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Aclidinium bromide is an inhaled long-acting muscarinic antagonist (LAMA). Although the initial potential increased cardiovascular and mortality risk among users of tiotropium has been ruled out by several observational studies, and clinical trials, there are still concerns related to the use of newer LAMA medications. The current study aimed to evaluate the risk of death among users of aclidinium and other LAMAs.We conducted a cohort and nested case-control study among patients with COPD aged 40 years or older to compare the risk of all-cause mortality among users of aclidinium and other COPD medications with the risk among users of long-acting β2 agonists (LABA), in the Clinical Practice Research Datalink (CPRD) in the United Kingdom (2012-2017).Mortality rates per 1,000 person-years were 32.9 for aclidinium, 43.8 for tiotropium, 38.0 for other LAMA, 47.1 for LABA/ICS, and 38.1 for LABA. The RR of death compared with current use of LABA was 0.54 (confidence interval [95% CI], 0.40-0.72) for aclidinium, 0.96 (95% CI, 0.76-1.21) for tiotropium, 0.76 (95% CI, 0.58-0.99) for other LAMA, and 1.08 (95% CI, 0.90-1.31) for LABA/ICS. Decreased risk for death observed among users of aclidinium was driven by overall current single use (RR = 0.41; 95% CI, 0.22-0.79), which corresponded to 26% of the aclidinium users (15 cases) and not by multiple use (RR = 1.02; 95% CI, 0.71-1.48).Use of aclidinium, tiotropium, other LAMA, or LABA/ICS was not associated with an increased risk of all-cause mortality as compared with the use of LABAs.

Purpose To evaluate availability of spirometry and symptom data in the Clinical Practice Research Datalink (United Kingdom) to assess COPD severity using the Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2016 definition and comparing it with an algorithm used in other studies. Methods This was a descriptive, noninterventional, secondary database cohort study of patients with COPD aged 40 years or older, who initiated treatment with specific COPD medications. Patients were classified according to COPD severity (1) in GOLD 2016 "ABCD" categories based on symptoms (Medical Research Council dyspnea grade, COPD Assessment Test, breathlessness), percent predicted FEV1, and exacerbation history and (2) as mild, moderate, severe, or very severe based on treatment and exacerbation history. Results The study included 63 900 patients with COPD aged 40 years or older that were new users of 1 or more COPD medication of interest. Percent predicted FEV1 was available for 80.9% of patients; symptoms for 75.6% of patients. Classification into GOLD 2016 ABCD categories was possible for 75.6% of the patients. The GOLD 2016 ABCD definition classified more patients under the high-risk categories (22.1%, A; 18.8%, B; 21.3%, C; 37.9%, D) than did the adapted algorithm (7.9%, mild; 48.6%, moderate; 42.1%, severe; 1.4%, very severe). Conclusion Using our adaptation of the GOLD 2016 COPD severity classification, the information in the Clinical Practice Research Datalink allowed us to ascertain COPD severity in approximately 75% of patients with COPD. Algorithms that include medication use tend to misclassify patients with the extreme COPD severity categories.

Purpose To describe the characteristics of new users of cilostazol in Europe with the aim to support the evaluation of its benefit/risk as used in regular clinical practice before the implementation of labeling changes recommended by the European Medicines Agency. Methods New users of cilostazol were identified in populations enrolled in five European health automated databases in the UK (The Health Improvement Network [THIN]), Spain (EpiChron cohort and Information System for the Improvement of Research in Primary Care [SIDIAP]), Sweden (National Registers), and Germany (German Pharmacoepidemiological Research Database [GePaRD]) between 2002 and 2012. New users were characterized according to the prevalence of cardiovascular disease and other comorbidities, concurrent use of interacting medications, new contraindications, duration of use, and potential off-label prescribing. Results We identified 22 593 new users of cilostazol. The median age was between 68.0 (THIN) and 73.7 (Sweden) years. More than 78% of users had concomitant cardiovascular disease, and between 78.8% (GePaRD) and 91.6% (THIN) were treated with interacting medications. Prevalence of new cardiovascular contraindications ranged from 1.5% (THIN) to 11.6% (GePaRD), and concurrent use of two or more antiplatelet drugs ranged from 6.3% (SIDIAP) to 13.5% (EpiChron cohort). Between 39.4% (Sweden) and 52.9% (THIN) of users discontinued cilostazol in the first 3 months. Between 41.0% (SIDIAP) and 93.4% (THIN) were considered to have received cilostazol according to the European Medicines Agency labeling. Conclusions In this collaborative European study, most cilostazol users were elderly patients with a high prevalence of cardiovascular diseases and other comorbidity and concurrent use of interacting drugs, indicating that this is a vulnerable population at high risk of complications, especially cardiovascular events. © 2017 The Authors. Pharmacoepidemiology and Drug Safety Published by John Wiley & Sons Ltd.

This is the peer reviewed version of the following article: Forns, J. [et al.]. Validity of ICD-9 and ICD-10 codes used to identify acute liver injury: a study in three European data sources. "Pharmacoepidemiology and drug safety", 6 Juny 2019, vol. 28, núm. 7, p. 965-975, which has been published in final form at 10.1002/pds.4803. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving." Purpose Validating cases of acute liver injury (ALI) in health care data sources is challenging. Previous validation studies reported low positive predictive values (PPVs). Methods Case validation was undertaken in a study conducted from 2009 to 2014 assessing the risk of ALI in antidepressants users in databases in Spain (EpiChron and SIDIAP) and the Danish National Health Registers. Three ALI definitions were evaluated: primary (specific hospital discharge codes), secondary (specific and nonspecific hospital discharge codes), and tertiary (specific and nonspecific hospital and outpatient codes). The validation included review of patient profiles (EpiChron and SIDIAP) and of clinical data from medical records (EpiChron and Denmark). ALI cases were confirmed when liver enzyme values met a definition by an international working group. Results Overall PPVs (95% CIs) for the study ALI definitions were, for the primary ALI definition, 84% (60%-97%) (EpiChron), 60% (26%-88%) (SIDIAP), and 74% (60%-85%) (Denmark); for the secondary ALI definition, 65% (45%-81%) (EpiChron), 40% (19%-64%) (SIDIAP), and 70% (64%-77%) (Denmark); and for the tertiary ALI definition, 25% (18%-34%) (EpiChron), 8% (7%-9%) (SIDIAP), and 47% (42%-52%) (Denmark). The overall PPVs were higher for specific than for nonspecific codes and for hospital discharge than for outpatient codes. The nonspecific code “unspecified jaundice” had high PPVs in Denmark. Conclusions PPVs obtained apply to patients using antidepressants without preexisting liver disease or ALI risk factors. To maximize validity, studies on ALI should prioritize hospital specific discharge codes and should include hospital codes for unspecified jaundice. Case validation is required when ALI outpatient cases are considered.

Acute liver injury; Antidepressants; Case-control Lesió hepàtica aguda; Antidepressius; Control de casos Lesión hepática aguda; Antidepresivos; Control de casos Background Agomelatine is a melatonin receptor agonist and serotonin 5-HT2C receptor antagonist indicated for depression in adults. Hepatotoxic reactions like acute liver injury (ALI) are an identified risk in the European risk management plan for agomelatine. Hepatotoxic reactions have been reported for other antidepressants, but population studies quantifying these risks are scarce. Antidepressants are widely prescribed, and users often have risk factors for ALI (e.g. metabolic syndrome). Objective The goal was to estimate the risk of ALI associated with agomelatine and other antidepressants (fluoxetine, paroxetine, sertraline, escitalopram, mirtazapine, venlafaxine, duloxetine, and amitriptyline) when compared with citalopram in routine clinical practice. Method A nested case–control study was conducted using data sources in Denmark, Germany, Spain, and Sweden (study period 2009–2014). Three ALI endpoints were defined using International Classification of Diseases (ICD) codes: primary (specific codes) and secondary (all codes) endpoints used only hospital discharge codes; the tertiary endpoint included both inpatient and outpatient settings (all codes). Validation of endpoints was implemented. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for current use were estimated for each data source and combined. Results We evaluated 3,238,495 new antidepressant and 74,440 agomelatine users. For the primary endpoint, the OR for agomelatine versus citalopram was 0.48 (CI 0.13–1.71). Results were also

Background Use of selective COX-2 non-steroidal anti-inflammatory drugs (NSAIDs) (coxibs) has been associated with an increased risk of acute myocardial infarction (AMI). However, the risk of AMI has only been studied for very few NSAIDs that are frequently used. Objectives To estimate the risk of AMI for individual NSAIDs. Methods A nested case-control study was performed from a cohort of new NSAID users ≥ 18 years (1999-2011) matching cases to a maximum of 100 controls on database, sex, age, and calendar time. Data were retrieved from six healthcare databases. Adjusted odds ratios (ORs) of current use of individual NSAIDs compared to past use were estimated per database. Pooling was done by two-stage pooling using a random effects model (ORmeta) and by one-stage pooling (ORpool). Results Among 8.5 million new NSAID users, 79,553 AMI cases were identified. The risk was elevated for current use of ketorolac (ORmeta 2.06;95%CI 1.83-2.32, ORpool 1.80; 1.49- 2.18) followed, in descending order of point estimate, by indometacin, etoricoxib, rofecoxib, diclofenac, fixed combination of diclofenac with misoprostol, piroxicam, ibuprofen, naproxen, celecoxib, meloxicam, nimesulide and ketoprofen (ORmeta 1.12; 1.03-1.22, ORpool 1.00;0.86-1.16). Higher doses showed higher risk estimates than lower doses. Conclusions The relative risk estimates of AMI differed slightly between 28 individual NSAIDs. The relative risk was highest for ketorolac and was correlated with COX-2 potency, but not restricted to coxibs.

Cilostazol; Intermittent claudication; Peripheral artery disease; Risk minimization Claudicació intermitent; Malaltia vascular perifèrica; Minimització del risc Claudicación intermitente; Enfermedad vascular periférica; Minimización del riesgo Purpose: The purpose of the study is to evaluate the effectiveness of risk minimization measures—labeling changes and communication to health care professionals—recommended by the European Medicines Agency for use of cilostazol for the treatment of intermittent claudication in Europe. Methods: Observational study of cilostazol in The Health Improvement Network (United Kingdom), EpiChron Cohort (Spain), SIDIAP (Spain), Swedish National Databases, and GePaRD (Germany). Among new users of cilostazol, we compared the prevalence of conditions targetedby the risk minimization measures in the periods before (2002‐2012) and after (2014) implementation. Conditions evaluated were prevalence of smoking, cardiovascular conditions, concurrent use of≥2 antiplatelet agents, concurrent use of potentCYP3A4/CYP2C19 inhibitors and high‐dose cilostazol, early monitoring of all users, and continuous monitoring of users at high cardiovascular risk. Results: We included 22593 and 1821 new users of cilostazol before and afterimplementation of risk minimization measures, respectively. After implementation, the frequency of several conditions related to the labeling changes improved in all the study populations: prevalence of use decreased between 13% (EpiChron) and 57% (SIDIAP), frequency of cardiovascular contraindications decreased between 8% (GePaRD) and 84% (EpiChron), and concurrent use of high‐dose cilostazol and potent CYP3A4/CYP2C19 inhibitors decreased between 6% (Sweden) and 100% (EpiChron).The frequency of other conditions improved in most study populations, except smoking, which decreased only in EpiChron (48% reduction). Conclusions: This study indicates that the risk minimization measures implemented by the EMA for the use of cilostazol have been effective in all European countries studied, except for smoking cessation before initiating cilostazol, which remains an area of improvement Otsuka Pharmaceutical Europe Ltd.

Background: Despite the concerns about a potential increased risk of skin cancer and lymphoma with the use of topical tacrolimus and pimecrolimus, no population-based studies have given an overview of the use of these drugs in Europe. Objective: To assess the use of topical tacrolimus and pimecrolimus in children and adults in Europe. Methods: Multicentre database cohort study comprising data from the Netherlands, Denmark, Sweden and the UK. We analysed users of topical tacrolimus and pimecrolimus starting from the date of first availability (between 2002 and 2003) or start establishment of the prescription database in Sweden (2006) through 2011. Use was assessed separately for children (≤ 18 years) and adults. Results: 32,052 children and 104,902 adults were treated with topical tacrolimus, and 32,125 children and 58,280 adults were treated with topical pimecrolimus. The number of users increased rapidly after first availability, especially for topical tacrolimus. Topical tacrolimus was more frequently used in all countries except Denmark. For both drugs, there was a decrease in users after 2004 in the Netherlands and Denmark and after 2005 in the UK, especially among children. This decrease was largest in Denmark. The decrease in the number of users was temporary for topical tacrolimus, while use remained relatively low for topical pimecrolimus. Conclusions: The number of topical tacrolimus and pimecrolimus users increased rapidly after regulatory approval. A transient reduction in topical tacrolimus use and a persistent reduction in topical pimecrolimus use was seen after 2004 in the Netherlands and Denmark and after 2005 in the UK.

Jordi Castellsague,1 Josephina G Kuiper,2 Anton Pottegård,3 Ingegärd Anveden Berglind,4 Daniel Dedman,5 Lia Gutierrez,1 Brian Calingaert,6 Myrthe PP van Herk-Sukel,2 Jesper Hallas,3 Anders Sundström,4 Arlene M Gallagher,5 James A Kaye,7 Carolina Pardo,8 Kenneth J Rothman,7 Susana Perez-Gutthann1 1Department of Epidemiology, RTI Health Solutions, Barcelona, Spain; 2Department Research, PHARMO Institute for Drug Outcomes Research, Utrecht, the Netherlands; 3Clinical Pharmacology and Pharmacy, Department of Public Health, University of Southern Denmark, Odense, Denmark; 4Centre for Pharmacoepidemiology, Unit of Clinical Epidemiology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden; 5Clinical Practice Research Datalink, Medicines and Healthcare products Regulatory Agency, London, UK; 6Department Epidemiology, RTI Health Solutions, Research Triangle Park, NC, 7Department of Epidemiology, RTI Health Solutions, Waltham, MA, USA; 8Pharmacovigilance Department, Astellas Pharma Europe B.V., Leiden, the Netherlands Background: There is a concern that topical tacrolimus and pimecrolimus, indicated for second-line treatment of atopic dermatitis, may increase the risk of lymphoma and skin cancer, particularly in children.Objective: The aim of this study was to compare incidence rates (IRs) of lymphoma and skin cancer between new users of topical tacrolimus or pimecrolimus and users of moderate- to high-potency topical corticosteroids (TCSs) and untreated subjects.Methods: This is a multicenter cohort study with frequency matching by strata of propensity scores in population databases in the Netherlands, Denmark, Sweden, and the UK. IR ratios (IRRs) were estimated using Mantel–Haenszel methods for stratified analysis.Results: We included 19,948 children and 66,127 adults initiating tacrolimus, 23,840 children and 37,417 adults initiating pimecrolimus, 584,121 users of TCSs, and 257,074 untreated subjects. IRs of lymphoma per 100,000 person-years were 10.4 events in children and 41.0 events in adults using tacrolimus and 3.0 events in children and 27.0 events in adults using pimecrolimus. The IRR (95% confidence interval [CI]) for lymphoma, tacrolimus versus TCSs, was 3.74 (1.00–14.06) in children and 1.27 (0.94–1.71) in adults. By lymphoma type, the highest IRR was 3.17 (0.58–17.23) for Hodgkin lymphoma in children and 1.76 (95% CI, 0.81–3.79) for cutaneous T-cell lymphoma (CTCL) in adults. For pimecrolimus versus TCSs, the highest IRR was 1.31 (95% CI, 0.33–5.14) for CTCL in adults. Compared with untreated subjects, adults using TCSs had a higher incidence of CTCL (IRR, 10.66; 95% CI, 2.60–43.75). Smaller associations were found between tacrolimus and pimecrolimus use and the risk of malignant melanoma or nonmelanoma skin cancer.Conclusion: Use of topical tacrolimus and pimecrolimus was associated with an increased risk of lymphoma. The low IRs imply that even if the increased risk is causal, it represents a small excess risk for individual patients. Residual confounding by severity of atopic dermatitis, increased monitoring of severe patients, and reverse causation could have affected the results. Keywords: topical calcineurin inhibitors, cutaneous T-cell lymphoma, malignant melanoma skin cancer, database study

Study Objective To estimate the incidence and relative risk of a hospitalization or emergency visit for noninfectious liver injury in users of eight oral antimicrobials—amoxicillin, amoxicillin-clavulanic acid, clarithromycin, cefuroxime, doxycycline, levofloxacin, moxifloxacin, telithromycin—compared with nonusers of these antimicrobials. Design Retrospective, observational cohort study with a nested case-control analysis. Data Source HealthCore Integrated Research Database. Patients Adults with continuous health plan enrollment for at least 6 months before study entry who had a new dispensing of a study antimicrobial between July 1, 2001, and March 31, 2009. Cases had diagnoses indicating noninfectious liver injury during follow-up. To control for potentially confounding risk factors, 10 controls at risk for liver injury during follow-up were matched to each case by age, sex, and event date (liver injury date of the case), and analyses were adjusted for medical history, concomitant drugs, and health care service use. Measurements and Main Results Two physician reviewers (blind to exposure) validated the cases. Among 1.3 million antimicrobial users, we identified 607 cases of liver injury, including 82 cases of severe hepatocellular injury and 11 cases of liver failure. Liver injury incidence in nonusers of study antimicrobials was 35/100,000 person-years (95% confidence interval [CI] 29–42/100,000 person-years). For valid cases, the adjusted relative risk among current users of multiple antimicrobials was 3.2 (95% CI 1.6–6.7). Levofloxacin had the highest relative risk for current single use (3.2, 95% CI 1.8–5.8). Relative risks were also elevated for amoxicillin-clavulanic acid (2.5, 95% CI 1.3–5.0), doxycycline (2.5, 95% CI 1.2–5.2), moxifloxacin (2.3, 95% CI 1.1–4.7), and amoxicillin (2.3, 95% CI 1.1–4.7). Conclusion The results support a comparatively high adjusted relative risk of liver injury among patients exposed concurrently to multiple antimicrobials and modest elevations in the risk for several antimicrobials used alone; however, we found little evidence of any strong effect of commonly used antimicrobials on the risk of liver injury.

Purpose To describe the characteristics of new users of cilostazol in Europe with the aim to support the evaluation of its benefit/risk as used in regular clinical practice before the implementation of labeling changes recommended by the European Medicines Agency. Methods New users of cilostazol were identified in populations enrolled in five European health automated databases in the UK (The Health Improvement Network [THIN]), Spain (EpiChron cohort and Information System for the Improvement of Research in Primary Care [SIDIAP]), Sweden (National Registers), and Germany (German Pharmacoepidemiological Research Database [GePaRD]) between 2002 and 2012. New users were characterized according to the prevalence of cardiovascular disease and other comorbidities, concurrent use of interacting medications, new contraindications, duration of use, and potential off‐label prescribing. Results We identified 22 593 new users of cilostazol. The median age was between 68.0 (THIN) and 73.7 (Sweden) years. More than 78% of users had concomitant cardiovascular disease, and between 78.8% (GePaRD) and 91.6% (THIN) were treated with interacting medications. Prevalence of new cardiovascular contraindications ranged from 1.5% (THIN) to 11.6% (GePaRD), and concurrent use of two or more antiplatelet drugs ranged from 6.3% (SIDIAP) to 13.5% (EpiChron cohort). Between 39.4% (Sweden) and 52.9% (THIN) of users discontinued cilostazol in the first 3 months. Between 41.0% (SIDIAP) and 93.4% (THIN) were considered to have received cilostazol according to the European Medicines Agency labeling. Conclusions In this collaborative European study, most cilostazol users were elderly patients with a high prevalence of cardiovascular diseases and other comorbidity and concurrent use of interacting drugs, indicating that this is a vulnerable population at high risk of complications, especially cardiovascular events. © 2017 The Authors. Pharmacoepidemiology and Drug Safety Published by John Wiley & Sons Ltd.

This article summarizes the outcome from an international consensus meeting, which took place in Vienna on 4 November 2014.The aim of the meeting was to provide the state of the art on the pathophysiology and treatment of acute pain with special emphasis on nimesulide, a non-steroidal anti-inflammatory drug (NSAID) indicated for the treatment of acute pain and primary dysmenorrhea. Besides the data on the mechanisms of acute inflammatory pain and on the efficacy and safety of nimesulide in patients affected by different forms of acute pain, the clinical experience of attending experts was discussed based on selected case reports.The members of this consensus group recognized that nimesulide is a NSAID highly effective in the treatment of several painful situations with an acute inflammatory component including primary dysmenorrhea. Although safety concerns regarding nimesulide have emerged in recent years, both robust new epidemiological data and clinical experience confirm a positive benefit/risk profile of nimesulide in the treatment of several forms of acute pain.The members of this international consensus group concluded that nimesulide, when used appropriately, remains a particularly valuable and safe option for the treatment of several conditions characterized by the presence of acute inflammatory pain because of the rapid onset of the analgesic action, and the positive evidence-based benefit/risk profile.

Purpose Information on the risk of upper gastrointestinal complications (UGIC) in users of nimesulide, the most used nonsteroidal anti-inflammatory drug (NSAID) in Italy, is scarce. In the context of the European regulatory review on nimesulide, we estimated and compared the risk associated with nimesulide and other individual NSAIDs with the risk in nonusers. Methods We used 2001–2008 data from regional health databases in Friuli Venezia Giulia (FVG), Italy, to conduct a cohort and nested case–control study of users of NSAIDs. Cases were identified by specific and nonspecific hospital discharge diagnoses in primary and secondary position and validated through hospital records. Ten controls per case were selected using density-based sampling from the cohort. Conditional logistic regression was used to estimate adjusted relative risks (RRs) and 95% confidence intervals (CIs). Results The cohort included 588 827 NSAIDs users and 3031 UGIC cases. Nonspecific codes contributed to 23% of cases and secondary codes to 5%. Among current users, IR per 1000 person-years decreased from 4.45 cases in 2001 to 2.21 cases in 2008. The RR (95%CI) for current use of NSAIDs was 3.28 (2.86, 3.76). RR was

This cohort study of postmenopausal women in the United Kingdom aged ≥50years determined the incremental cost of health care and clinical outcomes in the 12months following incident, selected fractures (non-vertebral non-hip [NVNHF], vertebral [VF] and multiple [MF]). Incremental costs and outcomes of the fracture cohorts were compared with those of cohorts comprised of women without fractures who were individually matched on age and comorbidity. Cohorts were identified from The Health Improvement Network database, a primary health care database, from 2001 to 2005. We estimated 1-year incremental costs (hospitalizations; general practice, accident/emergency, and referral visits; and prescription medications) associated with each fracture type. Descriptive analyses examined occurrence of subsequent fractures and death. No long-term health care costs or outcomes were assessed. Overall, 14,030 women had NVNHF, 1471 had VF, and 193 had MF. The risk of death was greater for women with fractures than for women in the non-fracture cohorts. Mean incremental cost for fractures compared with no fractures was £1152 for VF; £690 for NVNHF, and £2581 for MF. Of the total incremental cost, hospitalizations represented 54%-90% and medications represented 7%-29%. In all fracture cohorts, most of the total annual costs were concentrated in the 6months after the date of fracture. Fractures among postmenopausal women represent an important burden to the health system due to the increase in health resource utilization and related costs. In this study, hospitalizations were the main driver of the overall incremental cost during the 12months following the fracture. Mortality in women in the selected fracture cohorts was higher than in women in the non-fracture cohorts.

textabstractAims: To perform a quantitative systematic review of observational studies on the risk of stroke associated with the use of individual NSAIDs. Methods and results: Searches were conducted using the Medline database within PubMed (1990-2008). Observational cohort or case-control studies were eligible if reported on the risk of cardiovascular events associated with individual NSAIDs versus the nonuse of NSAIDs. We found 3193 articles, in which 75 were eligible for review and abstraction. Of the 75 articles, 6 reported relative risk (RR) of stroke. Data were abstracted into a database using a standardized entry form. Two authors assessed study quality, and discrepancies were resolved by consensus. The pooled RR of all subtypes of incident stroke was increased with the current use of rofecoxib (RR=1.64, 95% CI=1.15-2.33) and diclofenac (RR=1.27, 95% CI=1.08-1.48). The pooled estimates for naproxen, ibuprofen, and celecoxib were close to unity. The risk of ischemic stroke was also increased with rofecoxib (RR=1.82, 95% CI=1.09-3.04) and diclofenac (RR=1.20, 95% CI=0.99-1.45). Data were inadequate to estimate the pooled RR by dose and duration, for other individual NSAIDs or nonischemic stroke subtypes. Conclusion: This meta-analysis supports an increased risk of ischemic stroke with the current use of rofecoxib and diclofenac. Additional studies are required to evaluate most individual NSAIDS, the effect of dose and duration, and the subtypes of stroke.

Current asthma guidelines recommend the use of long-acting beta-agonists (LABAs) in combination with inhaled corticosteroids (ICSs) for long-term control and prevention of symptoms in persistent asthma. Data on the risk of asthma exacerbations of LABAs in combination with ICSs, as prescribed in typical clinical practice, are very scarce.The authors conducted a systematic literature review and meta-analysis of observational studies to examine the risk of asthma exacerbations, measured as asthma-related hospitalization and/or asthma-related emergency room (ER) visits, in adults receiving LABAs plus ICSs in a fixed-dose combination compared with patients receiving ICSs alone.Seven studies, all retrospective cohort studies conducted in the United States, representing approximately 96,000 patients, were included in the meta-analysis. The meta-analysis found that the use of ICSs plus LABAs was associated with a lower risk of asthma-related hospitalizations and/or ER visits than ICSs alone (odds ratio: 0.82; 95% confidence interval: 0.72-0.94). Sensitivity analyses to explore heterogeneity of endpoint definition, duration of follow-up, and patient characteristics did not significantly alter the findings.Overall, this systematic meta-analysis suggests that patients in clinical practice treated with a single inhaler containing ICSs plus LABAs experience fewer asthma exacerbations than similar patients treated with ICSs alone.

Study Objective. To estimate the risk of upper gastrointestinal complications associated with use of cyclooxygenase-2 (COX-2) selective (celecoxib and rofecoxib) and individual nonselective nonsteroidal antiinflammatory drugs (NSAIDs) compared with nonuse of these drugs. Design. Nested case-control study. Data Source. Administrative health care databases of Saskatchewan, Canada. Patients. Among a population of men and women aged 20–89 years who were covered by public health insurance with prescription drug benefits between November 15, 1999, and December 31, 2001, 726 case patients with first hospitalization for upper gastrointestinal complications (with validation of cases through review of hospital medical records) were confirmed from 1,054,532 person-years of follow-up, and 20,002 control patients were randomly selected from all eligible controls, frequency matched to cases on their index date (± 3 mo). Measurements and Main Results. Logistic regression was used to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for the association between upper gastrointestinal complications and use of NSAIDs. Current rofecoxib and naproxen users had the highest risk for upper gastrointestinal complications with adjusted ORs of 3.6 (95% CI 2.2–5.7) and 3.4 (95% CI 1.8-6.7), respectively. No association was found between the risk of upper gastrointestinal complications and use of celecoxib (OR 1.1, 95% CI 0.7-1.8) or the use of diclofenac plus misoprostol (OR 0.7, 95% CI 0.3-1.8). A dose-response relationship was observed for rofecoxib and naproxen with ORs for high dose of 5.2 (95% CI 2.5–10.6) and 5.1 (95% CI 2.1–12.3), respectively. Short-term users of celecoxib and naproxen had a higher risk than long-term users, whereas among users of rofecoxib the risk was higher among long-term than short-term users. Conclusion. These findings support the variability of individual NSAIDs in the elevated risk of upper gastrointestinal complications. Our results suggest that the risk for rofecoxib is similar to that for naproxen. Celecoxib users appear to have a similar risk for upper gastrointestinal complications as nonusers; however, the risk may be increased at the start of treatment with celecoxib.

Purpose To validate ICD 9 codes with a high positive predictive value (PPV) for incident strokes. The study population consisted of Tennessee Medicaid enrollees aged from 50 to 84 years. Methods We identified all patients who were hospitalized with a discharge diagnosis of stroke between 1999 and 2003 using highly specific codes (ischemic stroke ICD 9-CM codes 433.x1, 434 [excluding 434.x0], or 436; intracerebral hemorrhage [431]; and subarachnoid hemorrhage [430]). We reviewed medical records of a systematic sample of 250 cohort members. We randomly selected 10–30 eligible records for review from hospitals with at least 10 stroke hospitalizations. Results We reviewed 231 charts (93% of total sampled), and 205 (89%) met study criteria for new outpatient stroke. Of the 205 confirmed new outpatient strokes, 196 had stroke listed as the primary discharge diagnosis (PPV = 96%). However, 46 (23%) of the 196 patients identified by the primary diagnosis also had a remote stroke history (recurrent stroke not incident). Thus the PPV of the primary discharge diagnosis for identifying incident stroke decreased to 74%. When we applied an algorithm that restricted our population to those with stroke as the primary diagnosis and excluded patients with any prior outpatient diagnosis of stroke, we identified incident stroke events with more precision (PPV = 80%). Conclusion The PPV of incident strokes was 80% using our strategy of primary discharge diagnosis and excluding prior outpatient diagnoses of stroke. Although an unknown percentage of incident strokes are missed, this group of proven incident stroke patients can be used for etiologic studies of medication exposures. Copyright © 2007 John Wiley & Sons, Ltd.

Objectives: To estimate the risk of a first hospital admission for heart failure (HF) associated with the use of non-steroidal anti-inflammatory drugs (NSAIDs). Methods: Cohort study with a nested case–control analysis based on the UK General Practice Research Database. Overall, 1396 cases of first hospital admission for non-fatal HF were identified (January 1997 to December 2000) and compared with a random sample of 5000 controls. Results: The incidence rate was 2.7/1000 person years. Prior clinical diagnosis of HF was the main independent risk factor triggering a first HF hospitalisation (relative risk 7.3, 95% confidence interval (CI) 6.1 to 8.8). The risk of a first hospital admission for HF associated with current use of NSAIDs was 1.3 (95% CI 1.1 to 1.6) after controlling for major confounding factors. No effects of dose and duration were found. The relative risk in current users of NSAIDs with prior HF was 8.6 (95% CI 5.3 to 13.8) compared with patients who did not use NSAIDs and without prior clinical diagnosis of HF. Conclusion: Use of NSAIDs was associated with a small increase in risk of a first hospitalisation for HF. In patients with prior clinical diagnosis of HF, the use of NSAIDs may lead to worsening of pre-existing HF that triggers their hospital admission. This increased risk, although small, may result in considerable public health impact, particularly among the elderly.

Objective To assess use and channeling of cyclooxygenase 2 selective inhibitors (coxibs) over time and to estimate the percentage of coxib users with cardiovascular contraindications. Methods The study population comprised all coxib and nonselective nonsteroidal antiinflammatory drug (NSAID) users in the Integrated Primary Care Information project between January 2000 and December 2004. The prevalence of risk factors for NSAID-related upper gastrointestinal ulcer complications, cardiovascular disease, and cerebrovascular disease at the start of treatment was compared between users of coxibs and users of nonselective NSAIDs. Results The study population included 72,841 nonselective NSAID users and 10,739 coxib users. The prevalence of risk factors for NSAID-related gastrointestinal complications was higher in coxib users than nonselective NSAID users (odds ratio [OR] 1.18, 95% confidence interval [95% CI] 1.10–1.26). Similarly, the prevalence of prior cardiovascular disease was higher in coxib users than in nonselective NSAID users (OR 1.35, 95% CI 1.28–1.43). Channeling of coxibs to patients with NSAID-related gastrointestinal risk factors declined after 2001 but increased again in 2004, whereas the channeling of coxibs to patients with cardiovascular disease remained constant. Less than 15% of all coxib users had history of ischemic coronary or cerebrovascular disease. Among coxib users with increased risk for NSAID-related gastrointestinal disorders, 27% had history of ischemic coronary or cerebrovascular disease. Conclusion This study demonstrates that coxibs were preferentially prescribed to patients with risk factors for NSAID-related gastrointestinal disorders and/or cardiovascular diseases. Only one-quarter of coxib users with increased risk for NSAID-related gastrointestinal complications had cardiovascular conditions compatible with recent European safety contraindications for coxibs.

The long-term efficacy and safety of formoterol dry powder capsules for inhalation in pediatric asthma have not previously been evaluated.We examined the effectiveness of inhaled formoterol over a period of 12 months in asthmatic children who were still symptomatic despite anti-inflammatory treatment.After a run-in period, 518 patients (5 to 12 years old) were randomized in a double-blind manner to receive 12 or 24 microg formoterol dry powder (Foradil, Novartis Pharma AG, Basel, Switzerland) or placebo twice daily for 12 months. The drug was administered by inhaler (Aerolizer, Novartis Pharma AG) and was given in addition to their anti-inflammatory treatment. The primary variable was the area under the curve for forced expiratory volume in 1 second measured over 12 hours after the morning dose of study medication.The area under the curve for forced expiratory volume in 1 second after the first dose of treatment and after 3 and 12 months of treatment was significantly greater for patients receiving formoterol 12 microg and 24 microg than for patients receiving placebo (all Por = 0.0062). Compared with placebo, both doses of formoterol significantly improved morning and evening premedication peak expiratory flow rate (all P0.001). In the group treated with formoterol 24 microg, median symptom score and median dose of rescue medication at night were lower than during the run-in period, whereas the opposite occurred in the placebo group. The incidence of hospitalizations for asthma was higher in the formoterol groups than in the placebo group.Our results indicate that, in asthmatic children who are still symptomatic despite anti-inflammatory therapy, the addition of formoterol consistently improves airflow obstruction and nocturnal symptoms and reduces the use of rescue medication. However, this treatment requires close disease monitoring to detect early signs of acute exacerbation.

We characterized the population of users of inhaled long-acting β 2 -agonists in the region of Friuli-Venezia Giulia, in Italy, and assessed changes in asthma treatment and control after initiating long-acting β 2 -agonists. All residents using formoterol or salmeterol between 1992 and 1996 were identified in the regional Health Databases. Utilization rates of asthma medications and hospitalization rates for asthma were computed for the year before and after the date of the first long-acting β 2 -agonist prescription. There were 3803 users of formoterol and 20 054 users of salmeterol. Overall, 65% of users were older than 54 years of age. All formoterol users and 86% of salmeterol users received their first prescription for the respective drug during the study period (new users). Among these new users, 50% had not received any asthma drug during the 4 months preceding the start of long-acting β 2 -agonist administration. Prior 1 yr utilization rates of asthma medications and hospitalization rates for asthma were greater among new users of long-acting β 2 -agonists than among new users of salbutamol and xanthines. In addition, formoterol new users had higher prior use of asthma drugs than new users of salmeterol. One year prior hospitalization rates for asthma were also higher among formoterol than salmeterol new users with rate ratios of 1·7 (95% CI 1·3-2·2) for patients younger than 45 and 1·5 (1·2-1·9) for older patients. Use of short-acting β 2 -agonists, oral steroids and xanthines significantly declined after starting formoterol, whereas the use of inhaled steroids increased after the start of either formoterol or salmeterol. Asthma hospitalizations decreased by 32% in patients under age 45, by 43% in older patients, during the year following the start of formoterol, and by 15% and 24%, respectively, after the start of salmeterol. We conclude that long-acting β 2 -agonists were mainly prescribed to middle-aged and elderly patients and that formoterol appeared to be preferentially prescribed to patients with more severe asthma than salmeterol. Changes in asthma treatment and reduction in hospitalization rates for asthma after starting formoterol and salmeterol are compatible with an improvement in the control of asthma.

The association between use of hormone replacement therapy (HRT) and the risk of venous thromboembolism (VTE) has been assessed in relatively few epidemiological studies. Evidence from the earliest studies did not support an increased risk of VTE among HRT users. However, methodological limitations in most studies, including small sample size and inadequate control of confounding, did not allow firm conclusions to be made. Most of these limitations have been overcome in 5 recent studies which consistently show that the risk of VTE among women currently using HRT is 2 to 3 times higher than among women not using HRT. The overall relative risk of VTE for women currently using HRT obtained from these studies was 2.6 (95% confidence interval 1.6 to 4.2). This association is unlikely to be explained by confounding or other potential biases affecting observational studies. The risk appears to be more prominent during the first year of HRT use, and in 2 studies the risk disappeared after the first year of therapy. A dose-response relationship, with a doubling of risk among users of high doses of estrogens, was shown in 2 of these studies. No major differences were observed with the different types of therapy, but users of unopposed estrogen therapy and transdermal therapy might be at lower risk than users of opposed regimens and oral preparations. Evidence from these new studies indicates that, among healthy post-menopausal women, between 1 and 2 additional cases of VTE per 10,000 women can be annually attributed to current use of HRT. The Committee on Safety of Medicines in the UK evaluated this risk as small and considered that it does not change the overall benefit-risk profile of HRT for most women.

We quantified the contribution to pharmacoepidemiologic research of studies conducted in automated health care databases over the last decade. We reviewed abstracts accepted at the International Conference of Pharmacoepidemiology in 2000 and 2011 to identify studies on drug safety, drug utilization, validation of database data, and disease epidemiology conducted in databases. We abstracted data on study objectives, database name and country, and number of databases used in each study. The total number of ICPE abstracts doubled from 389 in 2000 to 806 in 2011. Abstracts on database studies contributed 36 percent (139 of 389) of all abstracts in 2000 and 45 percent (360 of 806) in 2011. The most common study objective in both years was to evaluate drug safety. Abstracts on validation of database data increased from 2 to 39. Multiple-database abstracts increased from 9 to 43. The number of countries contributing to database abstracts increased from 14 to 22; the increase in countries was primarily in Europe and the Asian Pacific region. This study indicates that the use of health care databases in pharmacoepidemiologic research is growing in many countries. The different types of database studies and the number of studies conducted using multiple databases is also increasing, suggesting that larger study populations and greater collaboration among investigators are becoming more common.

We conducted a cohort study of acute, noninfectious liver injury among oral antimicrobial users. Potential cases were identified in the HealthCore Integrated Research Database (HIRD(SM)) population between July 1, 2001, and March 31, 2009, using ICD-9-CM codes primarily for acute and subacute necrosis of the liver, hepatic coma, and unspecified hepatitis. Liver test results were used to confirm case status according to published criteria. Two physician reviewers experienced in studying acute liver injury (blinded to study drug exposures) evaluated data abstracted from hospital and emergency department records to validate potential cases. Of 715 potential cases having claims associated with any of the primary screening codes, 312 (44%) were valid cases, 108 (15%) were not cases, and 295 (41%) were of uncertain status (records inadequate for validation). Among potential cases with adequate medical records, the PPV for presence of any of the primary codes was 74% (95% CI, 70%-78%). The highest PPV for a single code was for acute and subacute necrosis of the liver (84%; 95% CI, 77%-90%). Evaluation of cases of noninfectious liver injury using hospital and emergency department medical records continues to represent the preferred approach in studies using insurance claims data.

Objective To conduct a systematic review of observational studies on the risk of acute myocardial infarction (AMI) with use of individual nonsteroidal anti-inflammatory drugs (NSAIDs). Methods A search of Medline (PubMed) for observational studies published from 1990 to 2011 identified 3829 articles; 31 reported relative risk (RR) of AMI with use of individual NSAIDs versus nonuse of NSAIDs. Information abstracted in a standardized form from 25 publications was used for the meta-analysis on 18 independent study populations. Results Random-effects RR (95% confidence interval (CI)) was lowest for naproxen 1.06 (0.94–1.20), followed by celecoxib 1.12 (1.00–1.24), ibuprofen 1.14 (0.98–1.31), meloxicam 1.25 (1.04–1.49), rofecoxib 1.34 (1.22–1.48), diclofenac 1.38 (1.26–1.52), indometacin 1.40 (1.21–1.62), etodolac 1.55 (1.16–2.06), and etoricoxib 1.97 (1.35–2.89). Heterogeneity between studies was present. For new users, RRs (95% CIs) were for naproxen, 0.85 (0.73–1.00); ibuprofen, 1.20 (0.97–1.48); celecoxib, 1.23 (1.00–1.52); diclofenac, 1.41 (1.08–1.86); and rofecoxib, 1.43 (1.21–1.66). Except for naproxen, higher risk was generally associated with higher doses, as defined in each study, overall and in patients with prior coronary heart disease. Low and high doses of diclofenac and rofecoxib were associated with high risk of AMI, with dose–response relationship for rofecoxib. In patients with prior coronary heart disease, except for naproxen, duration of use ≤3 months was associated with an increased risk of AMI. Conclusions Most frequently NSAIDs used in clinical practice, except naproxen, are associated with an increased risk of AMI at high doses or in persons with diagnosed coronary heart disease. For diclofenac and rofecoxib, the risk was increased at low and high doses. Copyright © 2013 John Wiley & Sons, Ltd.

Information on the risk of upper gastrointestinal complications (UGIC) in users of nimesulide, the most used nonsteroidal anti-inflammatory drug (NSAID) in Italy, is scarce. In the context of the European regulatory review on nimesulide, we estimated and compared the risk associated with nimesulide and other individual NSAIDs with the risk in nonusers.We used 2001-2008 data from regional health databases in Friuli Venezia Giulia (FVG), Italy, to conduct a cohort and nested case-control study of users of NSAIDs. Cases were identified by specific and nonspecific hospital discharge diagnoses in primary and secondary position and validated through hospital records. Ten controls per case were selected using density-based sampling from the cohort. Conditional logistic regression was used to estimate adjusted relative risks (RRs) and 95% confidence intervals (CIs).The cohort included 588,827 NSAIDs users and 3031 UGIC cases. Nonspecific codes contributed to 23% of cases and secondary codes to 5%. Among current users, IR per 1000 person-years decreased from 4.45 cases in 2001 to 2.21 cases in 2008. The RR (95%CI) for current use of NSAIDs was 3.28 (2.86, 3.76). RR was2 for rofecoxib, celecoxib, and nimesulide; 2 to5 for naproxen, ibuprofen, diclofenac, etoricoxib, and meloxicam; and ≥ 5 for ketoprofen, piroxicam, and ketorolac.IRs of UGIC in FVG decreased about 50% between 2001 and 2008. Nimesulide was in the low-medium range of RR. A complete ascertainment of UGIC cases in databases may require validation of nonspecific codes, secondary codes, and additional codes such as peritonitis and acute posthemorrhagic anemia.

Background: The risk of upper gastrointestinal (GI) complications associated with the use of NSAIDs is a serious public health concern. The risk varies between individual NSAIDs; however, there is little information on the risk associated with some NSAIDs and on the impact of risk factors. These data are necessary to evaluate the benefit-risk of individual NSAIDs for clinical and health policy decision making. Within the European Community’s Seventh Framework Programme, the Safety Of non-Steroidal anti-inflammatory drugs (NSAIDs) [SOS] project aims to develop decision models for regulatory and clinical use of individual NSAIDs according to their GI and cardiovascular safety. Objective: The aim of this study was to conduct a systematic review and meta-analysis of observational studies to provide summary relative risks (RR) of upper GI complications (UGIC) associated with the use of individual NSAIDs, including selective cyclooxygenase-2 inhibitors. Methods: We used the MEDLINE database to identify cohort and case-control studies published between 1 January 1980 and 31 May 2011, providing adjusted effect estimates for UGIC comparing individual NSAIDs with non-use of NSAIDs. We estimated pooled RR and 95% CIs of UGIC for individual NSAIDs overall and by dose using fixed- and random-effects methods. Subgroup analyses were conducted to evaluate methodological and clinical heterogeneity between studies. Results: A total of 2984 articles were identified and 59 were selected for data abstraction. After review of the abstracted information, 28 studies met the meta-analysis inclusion criteria. Pooled RR ranged from 1.43 (95% CI 0.65, 3.15) for aceclofenac to 18.45 (95% CI 10.99, 30.97) for azapropazone. RR was less than 2 for aceclofenac, celecoxib (RR 1.45; 95% CI 1.17, 1.81) and ibuprofen (RR 1.84; 95% CI 1.54, 2.20); 2 to less than 4 for rofecoxib (RR 2.32; 95% CI 1.89, 2.86), sulindac (RR 2.89; 95% CI 1.90, 4.42), diclofenac (RR 3.34; 95% CI 2.79, 3.99), meloxicam (RR 3.47; 95% CI 2.19, 5.50), nimesulide (RR 3.83; 95% CI 3.20, 4.60) and ketoprofen (RR 3.92; 95% CI 2.70, 5.69); 4–5 for tenoxicam (RR 4.10; 95% CI 2.16, 7.79), naproxen (RR 4.10; 95% CI 3.22, 5.23), indometacin (RR 4.14; 95% CI 2.91, 5.90) and diflunisal (RR 4.37; 95% CI 1.07, 17.81); and greater than 5 for piroxicam (RR 7.43; 95% CI 5.19, 10.63), ketorolac (RR 11.50; 95% CI 5.56, 23.78) and azapropazone. RRs for the use of high daily doses of NSAIDs versus non-use were 2-3 times higher than those associated with low daily doses. Conclusions: We confirmed variability in the risk of UGIC among individual NSAIDs as used in clinical practice. Factors influencing findings across studies (e.g. definition and validation of UGIC, exposure assessment, analysis of new vs prevalent users) and the scarce data on the effect of dose and duration of use of NSAIDs and on concurrent use of other medications need to be addressed in future studies, including SOS.

objective: To document the prevalence of digitalis use and the incidence of hospitalization caused by digitalis toxicity. design: Observational cohort followed for 6 years. setting: Urban community. participants: Persons were eligible if they were (1) enrolled in the Yale Health and Aging Project and (2) using digitalis when interviewed in 1982 or 1985. The Project comprises a sample of noninstitutionalized persons aged 65 years and over living in New Haven, Connecticut. methods: Between 1982 and 1988 when a Project participant was hospitalized in New Haven, a researcher reviewed the medical record and coded up to 16 International Classification of Diseases-Class 9 (ICD-9) diagnoses. To identify hospitalizations caused by digitalis, we reexamined records with ICD-9 codes suggesting toxicity. We confirmed the admission illness was an adverse drug reaction with a decision algorithm. results: The prevalence of digitalis use was 13% in 1982 and 12% in 1985. The incidence of hospitalization caused by definite or probable toxicity was 4.2% (95% confidence interval=0.3% to 8.1%) over 6 years. Manifestations of toxicity were malaise or gastrointestinal symptoms (two patients) and heart block plus malaise or gastrointestinal symptoms (six patients). Use of quinidine was associated (P conclusion: Knowledge about the incidence of severe, morbid toxicity may help clinicians estimate and compare the risks and benefits of digitalis and alternate therapies.

Background— The cardiovascular safety of individual nonsteroidal antiinflammatory drugs (NSAIDs) is highly controversial, particularly in persons with serious coronary heart disease. Methods and Results— We conducted a multisite retrospective cohort study of commonly used individual NSAIDs in Tennessee Medicaid, Saskatchewan Health, and United Kingdom General Practice Research databases. The cohort included 48566 patients recently hospitalized for myocardial infarction, revascularization, or unstable angina pectoris with more than 111000 person-years of follow-up. Naproxen users had the lowest adjusted rates of serious coronary heart disease (myocardial infarction, coronary heart disease death) and serious cardiovascular disease (myocardial infarction, stroke)/death from any cause, with respective incidence rate ratios (relative to NSAID nonusers) of 0.88 (95% CI, 0.66 to 1.17) and 0.91 (0.78 to 1.06). Risk did not increase with doses ≥1000 mg. Relative to NSAID nonusers, serious coronary heart disease risk increased with short term (P =0.076) and serious cardiovascular disease/death (1.52 [1.22 to 1.89], P =0.0002), and those of ibuprofen had increased risk of the latter end point (1.25 [1.02 to 1.53], P =0.032). Compared to naproxen in doses ≥1000 mg, serious coronary heart disease incidence rate ratios were increased for rofecoxib >25 mg (2.29 [1.24 to 4.22], P =0.008) and celecoxib >200 mg (1.61 [1.01 to 2.57], P =0.046). Conclusions— In patients recently hospitalized for serious coronary heart disease, naproxen had better cardiovascular safety than did diclofenac, ibuprofen, and higher doses of celecoxib and rofecoxib.

Background Meta-analyses of observational studies show variability in the risk of acute myocardial infarction (AMI) among non-steroidal anti-inflammatory drugs (NSAIDs), with an increase in risk for rofecoxib and diclofenac, and no increase in risk for celecoxib, naproxen, or ibuprofen. Methods and Results We identified a cohort of 364 658 individuals aged 40–84 years who were enrolled in Saskatchewan Health, Canada, from 15 November 1999 to 31 December 2001. A nested case–control analysis compared 3252 incident cases of hospitalized AMI and out-of-hospital CHD deaths with 20 002 controls randomly sampled from the cohort. The incidence of AMI/CHD was 5.1 per 1000 person-years (95%CI: 5.0–5.3). The adjusted ORs (95%CI) of AMI/CHD in current users of individual NSAIDs compared with non-use were: celecoxib (1.11; 0.84–1.47), rofecoxib (1.32; 0.91–1.91), diclofenac (1.02; 0.75–1.38), naproxen (1.57; 0.98–2.52), ibuprofen (1.59; 0.88–2.89), and indomethacin (1.34; 0.81–2.19). Long-term use of rofecoxib was compatible with an increased risk (OR = 1.46; 0.97–2.22) while estimates of other individual NSAIDs were close to unity. Overall NSAID use was associated with a 30% increased risk of nonfatal AMI but was absent for fatal AMI/CHD. Conclusions This study showed a modest increased risk of AMI/CHD with various traditional NSAIDs and COX-2 inhibitors. Confidence intervals of estimated ORs included the null value for most comparisons. The study confirmed that the differentiation between traditional NSAIDs and COX-2 inhibitors is not a reliable tool for predicting cardiovascular risk associated with NSAIDs. Copyright © 2009 John Wiley & Sons, Ltd.

Purpose To assess the relative incidence of peptic ulcer bleeding and perforation (PUBP) in users of selective cyclooxygenase-2 (COX-2) inhibitors and nonselective nonsteroidal anti-inflammatory drugs (NSAIDs). Methods This was a retrospective case–control study based on insurance claims, with chart review to confirm cases. The base population consisted of 2.2 million adult users of celecoxib, diclofenac, ibuprofen, naproxen, rofecoxib, or valdecoxib who were covered by commercial health insurance in the United States from 1999–2003. For 790 persons hospitalized for PUBP and 7887 controls, most recent NSAID/COX-2 use and a variety of medical and pharmacy risk factors were ascertained from the insurance files and analyzed by conditional logistic regression. The main outcome measure was the odds ratio (OR) associated with use of each drug by comparison to naproxen, and in successive intervals after last dispensing. Results Hospitalization for PUBP was highest from the date of NSAID/COX-2 dispensing through the end of an exposure period that corresponded to the days supply; the rate dropped steadily thereafter. The covariate-adjusted ORs by comparison to naproxen were: ibuprofen 0.86 (95% confidence interval (CI) 0.68, 1.09), rofecoxib 0.79 (0.62, 1.02), diclofenac 0.66 (0.47, 0.94), valdecoxib 0.50 (0.26, 0.97), and celecoxib 0.45 (0.35, 0.58). The nonselective NSAIDs had an OR for PUBP of 1.51 (1.26, 1.98) compared to the selective COX-2 inhibitors. Conclusion Nonselective NSAIDs convey half again as much risk of hospitalization for PUBP as do COX-2 inhibitors. Celecoxib users had about half the hospitalization rate of users of naproxen. Copyright © 2008 John Wiley & Sons, Ltd.

Background Case definitions are essential to epidemiological research. Objectives To evaluate ICD-9 codes 410 and 411 to identify cases of acute coronary syndromes (ACS), and the clinical information availability in the administrative and hospital discharge records of Saskatchewan, Canada. Methods In the context of a safety cohort study, we identified hospitalisations with primary discharge codes 410 (2260) and 411 (799). We selected all records with code 411, and a random sample (200) with code 410. Based on information obtained by trained abstractors from hospital records, events were classified by two cardiologists as definite or possible according to adapted AHA/ESC criteria. The validity of 410 and 411 codes was assessed by calculating the positive predictive value (PPV). Completeness of the recorded information on risk factors and use of aspirin was explored. Results The PPVs of the codes 410 and 411 for ACS were 0.96 (95%CI: 0. 92–0.98) and 0.86 (95%CI: 0.83–0.88), respectively. The PPV of 410 for acute myocardial infarction (AMI) was 0.95 (95%CI: 0.91–0.98). The PPV of 411 was 0.73 (95%CI: 0.70–0.77) for primary unstable angina (UA) and 0.09 (95%CI: 0.07–0.11) for AMI. Hospital charts review revealed key information for clinical variables, smoking, obesity and use of aspirin at admission. Conclusions ICD-9 410 code has high PPV for AMI cases, likewise 411 for UA cases. Case validation remains important in epidemiological studies with administrative health databases. Given the pathophysiology of ACS, both AMI and UA might be used as study end points. In addition to code 410, we recommend the use of 411 plus validation. Copyright © 2008 John Wiley & Sons, Ltd.

Purpose To estimate the net cardiovascular (CV) (coronary heart disease, stroke, congestive heart failure), and gastrointestinal (GI) (peptic ulcer complications) risk-benefit public health impact of the use of celecoxib compared to non-selective NSAIDs in the arthritis population. Methods We applied discrete event simulation models to data from the US National Health Surveys, CV risk-prediction models from the Framingham Heart Study, and population-based studies. Models took into account the multifactorial effect of risk factors, comorbidity, and competing risk of mortality. We simulated the natural history of CV and GI disease in the U.S. arthritis population over 1 year, through the individual baseline cardiovascular and gastrointestinal risk profile. This model was modified with relative risks associated with the use of each treatment. The mean number of events was estimated for each end-point in each model: natural history, celecoxib, diclofenac, ibuprofen, naproxen. The number of events for celecoxib was compared with each NSAID. Results The evaluation included 1% of the U.S. population with arthritis. Celecoxib, when applied to 100 000 patients over 1 year, resulted in 570 (range from sensitivity analysis: 440–691), 226 (124–313), and 746 (612–868) fewer ulcer complications than diclofenac, ibuprofen, and naproxen, respectively. There were 20 (16–25), 8 (4–12), and 27 (22–32) fewer deaths from ulcer complications, respectively. No increase in cardiovascular events or all cause mortality was observed for celecoxib versus the other individual NSAIDs. Conclusion Results from these simulations suggest a gastrointestinal benefit for celecoxib not offset by increased cardiovascular events or mortality. The methodology used here provides a risk-benefit assessment framework for evaluating the public heath impact of drugs. Copyright © 2006 John Wiley & Sons, Ltd.

Hepatic adverse events associated with the use of nonaspirin drugs and NSAIDs are uncommon, but the widespread use of these drugs may impact public health.We conducted a case/noncase analysis of spontaneous reports to compare the hepatic safety profile of cyclooxygenase (COX)-2 selective inhibitors with that of nonselective NSAIDs.This case/noncase analysis was conducted using the US Food and Drug Administration Freedom of Information (FDA/FOI) database (through quarter 1, 2003) and the World Health Organization Uppsala Monitoring Centre (WHO/UMC) database (through quarter 3, 2003). Council for International Organizations of Medical Sciences and WHO Adverse Reaction Terminology preferred terms were used to classify hepatic disorders with broad and specific case definitions. After reports involving established hepatotoxic drugs (bromfenac, nimesulide, sulindac) were excluded, the proportion of reports (PRs) of each case definition was calculated for each NSAID. Crude and adjusted reporting odds ratios (RORs) were used to compare the overall proportions of hepatic disorders and hepatic failure of celecoxib and rofecoxib versus nonselective NSAIDs.A total of 158,539 and 185,253 reports of NSAIDs were identified in the FDA/FOI and WHO/UMC databases and 25% and 16%, respectively, involved other hepatotoxic drugs. The PRs of hepatic disorders for all COX-2 selective inhibitors and non-selective NSAIDs were 3.0% in the FDA/FOI database and 2.7% in the WHO/UMC database. In the FDA/FOI and WHO/UMC databases, respectively, mmesulide (16.7% and 14.4%), bromfenac (12.0% and 20.7%), diclofenac (8.1% and 4.7%), and sulindac (6.1 % and 9.9%) were reported to be associated with higher proportions of overall hepatic disorders compared with those of other NSAIDs. Crude and adjusted RORs for the prevalences of overall hepatic disorders and hepatic failure with celecoxib and rofecoxib versus the other NSAIDs were1 (indicating that the proportion was not higher than that of the comparator) in both databases. The interpretation of the results was unchanged when bromfenac, nimesulide, and sulindac were excluded from the analysis.In this case/noncase analysis, bromfenac, nimesulide, sulindac, and diclofenac had higher proportions of reports of hepatic disorders compared with those of other NSAIDs in the FDA/FOI and WHO/UMC databases. The analysis did not raise a safety concern for celecoxib or rofecoxib versus NSAIDs for overall hepatic disorders and hepatic failure.

Introduction A few epidemiological studies suggested an increased coronary heart disease (CHD) risk with high doses of oral corticosteroids. Methods We performed a cohort study with nested case-control analysis to estimate the risk of acute myocardial infarction (AMI) associated with the use of oral corticosteroids by dose and duration. We followed-up 404,183 persons, 50–84 years old, without cancer from the general UK population. After validation of a random sample (confirmation rate of 96%), we included 4795 hospitalised cases of AMI or CHD deaths. We randomly sampled 20,000 controls, frequency matched by sex, age and calendar year. Relative risks were estimated using unconditional logistic regression. Results The adjusted OR for AMI in current users of oral corticosteroids compared to non-users was 1.42 (95% CI: 1.17–1.72). The risk during the first 30 days of use (OR = 2.24; 95% CI: 1.56–3.20) was greater than with longer duration (OR = 1.22; 95% CI 0.98–1.52). The risk was more pronounced (OR = 2.15; 95% CI 1.45–3.14) among users of prednisolone equivalent doses >10 mg/day. The dose effect was observed both among patients with and without CHD or COPD/asthma. Conclusion These results suggest a small increased risk of AMI with oral corticosteroid use with a greater risk observed among users of high corticosteroid dose.

This commentary reviews the work of John Graunt and Kenneth J. Rothman on statistical significance and the need for prespecification of study end points. The authors argue that it is dangerous to substitute oversimplifications based exclusively on whether a result has reached statistical significance for a rational process of causal inference. An example is given based on the Celecoxib Long-term Arthritis Safety Study.

Background Serious skin disorders have been associated with the use of oral antifungals in a number of case reports and series of cases. However the incidence of these disorders remains unknown. Methods We estimated the risk of serious skin disorders in a cohort of users of oral antifungals identified in the general population of the General Practice Research Database in the UK. The cohort included 61,858 patients, 20 to 79 years old, who had received at least one prescription for either oral fluconazole, griseofulvin, itraconazole, ketoconazole, or terbinafine. Results The background rate of serious cutaneous adverse reactions (the one corresponding to non use of oral antifungals) was 3.9 per 10,000 person-years (95% CI 2.9–5.2). Incidence rates for current use were 15.4 per 10,000 person-years (1.9–55.7) for itraconazole, 11.1 (3.0–28.5) for terbinafine, 10.4 (1.3–37.5) for fluconazole, and 4.6 (0.1–25.8) for griseofulvin. Itraconazole was the antifungal associated with the highest relative risk, 3.9 (0.5–15.0), when compared to the risk among non users, followed by terbinafine and fluconazole, with relative risks of 2.8 (0.7–7.8) and 2.6 (0.3–10.1), respectively. Conclusions We conclude that cutaneous disorders associated with the use of oral antifungals in this study were all of mild severity and that the risk associated with the use of oral antifungals was slightly higher than the risk in non-users. The safety profile of terbinafine regarding cutaneous disorders is similar to other antifungals and in the very low range of risks associated with other drugs.

Add-on therapy with omalizumab, an anti-immunoglobulin E antibody, is effective in improving disease control in patients with allergic asthma of varying severity. The aim of the present study was to determine the efficacy of omalizumab in a subgroup of patients at high risk of serious asthma-related morbidity and mortality.A meta-analysis was performed of three randomised, double-blind, placebo-controlled studies (studies 1, 2 and 3) that enrolled 1412 patients with moderate or severe allergic asthma, all requiring daily treatment with inhaled corticosteroids (ICS). Omalizumab was administered subcutaneously every 2 or 4 weeks at a total 4-weekly dose of at least 0.016 mg/kg/IgE [IU/ml]. Each study consisted of a 16-week steroid-stable phase and a 12-16-week steroid-reduction phase, followed by a 24-week extension phase (studies 1 and 2 only). The primary outcome measure was the annualised rate of significant asthma exacerbation episodes (sAEEs) during the steroid-stable phase for the pooled subgroup of 254 high-risk patients (omalizumab, n = 135; placebo, n = 119). sAEEs were those requiring a doubling of baseline ICS dose (studies 1 and 2 only) or use of systemic steroids (all three studies).Overall, the number of patients with at least one sAEE during the steroid-stable phase was reduced from 35% (42/119) with placebo to 18% (24/135) with omalizumab. Mean sAEE rates were 1.56 and 0.69 per patient-year, respectively, a reduction of 56% with omalizumab (p = 0.007). Similar reductions in exacerbations in favour of omalizumab were observed for the whole study period and for all AEEs. In those with a history of hospitalisation in the last year, 6/49 (12%) on placebo vs. 2/44 (4.5%) on omalizumab were re-hospitalised during the study period. Patients treated with omalizumab also showed significantly greater improvements from baseline in PEFR (p = 0.026), overall AQoL (p = 0.042) and mean nocturnal (p = 0.007) and mean total (p = 0.011) asthma symptom scores compared with placebo.In patients at high risk of serious asthma-related morbidity and mortality, treatment with omalizumab offers the potential to halve the rate of asthma exacerbations and improve disease control.

Background . Proton pump inhibitors (PPIs) are commonly coprescribed to reduce gastroduodenal injury caused by Non Steroidal Anti-Inflammatory Drugs (NSAIDs). However, while suppression of gastric acid secretion by PPIs is highly effective in reducing gastric injury, PPIs might worsen intestinal injury caused by non selective COX inhibitors. This so-called NSAIDs-PPIs enteropathy has been linked to development of an altered microbiota. Aims. To investigate whether probiotics prevent development of intestinal injury in a model of NSAIDs-PPIs enteropathy.Methods. Mice administered with omeprazole 10 mg/kg (ip twice daily) for 9 days, treated with naproxen (50 mg/kg per os) on the final 4 days. The probiotic VSL#3 at the dose of 18 x109 UCF daily (per os) was administered for 9 days. Small intestinal damage was scored, changes in hematocrit, gastric pH, intestinal expression of IL-1 β, and TNFαmRNA were measured. Change in small intestinal microbiota was assessed by terminal restriction fragment lenght polymorphisms (T-RFLP). To produce terminal restriction fragments the 16S rRNA was amplified and digested with HaeIII. Results. Treating mice with omeprazole increased significantly gastric pH from 2,43±0,29 to 3,66±0,2 (naproxen +omeprazole group) and 3,9 ±0,18 (naproxen + omeprazole +VSL#3 group) and reduced significantly the severity of gastric injury score (mm of lesion) from 20,17±4,8 (naproxen group) to 6±1,15 (naproxen+ omeprazole group) and 7±2,4 (naproxen+ omeprazole+VSL#3 group). In contrast, intestinal injury (mm of lesion) caused by naproxen was exacerbated by omeprazole administration from 37,5±12,12 (naproxen group) to 84,17±11,56 (naproxen + omeprazole group; P,0.05). This effect was reversed by VSL#3. Naproxen alone and naproxen + omeprazole increased the ileal expression of IL-1 β and TNF α, two markers of mucosal inflammation. This effect was reversed by VSL#3. Finally, VSL#3 administration resulted in a robust colonization of small intestine as assessed by T-RFLP. Conclusions. Omeprazole exacerbates naproxen -induced intestinal damage at least in part because of significant shifts in enteric microbiota. VSL#3 has been shown effective in reducing intestinal injury caused by indomethacin in human (APT32:209) and might hold utility in the prevention of NSAIDs-PPIs enteropathy.