy adult volunteers were given 600 mg clomethiazole edisylate (corresponding to 390 mg clomethiazole base) in 2 capsules as a single oral or rectal dose in a double-masked, double-dummy, crossover fashion. Serum concentrations were measured up to 10 hours after administration using a specific high-performance liquid chromatography method. Computerized reaction-time measurement and visual analogue scales (VAS) were used to assess drug effects. Peak serum concentrations were significantly higher after oral administration (mean +/- SEM, oral 1.76 +/- 0.47 microg/mL vs rectal 0.48 +/- 0.14 microg/mL; P = 0.03) and appeared earlier (55 +/- 12 vs 89 +/- 11 min; P = 0.04). Area under the concentration-time curve values were similar after administration by both routes (oral 116 +/- 20.6 vs rectal 105 +/- 36.0 microg x min/mL), with a relative rectal bioavailability of 90% compared with oral administration. The objective pharmacodynamic effects on reaction time (increase of 104 +/- 26 vs 66 +/- 22 ms, oral vs rectal) and working speed (decrease of 132 +/- 38 vs 97 +/- 32 ms, oral vs rectal) were not significantly different. Subjective pharmacodynamic effects, as measured on the VAS, were comparable with both routes of administration. Clomethiazole was well tolerated, with a similar adverse effect profile for both routes of administration. The effects of rectal dosing of clomethiazole were similar to those of oral dosing but appeared to occur later. Our results suggest that rectal administration of a single 600-mg clomethiazole edisylate dose bears no safety risk. Therefore, rectal administration could be considered when neither oral nor parenteral administration is possible and a later onset of effect is not critical.

In a prospective, crossover study, we assessed the impact of a clinical pharmacist on identification and reporting of adverse drug events (ADEs) in hospitalized patients. The study was conducted on four units of a medical ward of a university hospital, with two units serving as test, the other two as control units. After 12 months, test and control units were switched. In the test units, a pharmacist participated in daily ward rounds, solicited additional information from physicians and nurses, and reviewed the charts of all patients. In control units, information on ADEs was based solely on voluntary reports from physicians and nurses. A total of 1,959 patients (941 in test, 1,018 in control units) were hospitalized during the study period. In 137 test units patients, 224 ADEs (14.6%; 95%-CI: 12.3%-16.9%) were detected (8 severe, 60 moderate, 156 mild), while 25 ADEs (1 severe, 11 moderate, 13 mild) occurring in 21 patients (2.1%; 95%-CI: 1.2%-3.0%) were reported from the control units (p < 0.0001). Of the ADEs in the test units, 51% were reported spontaneously, 39% were identified on rounds, and 10% by chart review. After changing the status of test and control units, the number of identified ADEs returned to preintervention levels. Clinical pharmacists as part of the medical care team can improve the identification of ADEs which may ultimately translate into improved quality of care.

Purpose: We assessed from an institutional perspective the direct costs of severe adverse cutaneous or hypersensitivity reactions due to antiepileptic drug (AED) therapy that led to hospitalization or prolonged hospital stay. Methods: Patients admitted for or developing severe AED-induced cutaneous or hypersensitivity reactions while in hospital from January 1990 through June 1996 were identified by ICD-9 codes E936, E937, E693, E695, 1, E995.1, and E995.2. Identified cases were analyzed retrospectively by chart review and were included in the analysis if a causal relationship was determined to be possible, probable, or definite. Clinical outcomes were abstracted and related direct costs of the adverse drug reactions (ADRs) calculated. Results: A total of 384 cases were identified by ICD-9 codes, of which 13 cases (mean age ± SD 52.9 ± 21.0 years) were included for further analysis. Eight patients (62%) were admitted because of an ADR (median length of stay 9.5 days; range 4-43), five (38%) experienced an ADR during hospitalization (median duration of ADR episodes 8.5 days; range: 7-21 days). The median direct medical costs of the ADRs were Canadian (CDN) $3,128 (range 1,149-21,293) per patient. Conclusions: The management of serious cutaneous and hypersensitivity ADRs due to AEDs is associated with considerable direct medical costs. These figures should be considered along with drug acquisition costs and treatment of clinical successes and failures in the overall assessment of the economic impact of pharmacotherapy. Prospective collection of direct costs associated with ADRs in clinical trials would be of value.

Background Safety data regarding exposure to artemisinin-based combination therapy in pregnancy are limited. This prospective cohort study conducted in Zambia evaluated the safety of artemether-lumefantrine (AL) in pregnant women with malaria. Methods Pregnant women attending antenatal clinics were assigned to groups based on the drug used to treat their most recent malaria episode (AL vs. sulphadoxine-pyrimethamine, SP). Safety was assessed using standard and pregnancy-specific parameters. Post-delivery follow-up was six weeks for mothers and 12 months for live births. Primary outcome was perinatal mortality (stillbirth or neonatal death within seven days after birth). Results Data from 1,001 pregnant women (AL n = 495; SP n = 506) and 933 newborns (AL n = 466; SP n = 467) showed: perinatal mortality (AL 4.2%; SP 5.0%), comprised of early neonatal mortality (each group 2.3%), stillbirths (AL 1.9%; SP 2.7%); preterm deliveries (AL 14.1%; SP 17.4% of foetuses); and gestational age-adjusted low birth weight (AL 9.0%; SP 7.7%). Infant birth defect incidence was 1.8% AL and 1.6% SP, excluding umbilical hernia. Abortions prior to antenatal care could not be determined: abortion occurred in 4.5% of women treated with AL during their first trimester; none were reported in the 133 women exposed to SP and/or quinine during their first trimester. Overall development (including neurological assessment) was similar in both groups. Conclusions These data suggest that exposure to AL in pregnancy, including first trimester, is not associated with particular safety risks in terms of perinatal mortality, malformations, or developmental impairment. However, more data are required on AL use during the first trimester.