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Alejandro Arana,1 Anton Pottegård,2 Josephina G Kuiper,3 Helen Booth,4 Johan Reutfors,5 Brian Calingaert,6 Lars Christian Lund,2 Elizabeth Crellin,4 Marcus Schmitt-Egenolf,5,7 James A Kaye,8 Karin Gembert,5 Kenneth J Rothman,8 Helle Kieler,5 Daniel Dedman,4 Eline Houben,3 Lia Gutiérrez,1 Jesper Hallas,2 Susana Perez-Gutthann1 1Department of Epidemiology, RTI Health Solutions, Barcelona, 08028, Spain; 2Clinical Pharmacology, Pharmacy and Environmental Medicine, Institute of Public Health, University of Southern Denmark, Odense C, 5000, Denmark; 3The PHARMO Institute, Utrecht, 3528 AE, the Netherlands; 4Clinical Practice Research Datalink (CPRD), The Medicines and Healthcare Products Regulatory Agency, London, E14 4PU, UK; 5Centre for Pharmacoepidemiology, Karolinska Institutet, Solna, 171 76, Stockholm, Sweden; 6Department of Epidemiology, RTI Health Solutions, Research Triangle Park, NC, 27709-2194, USA; 7Department of Public Health and Clinical Medicine, Umeå University, Umeå, 901 87, Sweden; 8Department of Epidemiology, RTI Health Solutions, Waltham, MA, 02451-1623, USACorrespondence: Alejandro AranaDepartment of Epidemiology, RTI Health Solutions, Av. Diagonal 605, 9-1, Barcelona, 08028, SpainTel +34 93 362 2805Fax +34 93 414 2610Email aarana@rti.orgPurpose: Evidence is insufficient to infer whether topical calcineurin inhibitors (TCIs; tacrolimus and pimecrolimus) cause malignancy. The study objective was to estimate the long-term risk of skin cancer and lymphoma associated with topical TCI use in adults and children, separately.Patients and Methods: A cohort study in Denmark, Sweden, UK, and the Netherlands was conducted. Adjusted incidence rate ratios (IRRs) and 95% confidence intervals (CIs) were calculated for nonmelanoma skin cancer (NMSC), melanoma, cutaneous T-cell lymphoma (CTCL), non-Hodgkin lymphoma (NHL) excluding CTCL, and Hodgkin lymphoma (HL) in new users of TCIs versus users of moderate/high-potency topical corticosteroids.Results: The study included 126,908/61,841 adults and 32,605/27,961 children initiating treatment with tacrolimus/pimecrolimus, respectively. Follow-up was ≥ 10 years for 19% of adults and 32% of children. Incidence rate ratios and (95% confidence intervals) for tacrolimus versus corticosteroid users in adults were < 1 for melanoma, non-Hodgkin lymphoma, and Hodgkin lymphoma; and 1.80 (1.25– 2.58) for cutaneous T-cell lymphoma. For pimecrolimus, IRRs in adults were < 1 for non-Hodgkin lymphoma, cutaneous T-cell lymphoma, and Hodgkin’s lymphoma; and 1.21 (1.03– 1.41) for melanoma; and 1.28 (1.20– 1.35) for nonmelanoma skin cancer. In children, results were inconclusive due to few events. In adults, incidence rate ratios ≥ 5 years after first topical calcineurin inhibitor exposure were not higher than in overall analyses.Conclusion: Overall, we found little evidence associating use of topical calcineurin inhibitors with skin cancer and lymphoma; confounding by indication, surveillance bias, and reverse causation may have influenced these results. Even if causal, the public health impact of these excess risks would be low and confined to the first years of exposure.Keywords: tacrolimus, pimecrolimus, cutaneous T-cell lymphoma, malignant melanoma, non-melanoma skin cancer, database study

International audience; PURPOSE: This post-authorisation safety study estimated the risk of anaphylaxis in patients receiving intravenous (IV) iron in Europe, with interest in iron dextran and iron non-dextrans. Studies conducted in the United States have reported risk of anaphylaxis to IV iron ranging from 2.0 to 6.8 per 10 000 first treatments. METHODS: Cohort study of IV iron new users, captured mostly through pharmacy ambulatory dispensing, from populations covered by health and administrative data sources in five European countries from 1999 to 2017. Anaphylaxis events were identified through an algorithm that used parenteral penicillin as a positive control. RESULTS: A total of 304 210 patients with a first IV iron treatment (6367 iron dextran), among whom 13–16 anaphylaxis cases were identified and reported as a range to comply with data protection regulations. The pooled unadjusted incidence proportion (IP) ranged from 0.4 (95% confidence interval [CI], 0.2–0.9) to 0.5 (95% CI, 0.3–1.0) per 10 000 first treatments. No events were identified at first dextran treatments. There were 231 294 first penicillin treatments with 30 potential cases of anaphylaxis (IP = 1.2; 95% CI, 0.8–1.7 per 10 000 treatments). CONCLUSION: We found an IP of anaphylaxis from 0.4 to 0.5 per 10 000 first IV iron treatments. The study captured only a fraction of IV iron treatments administered in hospitals, where most first treatments are likely to happen. Due to this limitation, the study could not exclude a differential risk of anaphylaxis between iron dextran and iron non-dextrans. The IP of anaphylaxis in users of penicillin was consistent with incidences reported in the literature.

Acute kidney injury is an expected adverse drug reaction listed in the European Union (EU) Summary of Product Characteristics (SmPC) for levetiracetam, one of the most widely used modern antiseizure medications (ASMs).We conducted a voluntary post-authorization safety study to characterize the rate of acute renal failure (ARF) in patients exposed to levetiracetam versus other ASMs.New users of ASMs without prior renal dysfunction were identified and followed for 30 days in the IBMOverall, 110,336 patients were eligible for the monotherapy cohort and 96,215 were eligible for the polytherapy cohort. The overall crude rate of ARF following a new ASM was 6.0 and 6.5 per 10,000 patients for the 'monotherapy' and 'polytherapy' cohorts, respectively, in the first 30 days after the index date. In the monotherapy cohort, the IRR for ARF was 1.37 (95% confidence interval [CI] 0.80-2.34) and the corresponding IRD was 2.0 (95% CI - 1.12 to 5.12) additional ARFs per 10,000 patient-months. In the polytherapy cohort, the adjusted IRR for ARF was 0.94 (95% CI 0.51-1.74) and the corresponding IRD was - 0.42 cases per 10,000 patient-months (95% CI - 4.01 to 3.17).The rate of ARFs in ASM new users was very low. In patients without prior ASMs, the estimated difference in risk of ARF associated with initiation of levetiracetam versus initiation of other ASMs was small, with 95% CIs compatible with small protective or harmful effects. In patients receiving polytherapy, the difference was compatible with the null and the 95% CI with small protective or harmful effects.

Purpose Strategies to identify and validate acute myocardial infarction (AMI) and stroke in primary‐care electronic records may impact effect measures, but to an unknown extent. Additionally, the validity of cardiovascular risk factors that could act as confounders in studies on those endpoints has not been thoroughly assessed in the United Kingdom Clinical Practice Research Datalink's (CPRD's) GOLD database. We explored the validity of algorithms to identify cardiovascular outcomes and risk factors and evaluated different outcome‐identification strategies using these algorithms for estimation of adjusted incidence rate ratios (IRRs). Methods First, we identified AMI, stroke, smoking, obesity, and menopausal status in a cohort treated for overactive bladder by applying computerized algorithms to primary care medical records (2004–2012). We validated these cardiovascular outcomes and risk factors with physician questionnaires (gold standard for this analysis). Second, we estimated IRRs for AMI and stroke using algorithm–identified and questionnaire–confirmed cases, comparing these with IRRs from cases identified through linkage with hospitalization/mortality data (best estimate). Results For AMI, the algorithm's positive predictive value (PPV) was >90%. Initial algorithms for stroke performed less well because of inclusion of codes for prevalent stroke; algorithm refinement increased PPV to 80% but decreased sensitivity by 20%. Algorithms for smoking and obesity were considered valid. IRRs based on questionnaire‐confirmed cases only were closer to IRRs estimated from hospitalization/mortality data than IRRs from algorithm‐identified cases. Conclusions AMI, stroke, smoking, obesity, and postmenopausal status can be accurately identified in CPRD. Physician questionnaire–validated AMI and stroke cases yield IRRs closest to the best estimate.

Cristina Rebordosa,1 Estel Plana,2 Annalisa Rubino,3 Jaume Aguado,2 David Martinez,2 Alejhandra Lei,4 Sami Daoud,5 Nuria Saigi-Morgui,1 Susana Perez-Gutthann,1 Elena Rivero-Ferrer1 1Department of Epidemiology and Risk Management, RTI Health Solutions, Barcelona, Spain; 2Department of Biometrics, RTI Health Solutions, Barcelona, Spain; 3Epidemiology, Respiratory and Immunology, AstraZeneca, Cambridge, UK; 4Patient Safety Biopharma, AstraZeneca, Barcelona, Spain; 5BioPharmaceuticals Research and Development, Late-Stage Development Respiratory and Immunology, AstraZeneca, Gaithersburg, MD, USACorrespondence: Cristina Rebordosa, RTI Health Solutions, Department of Epidemiology and Risk Management, Av. Diagonal, 605, 9-1, Barcelona, 08028, Spain, Tel +34.93.362.2807, Fax +34.93.760.8507, Email crebordosa@rti.orgBackground: The long-acting muscarinic antagonist (LAMA) aclidinium was approved in Europe in 2012 to relieve symptoms in adult patients with chronic obstructive pulmonary disease (COPD). A post-authorization safety study was initiated to assess potential cardiovascular risks associated with LAMAs versus long-acting beta2-agonists.Purpose: To estimate incidence rates and adjusted incidence rate ratios (IRRs) for acute myocardial infarction (AMI), stroke, and major adverse cardiac events (MACE) in new users of aclidinium, aclidinium/formoterol, tiotropium, other LAMA, long-acting beta-agonists/inhaled corticosteroids (LABA/ICS), and LAMA/LABA compared with initiators of LABA.Patients and Methods: This population-based cohort study included patients with COPD aged ≥ 40 years initiating COPD medications in the UK Clinical Practice Research Datalink (CPRD) Aurum database from 2012 to 2019. Poisson regression models were used to estimate the IRR for AMI, stroke, and MACE in users of COPD medications versus LABA, adjusting for clinically relevant covariables.Results: The study included 11,121 new users of aclidinium, 4804 of aclidinium/formoterol, 56,198 of tiotropium, 23,856 of other LAMA, 17,450 of LAMA/LABA, 70,289 of LABA/ICS, and 13,716 of LABA. During periods of continuous medication use after initiation (current use), crude incidence rates per 1000 person-years for AMI ranged from 8.7 (aclidinium/formoterol) to 12.4 (LAMA/LABA), for stroke ranged from 4.8 (aclidinium/formoterol) to 7.2 (LAMA/LABA), and for MACE ranged from 13.5 (aclidinium/formoterol) to 19.3 (LAMA/LABA). Using LABA as reference, adjusted IRRs [95% confidence intervals] were close to 1 for all study drugs for AMI (lowest for aclidinium/formoterol, 0.95 [0.60– 1.52], and highest for LAMA/LABA, 1.23 [0.91– 1.67]), stroke (lowest for aclidinium/formoterol, 0.64 [0.39– 1.06], and highest for tiotropium, 1.02 [0.81– 1.27] for tiotropium) and for MACE (lowest for aclidinium, 0.93 [0.75– 1.16], and highest for LAMA/LABA, 1.24 [0.97– 1.59]).Conclusion: Risks of AMI, stroke, and MACE in current users of aclidinium, aclidinium/formoterol, tiotropium, other LAMA, LAMA/LABA, or LABA/ICS were similar to the risks among current users of LABA.Keywords: aclidinium, acute myocardial infarction, LAMA, stroke, United Kingdom

Introduction During clinical trials, mirabegron, a β3-adrenoreceptor agonist, was associated with increased vital signs vs placebo in patients with overactive bladder. Objective The purpose of this study was to compare incidence rates of adverse cardiovascular (CV) outcomes following mirabegron or antimuscarinic use. Methods We conducted an observational post-marketing safety study utilising real-world data. The study population was identified within five sources: Danish and Swedish National Registers, Clinical Practice Research Datalink (UK), Optum (USA) and Humana (USA). Episodes of time when patients were new users of mirabegron or antimuscarinics (October 2012–December 2018) were sourced from prescriptions and matched on propensity scores. Occurrences of major adverse cardiovascular events (MACE), acute myocardial infarction (AMI), stroke, CV mortality and all-cause mortality were identified. Outcome incidence rates and hazard ratios from Cox models were estimated. Results Overall, 152,026 mirabegron and 152,026 antimuscarinic episodes were matched. The population consisted of 63.1% women and 72.6% were ≥ 65 years old. There were no appreciable differences in the incidence rates of MACE, AMI or stroke between users of mirabegron and antimuscarinics. Incidence rates of CV mortality (hazard ratio 0.83, 95% confidence interval 0.73–0.95) and all-cause mortality (hazard ratio 0.80, 95% confidence interval 0.76–0.84) were no higher with mirabegron vs antimuscarinics. Results restricted to episodes at high risk for CV events or stratified by age (< 65 years, ≥ 65 years) or prior overactive bladder medication use were consistent with overall findings. Conclusions This large, multinational study found no higher risk of MACE, AMI, stroke, CV mortality or all-cause mortality among users of mirabegron relative to users of antimuscarinics. Supplementary Information The online version contains supplementary material available at 10.1007/s40264-021-01095-7., Plain Language Summary During clinical trials, mirabegron, which is a treatment for overactive bladder, was associated with small increases in heart rate and blood pressure. This study was conducted to compare the frequency of cardiac events following the use of mirabegron or antimuscarinics, a group of treatments also used to treat overactive bladder. We obtained the data for this study from four countries: Denmark, Sweden, the UK and the USA. We identified people who were new users of mirabegron or antimuscarinics from 2012 to 2018 using prescription or dispensing records. Occurrences of major cardiac events, heart attack, stroke, death due to cardiac events and death from any cause were evaluated. Overall, we identified 152,026 times when mirabegron or antimuscarinics were each used as new treatments. Most of the people in the study were women (63.1%) and at least 65 years old (72.6%). There were no notable differences between the treatment groups with regard to how often major cardiac events, heart attack or stroke occurred. Further, death due to cardiac events and death from any cause were no higher with mirabegron compared with antimuscarinics. We obtained similar results when the data were assessed for patients who were at high risk for cardiac events or split by age (less than 65 years or at least 65 years) or a history of overactive bladder medication use. In conclusion, this large study involving data from several countries found no higher risk of major cardiac events, heart attack, stroke or death among people prescribed mirabegron compared with antimuscarinics. Supplementary Information The online version contains supplementary material available at 10.1007/s40264-021-01095-7.

Purpose Acute liver injury (ALI) is an important adverse drug reaction. We estimated the positive predictive values (PPVs) of ICD-10-GM codes of ALI used in an international postauthorisation safety study (PASS). Methods Analyses used routine data (2007 to 2016, adults) from a German academic hospital in a cross-sectional design. Two algorithms from the PASS were applied to extract potential cases from the hospital information system: specific end point (A) (discharge diagnosis of liver disease-specific codes) and less specific end point (B) (discharge and outpatient-specific and nonspecific codes suggestive of liver injury). ALI cases were confirmed on the basis of plasma liver enzyme activity elevation. Secondary analysis was performed following exclusion of cases with known cancer, chronic liver, biliary and pancreatic disease, heart failure, and alcohol-related disorders, as applied in the PASS. Results On the basis of ICD codes: outcome A, 154 cases (143 with case notes and lab data for case verification); outcome B, 485 cases (357 with case notes and lab data). ALI was confirmed in 71 outcome A cases, PPV of 49.7% (95% confidence interval [CI], 41.2%-58.1%), and 100 outcome B cases, PPV of 28.0% (95% CI, 23.4%-33.0%). Applying exclusion criteria increased PPV (95% CI) to 62.7% (50.0%-74.2%) for outcome A and 45.7% (37.2%-54.3%) for outcome B. Conclusions In safety studies on hepatotoxicity based on routine data using ICD-10-GM discharge codes and when validation of potential cases is not feasible, only the more specific codes should be used to describe ALI, and competing diagnoses for liver injury should be excluded to avoid substantial misclassification.

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.

Cristina Rebordosa, 1 Estel Plana, 1 Annalisa Rubino, 2 Jaume Aguado, 1 Alejhandra Lei, 3 Sami Daoud, 4 Nuria Saigi-Morgui, 1 Susana Perez-Gutthann, 1 Elena Rivero-Ferrer 1 1RTI Health Solutions, Barcelona, Spain; 2Epidemiology, Respiratory and Immunology, AstraZeneca, Cambridge, UK; 3Patient Safety Biopharma, AstraZeneca, Barcelona, Spain; 4BioPharmaceuticals Research and Development, Late-Stage Development Research and Innovation, AstraZeneca, Gaithersburg, MD, USACorrespondence: Cristina RebordosaRTI Health Solutions, Av. Diagonal, 605, 9-1, Barcelona, 08028, SpainTel +34 93 241 7766Fax +34 93 760 8507Email crebordosa@rti.orgBackground: The long-acting anticholinergic (LAMA) aclidinium was approved in Europe in 2012 to relieve symptoms in adults with chronic obstructive pulmonary disease (COPD). A Post-Authorisation Safety Study (PASS) was initiated to assess potential cardiovascular safety concerns for aclidinium.Objective: To estimate the adjusted incidence rate ratio (IRR) for hospitalisation for heart failure in patients with COPD who were new users of aclidinium, tiotropium, other LAMA, long-acting beta-agonists/inhaled corticosteroids (LABA/ICS), and LAMA/LABA were compared with initiators of LABA.Methods: This population-based cohort study included patients with COPD aged ≥ 40 years initiating COPD medications in the Clinical Practice Research Datalink (CPRD) GOLD in the United Kingdom from 2012 to 2017. Medications were identified via general practice prescriptions. The first-ever hospitalisations for heart failure were identified in the Hospital Episode Statistics, and general practitioner records from the CPRD. Poisson regression models were used to estimate the IRR for hospitalisation for heart failure in users of COPD medications versus LABA, adjusting for clinically relevant covariates.Results: The study included 4350 new users of aclidinium, 23,405 of tiotropium, 6977 of other LAMAs, 3122 of LAMA/LABA, 26,093 of LABA/ICS, and 5678 of LABA. Mean age was 69– 70 years across medication groups. Aclidinium users had the highest proportion of severe COPD, and LABA users had the lowest (35% vs 19%, respectively). Crude incidence rates per 1000 person-years for the first-ever hospitalisation for heart failure ranged from 6.9 in LABA to 9.5 in aclidinium. Using LABA as reference, adjusted IRRs (95% confidence interval) for first-ever hospitalisation for heart failure were 0.90 (0.53– 1.53) for aclidinium, 1.02 (0.69– 1.51) for tiotropium, 0.86 (0.50– 1.47) for other LAMAs, 1.09 (0.41– 2.92) for LAMA/LABA, and 1.01 (0.69, 1.48) for LABA/ICS.Conclusion: The study did not find increased risks of hospitalisations for heart failure in new users of aclidinium, tiotropium, other LAMAs, LAMA/LABA, and LABA/ICS compared with LABA.Keywords: aclidinium, LAMA, heart failure, United Kingdom

Objective: This post-authorization safety study (EU PAS Register Number: EUPAS16088) was designedto compare the incidence of cancer outcomes in patients treated with mirabegron versus antimuscarinicmedications.Methods: Cohorts of mirabegron initiators during 2012–2018 were propensity-score matched to antimuscarinicmedication initiators within real-world data sources (Danish National Registers, SwedishNational Registers, Clinical Practice Research Datalink [UK], Optum [US], and Humana [US]). Incidentcancer cases were identified during follow-up from direct linkage to cancer registers or validatedthrough medical record review or through physician questionnaires. Comparisons of sex-specific compositecancer outcomes (cancer of the lung/bronchus, colon/rectum, melanoma of skin, urinary bladder,non-Hodgkin lymphoma, kidney/renal pelvis, pancreas, prostate in men and breast and uterus inwomen) were made overall and for person-time in the first year and after the first year following startof treatment, for all ages and for the subgroup 65 years.Results: Among the 80,637 mirabegron initiators matched to 169,885 antimuscarinic medication initiators,68% were at least 65 years of age and 66% were women. Over 5000 incident cancer cases wereobserved overall. Incidence rates were higher for men than women for composite and individual canceroutcomes. The pooled fixed effects hazard ratios for composite cancer outcomes (all ages) were1.05 (95% confidence interval [CI]: 0.98–1.14) for women and 1.06 (95% CI: 0.98–1.14) for men. Resultswere similar in persons 65 years.Conclusions: The results suggest no association between mirabegron use and risk of cancer, comparedwith antimuscarinic medications, in either men or women.Registration: EU PAS Register Number: EUPAS16088

Introduction: During clinical trials, mirabegron, a β3-adrenoreceptor agonist, was associated with increased heart rate and systolic/diastolic blood pressure vs placebo in patients with overactive bladder (OAB). We studied the association between mirabegron and cardiovascular (CV) outcomes in an observational post-marketing safety study using real-world data. Methods: The study population was identified within five data sources: Danish and Swedish National Registers, Clinical Practice Research Datalink (UK), Optum (US), and Humana (US). Episodes of time when patients were new users of mirabegron or antimuscarinic medications (AMs) from 2012 to 2018 were sourced from prescription/dispensing information and matched on propensity scores. Major adverse CV events (MACE), acute myocardial infarction (AMI), stroke, and CV and all-cause mortality were identified from register linkage or validated through medical record review or physician questionnaires. Incidence rates of these outcomes during person-time of current use were estimated along with hazard ratios (HRs) from Cox models. Results: In total, 152,026 mirabegron episodes were matched to an equal number of AM episodes. The study population was 63.2% female and 72.6% were ≥65 years old. Baseline CV risk factors were similar between matched groups. There were no appreciable differences in the incidence rates of MACE, AMI, and stroke among current users of mirabegron relative to AMs (Table). The incidence rates of CV mortality (HR: 0.83, 95% confidence interval [CI]: 0.73, 0.95) and all-cause mortality (HR: 0.80, CI: 0.76, 0.84) were no higher with mirabegron vs AMs. Results restricted to episodes at high risk for CV events or stratified by age ( Conclusions: This large, multinational study found no higher risk of MACE, AMI, stroke, or CV or all-cause mortality among current users of mirabegron relative to users of AMs.

Background: Use of aclidinium bromide (AB) and aclidinium/formoterol (AB/FF) in the real world is not fully characterized in Europe. Aim: To describe characteristics of new users of AB, AB/FF, and other COPD medications in the United Kingdom (UK), Denmark, and Germany. Methods: Cohorts in the UK Clinical Practice Research Datalink GOLD (2015-2017), the Danish National Health Databases (2015-2017), and the German Pharmacoepidemiological Research Database (2015) included new users of long-acting muscarinic antagonists (LAMA) (AB, AB/FF, tiotropium, other LAMA), long-acting beta2-agonists (LABA), or LABA/inhaled corticosteroids (LABA/ICS). New users were characterized according to age, sex, lifestyle factors, comorbidity, COPD and asthma diagnoses, comedications, and COPD severity. Results: The study included 17,668 new users of AB and 14,808 new users of AB/FF. New users of LAMA medications were older (median range, 69-71 years) than users of LABA or LABA/ICS (median range, 53-67 years). Smoking was more frequent in LAMA users (20.1% to 39.9%) than in LABA or LABA/ICS users (7.9% to 26.8%). Hypertension, depressive disorders, urinary tract infections, and diabetes were frequent comorbidities. COPD diagnosis was more frequent in LAMA (46.8% to 92.8%) than in LABA or LABA/ICS (24.2% to 65.5%) users. In the UK, AB users had a higher proportion of severe COPD than AB/FF users; the opposite applied to the other countries. Conclusion: AB, AB/FF users showed similar characteristics to those of other LAMA users. Compared with LABA and LABA/ICS users, AB and AB/FF users were older, had a higher frequency of severe COPD, chronic comorbidities, and use of COPD comedications.

Hepatotoxic reactions are an important identified risk listed in the agomelatine risk management plan. This post-authorisation safety study evaluated the effectiveness of additional risk-minimisation measures (aRMMs) for agomelatine. The objective of this study was to evaluate, among physicians prescribing agomelatine and their patients, liver function monitoring adherence, compliance with contraindications and patients’ reasons for non-compliance with liver monitoring. A non-interventional cohort study was conducted among adults initiating agomelatine in routine clinical practice in Denmark, France, Germany and Spain through a retrospective medical record abstraction (MRA) before and after implementation of aRMMs and a cross-sectional patient survey. Fifty-four sites contributed data on 437 and 404 patients in the before- and after-RMM periods, and 237 patients completed the survey. No patient had cirrhosis in either study period; 98.2% of patients in the before- and 98.0% in the after-RMM period had no active liver disease reported at initiation or during treatment. Compliance to contraindicated medications was > 99% in both periods. The adherence to the liver-monitoring regimen was similar in both periods (15.1% before RMM and 16.3% after RMM). In the after-RMM period, 25.2% of patients had a liver test before or at treatment initiation; 61.5% had a liver test during treatment. Among patients surveyed who did not have a blood test before treatment initiation or during treatment, the most frequently cited reason was a test ordered but not yet performed. The overall adherence to liver-monitoring recommendations remained weakly influenced by aRMMs. However, patients treated with agomelatine are in compliance with relevant contraindications.

Using social media to collect patient perspectives on quality of life : A feasibility study

Epidemiological studies on heart failure (HF) using large health care databases are becoming increasingly frequent, as they represent an invaluable opportunity to characterize the importance and risk factors of HF from a population perspective. Nevertheless, because of its complex diagnosis and natural history, the heterogeneous use of the relevant terminology in routine clinical practice, and the limitations of some disease coding systems, HF can be a challenging condition to assess using large health care databases as the main source of information. In this narrative review, we discuss some of the challenges that researchers may face, with a special focus on the identification and validation of chronic HF cases and acute HF decompensations. For each of these challenges, we present some potential solutions inspired by the literature and/or based on our research experience, aimed at increasing the internal validity of research and at informing its interpretation. We also discuss future directions on the field, presenting constructive recommendations aimed at facilitating the conduct of valid epidemiological studies on HF in the coming years.

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.

Supplemental Digital Content is available in the text., Background: In the United Kingdom, hospital or cancer registry data can be linked to electronic medical records for a subset of general practices and years. Methods: We used Clinical Practice Research Datalink data (2004–2012) from patients treated for overactive bladder. We electronically identified provisional cases of 10 common cancers in General Practitioner Online Database data and validated them by medical profile review. In practices with linkage to Hospital Episodes Statistics and National Cancer Data Repository (2004–2010), we validated provisional cancer cases against these data sources. This linkage also let us identify additional cancer diagnoses in individuals without cancer diagnosis records in the General Practitioner Online Database. Results: Among 50,840 patients, 1,486 provisional cancer cases were identified in the General Practitioner Online Database for 2004–2012. Medical profile review confirmed 93% of 661 cases in nonlinked practices (range, 100% of non-Hodgkin lymphomas and uterine cancer to 77% of skin melanomas) and 96% of 825 cases in linked practices (100% of kidney and uterine cancers to 92% of melanomas). In the subset of linked practices, for 2004–2010, 720 cases were confirmed, of which 68% were identifiable in the General Practitioner Online Database (range, 90% of breast to 36% of kidney cancers). Conclusions: Most cases of cancer identified electronically in the General Practitioner Online Database were confirmed. A substantial proportion of cases, especially of cancer types not typically managed by general practitioners, would be missed without Hospital Episodes Statistics and National Cancer Data Repository data (and are likely missed in nonlinked practices). See video abstract at, http://links.lww.com/EDE/B315. Registration (before study conduct): European Union electronic Register of Post-Authorisation Studies (EU PAS Registry) number EUPAS5529, http://www.encepp.eu/encepp/viewResource.htm?id=11107.

tudy Objective To estimate the incidence of 10 common cancers among patients treated with antimuscarinic medications for overactive bladder (AMOAB). Design Retrospective cohort study. Data Source United Kingdom's Clinical Practice Research Datalink. Patients A total of 119,912 adults with no previous cancer diagnosis who were new users of AMOABs—darifenacin, fesoterodine, oxybutynin, solifenacin, tolterodine, or trospium—between January 2004 and December 2012. Measurements and Main Results Sex-specific incidence rates per 1000 person-years and 95% confidence intervals (CIs) were estimated for each study cancer (bladder, breast, colorectal, lung, melanoma, non-Hodgkin lymphoma, pancreatic, prostate, renal, and uterine cancer) overall and stratified by time since cohort entry and by cumulative AMOAB dose. Among the 119,912 patients followed for 399,365 person-years, 4117 incident study cancers occurred. The incidence rate of prostate cancer was 14.2 (95% CI 12.9–15.5) in the year after cohort entry and decreased markedly thereafter. The incidence rate of bladder cancer was also higher in the year after cohort entry than subsequently (men: 5.5, 95% CI 4.8–6.4; women: 1.2, 95% CI 1.0–1.5). The incidence rates of both prostate and bladder cancer decreased with increasing cumulative dose of AMOAB. We observed no similar relations between incidence rates of other study cancers and time since cohort entry. Conclusion incidence rates of bladder and prostate cancer soon after AMOAB initiation and a negative correlation between incidence and cumulative AMOAB dose suggest that protopathic bias is a more likely explanation for these findings than causality. (Protopathic bias in this context means patients’ urinary symptoms prompted treatment with an AMOAB, but the symptoms were actually due to a cancer that was already present, although not yet diagnosed or not yet recorded.) To avoid unnecessary delays in the diagnosis of prostate and bladder cancer, physicians should consider these diseases in patients for whom treatment with AMOABs is indicated. This article is protected by copyright. All rights reserved.

Aims Dexmedetomidine (dexdor®) is approved in the European Union (EU) for sedation of adults in the intensive care unit (ICU). The present observational, retrospective study was requested by the European Medicines Agency to investigate dexmedetomidine use in clinical practice, with a particular focus on off-label use, including the paediatric population. Methods Study countries and sites were chosen from those with highest dexmedetomidine use, based on sales. Site selection (blind) was conducted by a multispecialist, independent group. Anonymized data on demographics, treatment indication, dexmedetomidine dosing, concomitant medications and treatment effectiveness were collected retrospectively from records of all dexmedetomidine-treated patients at the site during the enrolment period. Informed consent was waived, to avoid influencing the prescribing of dexmedetomidine. Recruitment was completed within 18 months of first site initiation. Results Data from 2000 patients were collected from 16 hospitals in four EU countries (Finland 750, Poland 505, Germany 470, Austria 275). The median age was 62 years, with more males (70.2%) than females. Dexmedetomidine was primarily used in the adult ICU (86.0%) for ICU sedation (78.6%) and mostly dosed according the product label. The intended sedative effect was obtained in 84.9% of administrations. Paediatric use (5.9% of patients, mostly in Austria and Finland) occurred mainly in the adult or paediatric ICU (75.6%) for sedation (67.2%). Conclusions Overall, most patients were treated with dexmedetomidine according to the product labelling. Use in children was limited but significant and similar in scope to that in adults. Administrations not fully according to the product labelling usually occurred in an ICU environment and reflected extensively investigated clinical uses of dexmedetomidine.

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.

INTRODUCTION AND OBJECTIVE:The β3-adrenergic agonist mirabegron is an alternative to antimuscarinics (AMs) for treatment of overactive bladder. During mirabegron development, a greater number of ca...

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.

Background Blocking muscarinic receptors could have an effect on cardiac function, especially among elderly patients with overactive bladder (OAB). Study objective To investigate the risk of cardiovascular (CV) events in users of antimuscarinic drugs to treat OAB. Design, setting, and participants Cohort study of new users of darifenacin, fesoterodine, oxybutynin, solifenacin, tolterodine, or trospium, 18 years or older, in the United Kingdom's Clinical Practice Research Datalink (CPRD), 2004-2012. Outcome measurements and main results Using tolterodine as the reference, we estimated propensity-score-stratified incidence rate ratios (IRRs) for acute myocardial infarction, stroke, CV mortality, major adverse cardiac events (MACE, a combined end point of the previous three), and all-cause death for individual antimuscarinic drugs. The study cohort included 119,912 new users of OAB drugs. The mean age at cohort entry was 62 years, 70% were female, and the mean follow-up was 3.3 years. The adjusted IRR for MACE and current use of oxybutynin compared with current use of tolterodine was 1.14 (95% confidence interval [CI] 1.01-1.30). In contrast, the IRR was 0.65 (CI 0.56-0.76) for current use of solifenacin compared with tolterodine. In this study, performed with health care data, the distribution of risk factors was relatively similar across users of different OAB drugs and, although our analyses controlled for a range of measured potential confounders, residual confounding cannot be ruled out. Conclusions In an observational comparative study of users of medications to treat OAB conducted in routine clinical practice, the risk for CV side effects was increased in users of oxybutynin and decreased in users of solifenacin compared with users of tolterodine.

The purpose of this study was to estimate the incidence rate (IR) of 10 common cancers in new users of antimuscarinic overactive bladder (OAB) medications. We conducted a cohort study using data recorded in Danish registers for patients newly exposed to the OAB drugs, darifenacin, fesoterodine, oxybutynin, solifenacin, tolterodine or trospium in years 2004–2012, aged ≥18 years and without cancer before treatment initiation. We estimated IRs for each study cancer (bladder, breast, colorectal, lung, melanoma, non-Hodgkin lymphoma, pancreas, prostate, renal and uterine), standardised by age and sex and explored IR trends over time since treatment initiation. For all cancer analyses, only the first incident targeted cancer was considered. Of 72,917 patients (60% women; mean age at treatment start: 66 years), 3475 developed a study cancer during 259,072 person-years of follow-up. The most common study cancers were prostate (48.1% of study cancers in men), breast (40.0% of study cancers in women) and lung (15.4% of all study cancers). The overall standardised study cancer IR was 5.4 per 1000 person-years (95% confidence interval, 5.3–5.6); IRs were similar across individual OAB drugs. The standardised IRs for bladder and prostate cancers, which have symptoms in common with OAB, were highest in the first 6 months of treatment initiation and lower thereafter. In contrast, IRs for other study cancers were nearly constant during follow-up. Cancer IRs did not vary substantially by individual OAB drug. Protopathic bias is a plausible explanation for the higher rates of bladder and prostate cancers observed soon after starting OAB drug treatment.

Purpose: The purpose of this study is to explore the cardiovascular safety of antimuscarinic drugs to treat overactive bladder (OAB) in Denmark. Methods: This was a cohort study using data recorded in Danish registries from patients newly exposed to darifenacin, fesoterodine, oxybutynin, solifenacin, tolterodine, or trospium in 2004–2012. We estimated crude and standardized incidence rates (IRs) for acute myocardial infarction (AMI); stroke; cardiovascular mortality; major adverse cardiac events (MACE, a combined endpoint of the previous three outcomes); and all-cause death for the individual and combined drugs. We also estimated crude, standardized, and propensity score-stratified incidence rate ratios (IRRs) comparing individual antimuscarinic drugs to tolterodine as the reference. Results: Among 72,917 new users of OAB drugs (mean age, 66 years; 60% women), the standardized IR (95% confidence interval) per 1000 person-years for current use of any OAB drug was 2.7 (2.5–2.9) for AMI, 1.3 (1.2–1.5) for stroke, 7.8 (7.5–8.1) for MACE, 4.8 (4.5–5.0) for cardiovascular mortality, and 15.2 (14.8–15.6) for all-cause mortality. Propensity score-stratified IRRs for current use (reference, tolterodine) were close to the null for all drugs and endpoints. Conclusions: We did not identify differences in the risk of cardiovascular events or mortality among users of individual antimuscarinic OAB drugs.

Purpose To describe the use of antimuscarinic drugs to treat overactive bladder (OAB) in Denmark, Sweden, and the United Kingdom (UK). Methods We identified new users of darifenacin, fesoterodine, oxybutynin, solifenacin, tolterodine, and trospium aged 18 years or older from the Danish National Registers (2004–2012), the Swedish National Registers (2006–2012), and UK Clinical Practice Research Datalink (2004–2012). Users were followed until disenrollment, cancer diagnosis, death, or study end. Treatment episodes, identified by linking consecutive prescriptions, were described with respect to duration, drug switch, and drug add-on. Results Mean age of OAB drug users was 66 years in Denmark (n = 72,917) and Sweden (n = 130,944), and 62 years in the UK (n = 119,912); 60% of Danish and Swedish patients and 70% of UK patients were female. In Denmark, of 224,680 treatment episodes, 39% were with solifenacin, and 35% with tolterodine; 2% were with oxybutynin. In Sweden, of 240,141 therapy episodes, 37% were with tolterodine and 35% with solifenacin; 5% were with oxybutynin. In the UK, of 245,800 treatment episodes, 28% were with oxybutynin, 27% with solifenacin, and 26% with tolterodine. In the three countries, 49%-52% of treatment episodes comprised one prescription and over 80% of episodes ended because of no refill; less than 20% ended because of a switch to another antimuscarinic. During the study years, we observed a change in OAB treatment preference from tolterodine to solifenacin. Conclusions In these cohorts, persistence with antimuscarinic drugs was low. By 2012, the preferred drug was solifenacin; oxybutynin use was marginal in Nordic countries compared with 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

Objectives: To explore the challenges facing pharmacovigilance in Saudi Arabia and formulate recommendations to improve it from the perspective of healthcare professionals in Saudi Arabia. Methods: This was a qualitative study of 4 focus group discussions with pharmacists, physicians, and academicians held under the auspices of the King Saud University School of Pharmacy and the Center for Medicine in the Public Interest, Riyadh, Saudi Arabia. A total of 29 eligible healthcare professionals were invited to participate in the discussion. The predefined themes of the study were the current practice and major challenges facing pharmacovigilance in regulatory bodies, hospitals, the community, and academia, as well as recommendations to improve pharmacovigilance practice. Result: Of the 29 participants invited, 27 attended the discussion. Challenges facing regulatory bodies included complicated adverse drug reactions (ADR) reporting forms, lack of feedback on ADRs submitted to the Saudi Food and Drug Authority, lack of decisions from the local authority to withdraw medications, and lack of data on pharmacovigilance. The challenges to pharmacovigilance in hospitals included the lack of knowledge of the significance of ADR reporting, workload, blaming culture, and lack of collaboration between regulatory bodies and hospitals. However, challenges facing pharmaceutical industries included the lack of drug manufacturers in Saudi Arabia and lack of interest in pharmacovigilance. Recommendations to improve pharmacovigilance included the need for communication, stronger regulatory requirements, the need for research, the need for unified ADRs reporting, and continuous education and training. Conclusion: The study has identified the challenges facing pharmacovigilance in Saudi Arabia and made certain recommendations to overcome them. These recommendations might be helpful for regulatory bodies to enhance spontaneous reporting and promote pharmacovigilance.

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Purpose: To report and discuss estimated prevalence of potential off-label use and associated methodological challenges using a case study of dabigatran. Methods: Observational, cross-sectional study using 3 databases with different types of clinical information available: Cegedim Strategic Data Longitudinal Patient Database (CSD-LPD), France (cardiologist panel, n = 1706; general practitioner panel, n = 2813; primary care data); National Health Databases, Denmark (n = 28 619; hospital episodes and dispensed ambulatory medications); and Clinical Practice Research Datalink (CPRD), UK (linkable to Hospital Episode Statistics [HES], n = 2150; not linkable, n = 1285; primary care data plus hospital data for HES-linkable patients). Study period: August 2011 to August 2015. Two definitions were used to estimate potential off-label use: a broad definition of on-label prescribing using codes for disease indication (eg, atrial fibrillation [AF]), and a restrictive definition excluding patients with conditions for which dabigatran is not indicated (eg, valvular AF). Results: Prevalence estimates under the broad definition ranged from 5.7% (CPRD-HES) to 34.0% (CSD-LPD) and, under the restrictive definition, from 17.4% (CPRD-HES) to 44.1% (CSD-LPD). For the majority of potential off-label users, no diagnosis potentially related to anticoagulant use was identified. Key methodological challenges were the limited availability of detailed clinical information, likely leading to overestimation of off-label use, and differences in the information available, which may explain the disparate prevalence estimates across data sources. Conclusions: Estimates of potential off-label use should be interpreted cautiously due to limitations in available information. In this context, CPRD HES-linkable estimates are likely to be the most accurate.

Purpose To describe nepafenac use in the Netherlands and Denmark with reference to its approved indications. For context, we also describe the use of ketorolac and diclofenac. Methods We identified users in the PHARMO Database Network (the Netherlands, 2008–2013) and the Danish national health registers (Denmark, 1994–2014). We described prevalence of cataract surgery and duration of use in patients with cataract surgery with and without diabetes. Results In the Netherlands, 9530 nepafenac users (mean age, 71 years; 60% women) contributed 12 691 therapy episodes, of which 21% had a recently recorded cataract surgery. Of 2266 episodes in adult non-diabetic patients with cataract surgery, 60% had one bottle dispensed (treatment duration ≤21 days). Of 441 episodes in adult diabetic patients with cataract surgery, 90% had up to two bottles dispensed (≤60 days). Denmark had 60 403 nepafenac users (mean age, 72 years; 58% women) and 73 648 episodes (41% had recorded cataract surgery). Of 26 649 nepafenac episodes in adult non-diabetic patients with cataract surgery, 92% had one bottle dispensed. Of 3801 episodes in adult diabetic patients with cataract surgery, 99.8% had up to two bottles dispensed. Use patterns of nepafenac, ketorolac and diclofenac were roughly similar in the Netherlands, but not in Denmark. Conclusion Less than half of therapy episodes were related to cataract surgery; around 90% of episodes with surgery were within the approved duration. Underrecording of ophthalmic conditions and procedures was a challenge in this study.

Andrea V Margulis,1 Manel Pladevall,1 Nuria Riera-Guardia,1 Cristina Varas-Lorenzo,1 Lorna Hazell,2,3 Nancy D Berkman,4 Meera Viswanathan,4 Susana Perez-Gutthann,1 1RTI Health Solutions, Barcelona, Spain; 2Drug Safety Research Unit, Southampton, UK; 3Associate Department of the School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, UK; 4RTI International, Research Triangle Park, NC, USA Background: The study objective was to compare the Newcastle–Ottawa Scale (NOS) and the RTI item bank (RTI-IB) and estimate interrater agreement using the RTI-IB within a systematic review on the cardiovascular safety of glucose-lowering drugs. Methods: We tailored both tools and added four questions to the RTI-IB. Two reviewers assessed the quality of the 44 included studies with both tools, (independently for the RTI-IB) and agreed on which responses conveyed low, unclear, or high risk of bias. For each question in the RTI-IB (n=31), the observed interrater agreement was calculated as the percentage of studies given the same bias assessment by both reviewers; chance-adjusted interrater agreement was estimated with the first-order agreement coefficient (AC1) statistic. Results: The NOS required less tailoring and was easier to use than the RTI-IB, but the RTI-IB produced a more thorough assessment. The RTI-IB includes most of the domains measured in the NOS. Median observed interrater agreement for the RTI-IB was 75% (25th percentile [p25] =61%; p75 =89%); median AC1 statistic was 0.64 (p25 =0.51; p75 =0.86). Conclusion: The RTI-IB facilitates a more complete quality assessment than the NOS but is more burdensome. The observed agreement and AC1 statistic in this study were higher than those reported by the RTI-IB's developers. Keywords: systematic review, meta-analysis, quality assessment, AC1

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.

Background Most NSAIDs are thought to be able to cause hepatic injury and acute liver failure (ALF), but the event rates of those leading to transplantation (ALFT) remain uncertain. Objectives The aim of the study was to estimate population event rates for NSAID-associated ALFT Methods This was a case-population study of ALFT in 57 eligible liver transplant centres in seven countries (France, Greece, Ireland, Italy, The Netherlands, Portugal and the UK). Cases were all adults registered from 2005 to 2007 for a liver transplant following ALFT without identified clinical aetiology, exposed to an NSAID or paracetamol (acetaminophen) within 30 days before the onset of clinical symptoms. NSAID and paracetamol population exposures were assessed using national sales data from Intercontinental Marketing Services (IMS). Risk was estimated as the rate of ALFT per million treatment-years (MTY). Results In the 52 participating centres, 9479 patients were registered for transplantation, with 600 for ALFT, 301 of whom, without clinical aetiology, had been exposed to a drug within 30 days. Of these 301 patients, 40 had been exposed to an NSAID and 192 to paracetamol (81 of whom were without overdose). Event rates per MTY were 1.59 (95 % CI 1.1–2.2) for all NSAIDs pooled, 2.3 (95 % CI 1.2–3.9) for ibuprofen, 1.9 (95 % CI 0.8–3.7) for nimesulide, 1.6 (95 % CI 0.6–3.4) for diclofenac and 1.6 (95 % CI 0.3–4.5) for ketoprofen. For paracetamol, the event rate was 3.3 per MTY (95 % CI 2.6–4.1) without overdoses and 7.8 (95 % CI 6.8–9.0) including overdoses. Conclusions ALF leading to registration for transplantation after exposure to an NSAID was rare, with no major difference between NSAID. Non-overdose paracetamol-exposed liver failure was twice more common than NSAID-exposed liver failure. Electronic supplementary material The online version of this article (doi:10.1007/s40264-012-0013-7) contains supplementary material, which is available to authorized users.

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.

The results of observational studies evaluating and comparing the cardiovascular safety of glitazones, metformin and sufonylureas are inconsistent.To conduct and evaluate heterogeneity in a meta-analysis of observational studies on the risk of acute myocardial infarction (AMI) or stroke in patients with type 2 diabetes using non-insulin blood glucose–lowering drugs (NIBGLD). We systematically identified and reviewed studies evaluating NIBGLD in patients with type 2 diabetes indexed in Medline, Embase, or the Cochrane Library that met prespecified criteria. The quality of included studies was assessed with the RTI item bank. Results were combined using fixed- and random-effects models, and the Higgins I 2 statistic was used to evaluate heterogeneity. Sensitivity analyses by study quality were conducted. The summary relative risk (sRR) (95 % CI) of AMI for rosiglitazone versus pioglitazone was 1.13 (1.04–1.24) [I 2 = 55 %]. In the sensitivity analysis, heterogeneity was reduced [I 2 = 16 %]. The sRR (95 % CI) of stroke for rosiglitazone versus pioglitazone was 1.18 (1.02–1.36) [I 2 = 42 %]. There was strong evidence of heterogeneity related to study quality in the comparisons of rosiglitazone versus metformin and rosiglitazone versus sulfonylureas (I 2 ≥ 70 %). The sRR (95 % CI) of AMI for sulfonylurea versus metformin was 1.24 (1.14–1.34) [I 2 = 41 %] and for pioglitazone versus metformin was 1.02 (0.75–1.38) [I 2 = 17 %]. Sensitivity analyses decreased heterogeneity in most comparisons. Sulfonylureas increased the risk of AMI by 24 % compared with metformin; an imprecise point estimate indicated no difference in risk of AMI when comparing pioglitazone with metformin. The presence of heterogeneity precluded any conclusions on the other comparisons. The quality assessment was valuable in identifying methodological problems in the individual studies and for analysing potential sources of heterogeneity.

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

PURPOSE: The European Committee for Human Medicinal Products (CHMP) requested a multinational study with the aim to investigate the risk of acute liver failure (ALF) leading to registration for transplantation in patients exposed to non-steroidal anti-inflammatory drugs (NSAIDs). The method of this multinational, multicentre, retrospective case-population study, named SALT (Study of Acute Liver Transplant), is documented here. METHODS: This was a multicentre, multinational retrospective case-population study performed in France, Italy, Portugal, Greece, Ireland, the Netherlands and the UK. The study period was 3 years (1 January 2005-31 December 2007). Cases were patients ≥18 years of age with ALF at the time of registration on the transplant list for liver transplantation who had been exposed to an NSAID within 30 days preceding the initial symptoms of liver disease (index date). Exposure was defined as exposure to any NSAID. Per country rates of NSAID-exposed transplantation-registered ALF were computed as the ratio of the number of cases identified in the country to total population exposure. Overall and per-drug sales for NSAIDs and for paracetamol were obtained from Intercontinental Marketing Services (IMS) Health for all participating countries. Population exposure was measured as the defined daily dose and as estimated annual number of patients exposed (primary endpoint) with 95 % confidence intervals. RESULTS: The study protocol was approved by the CHMP. Of the 57 eligible liver transplant centres, 54 agreed to participate in the study. All national authorizations were received with relevant administrative burden, mainly due to bureaucracy. CONCLUSION: The present study created a multinational research network to estimate population-based absolute rates of drug-exposed ALF leading to registration on the transplantation list. This study design was chosen to obtain a fast response to a public health issue, namely, that of an increased risk of a rare, very serious adverse reaction. This model could be used to study other drug-related issues in ALF.