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Daniel Hsiang-Te Tsai,1,2 J Simon Bell,3 Shahab Abtahi,4 Brenda N Baak,5 Marloes T Bazelier,4 Ruth Brauer,6 Adrienne YL Chan,6– 9 Esther W Chan,9– 12 Haoqian Chen,13 Celine SL Chui,9,14,15 Sharon Cook,16 Stephen Crystal,16 Poonam Gandhi,13 Sirpa Hartikainen,17 Frederick K Ho,18 Shao-Ti Hsu,1 Jenni Ilomäki,3 Ju Hwan Kim,19 Olaf H Klungel,4 Marjaana Koponen,17 Wallis CY Lau,6,8,9 Kui Kai Lau,20,21 Terry YS Lum,22 Hao Luo,22 Kenneth KC Man,6,8,9 Jill P Pell,18 Soko Setoguchi,13,23 Shih-Chieh Shao,1,24 Chin-Yao Shen,1 Ju-Young Shin,19,25,26 Patrick C Souverein,4 Anna-Maija Tolppanen,17 Li Wei,6,9 Ian CK Wong,6,8,9,27 Edward Chia-Cheng Lai1 1School of Pharmacy, Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 2Centre for Neonatal and Paediatric Infection, St George’s University of London, London, UK; 3Centre for Medicine Use and Safety, Faculty of Pharmacy and Pharmaceutical Sciences, Monash University, Melbourne, Australia; 4Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands; 5PHARMO Institute for Drug Outcomes Research, Utrecht, the Netherlands; 6Research Department of Practice and Policy, UCL School of Pharmacy, London, UK; 7Groningen Research Institute of Pharmacy, Unit of Pharmacotherapy, ‐Epidemiology and ‐Economics, University of Groningen, Groningen, the Netherlands; 8Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, Special Administrative Region, People’s Republic of China; 9Laboratory of Data Discovery for Health (D24H), Hong Kong Science Park, Hong Kong, Special Administrative Region, People’s Republic of China; 10Centre for Safe Medication Practice and Research, Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, Special Administrative Region, People’s Republic of China; 11Department of Pharmacy, the University of Hong Kong-Shenzhen Hospital, Shenzhen, People’s Republic of China; 12The University of Hong Kong Shenzhen Institute of Research and Innovation, Shenzhen, People’s Republic of China; 13Center for Pharmacoepidemiology and Treatment Science (PETS), Institute for Health, Rutgers University, New Brunswick, NJ, USA; 14School of Nursing, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, Special Administrative Region, People’s Republic of China; 15School of Public Health, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, Special Administrative Region, People’s Republic of China; 16Center for Health Services Research, Rutgers University, New Brunswick, NJ, USA; 17Kuopio Research Centre of Geriatric Care and School of Pharmacy, University of Eastern Finland, Kuopio, Finland; 18School of Health and Wellbeing, University of Glasgow, Glasgow, UK; 19School of Pharmacy, Sungkyunkwan University, Suwon, South Korea; 20Division of Neurology, Department of Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, Special Administrative Region, People’s Republic of China; 21State Key Laboratory of Brain and Cognitive Sciences, University of Hong Kong, Hong Kong, Special Administrative Region, People’s Republic of China; 22Department of Social Work and Social Administration, University of Hong Kong, Hong Kong, Special Administrative Region, People’s Republic of China; 23Department of Medicine, Rutgers Robert Wood Johnson Medical School and Pharmacoepidemiology and Treatments Science, Institute for Health, Rutgers University, New Brunswick, NJ, USA; 24Department of Pharmacy, Keelung Chang Gung Memorial Hospital, Keelung, Taiwan; 25Samsung Advanced Institute for Health Sciences & Technology, Sungkyunkwan University, Seoul, South Korea; 26Department of Biohealth Regulatory Science, Sungkyunkwan University, Seoul, South Korea; 27Aston Pharmacy School, Aston University, Birmingham, UKCorrespondence: Edward Chia-Cheng Lai, School of Pharmacy and Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan, Email edward_lai@mail.ncku.edu.twPurpose: To describe and categorize detailed components of databases in the Neurological and Mental Health Global Epidemiology Network (NeuroGEN).Methods: An online 132-item questionnaire was sent to key researchers and data custodians of NeuroGEN in North America, Europe, Asia and Oceania. From the responses, we assessed data characteristics including population coverage, data follow-up, clinical information, validity of diagnoses, medication use and data latency. We also evaluated the possibility of conversion into a common data model (CDM) to implement a federated network approach. Moreover, we used radar charts to visualize the data capacity assessments, based on different perspectives.Results: The results indicated that the 15 databases covered approximately 320 million individuals, included in 7 nationwide claims databases from Australia, Finland, South Korea, Taiwan and the US, 6 population-based electronic health record databases from Hong Kong, Scotland, Taiwan, the Netherlands and the UK, and 2 biomedical databases from Taiwan and the UK.Conclusion: The 15 databases showed good potential for a federated network approach using a common data model. Our study provided publicly accessible information on these databases for those seeking to employ real-world data to facilitate current assessment and future development of treatments for neurological and mental disorders.Keywords: meta-data, data repository, Neurological and Mental Health Global Epidemiology Network, NeuroGEN

Dionne CW Braeken,1–3 Gernot GU Rohde,2 Frits ME Franssen,1,2 Johanna HM Driessen,3–5 Tjeerd P van Staa,3,6 Patrick C Souverein,3 Emiel FM Wouters,1,2 Frank de Vries3,4,7 1Department of Research and Education, CIRO, Horn, 2Department of Respiratory Medicine, Maastricht University Medical Centre (MUMC+), Maastricht, 3Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute of Pharmaceutical Sciences, Utrecht, 4Department of Clinical Pharmacy and Toxicology, Maastricht University Medical Centre (MUMC+), Maastricht, 5Department of Epidemiology, Care and Public Health Research Institute (CAPHRI), Maastricht, the Netherlands; 6Department of Health eResearch, University of Manchester, Manchester, 7MRC Lifecourse Epidemiology Unit, Southampton General Hospital, Southampton, UK Background: Smoking increases the risk of community-acquired pneumonia (CAP) and is associated with the development of COPD. Until now, it is unclear whether CAP in COPD is due to smoking-related effects, or due to COPD pathophysiology itself. Objective: To evaluate the association between COPD and CAP by smoking status. Methods: In total, 62,621 COPD and 191,654 control subjects, matched by year of birth, gender and primary care practice, were extracted from the Clinical Practice Research Datalink (2005–2014). Incidence rates (IRs) were estimated by dividing the total number of CAP cases by the cumulative person-time at risk. Time-varying Cox proportional hazard models were used to estimate the hazard ratios (HRs) for CAP in COPD patients versus controls. HRs of CAP by smoking status were calculated by stratified analyses in COPD patients versus controls and within both subgroups with never smoking as reference. Results: IRs of CAP in COPD patients (32.00/1,000 person-years) and controls (6.75/1,000 person-years) increased with age and female gender. The risk of CAP in COPD patients was higher than in controls (HR 4.51, 95% CI: 4.27–4.77). Current smoking COPD patients had comparable CAP risk (HR 0.92, 95% CI: 0.82–1.02) as never smoking COPD patients (reference), whereas current smoking controls had a higher risk (HR 1.23, 95% CI: 1.13–1.34) compared to never smoking controls. Conclusion: COPD patients have a fourfold increased risk to develop CAP, independent of smoking status. Identification of factors related with the increased risk of CAP in COPD is warranted, in order to improve the management of patients at risk. Keywords: COPD, respiratory infections, incidence, smoking risk

Erwin C Vasbinder,1 Svetlana V Belitser,2 Patrick C Souverein,2 Liset van Dijk,3 Arnold G Vulto,1 Patricia MLA van den Bemt1 1Erasmus University Medical Center, Department of Hospital Pharmacy, Rotterdam, 2Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3NIVEL, Utrecht, the Netherlands Background: Non-adherence to inhaled corticosteroids (ICSs) is a major risk factor for poor asthma control in children. However, little is known about the effect of adherence to ICS on the incidence of asthma exacerbations. The objective of this study was to examine the effect of poor adherence to ICS on the risk of exacerbations in children with asthma. Methods: In this nested case–control study using data from the Dutch PHARMO Record Linkage System, children aged 5–12 years who had an asthma exacerbation needing oral corticosteroids or hospital admission were matched to patients without exacerbations. Refill adherence was calculated as medication possession ratio from ICS-dispensing records. Data were analyzed using a multivariable multiplicative intensity regression model. Results: A total of 646 children were included, of whom 36 had one or more asthma exacerbations. The medication possession ratio was 67.9% (standard deviation [SD] 30.2%) in children with an exacerbation versus 54.2% (SD 35.6%) in the control group. In children using long-acting beta-agonist, good adherence to ICS was associated with a higher risk of asthma exacerbations: relative risk 4.34 (95% confidence interval: 1.20–15.64). Conclusion: In children with persistent asthma needing long-acting beta-agonist, good adherence to ICS was associated with an increased risk of asthma exacerbations. Possible explanations include better motivation for adherence to ICS in children with more severe asthma, and reduced susceptibility to the consequences of non-adherence to ICS due to overprescription of ICS to children who are in clinical remission. Further study into the background of the complex interaction between asthma and medication adherence is needed. Keywords: asthma exacerbation, children, database, inhaled corticosteroids, refill adherence pharmacoepidemiology, observational study, the Netherlands

MNA Van Steenis,1 JA Driesenaar,2 JM Bensing,2,3 R Van Hulten,4 PC Souverein,4 L Van Dijk,2,4 PAGM De Smet,5 AM Van Dulmen2,6,71Department of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands; 2NIVEL (Netherlands institute for health services research), Utrecht, The Netherlands; 3Department of Psychology, Faculty of Social and Behavioural Sciences, Utrecht University, Utrecht, The Netherlands; 4Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht University, Utrecht, The Netherlands; 5IQ Healthcare, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; 6Department of Primary and Community Care, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; 7Department of Health Sciences, Buskerud University College, Drammen, NorwayBackground: Beliefs play a crucial role in medication adherence. Interestingly, the relationship between beliefs and adherence varies when different adherence measures are used. How adherence, in turn, is related to asthma symptoms is still unclear. Our aim was to investigate the relationship between beliefs (ie, necessities and concerns) about inhaled corticosteroids (ICS) and subjectively as well as objectively measure adherence and the agreement between these measures. Further, the relationship between adherence and asthma symptoms was examined.Methods: A total of 280 patients aged 18–80 years who filled at least two ICS prescriptions in the preceding year were recruited to complete a questionnaire. The questionnaire included the Beliefs about Medicines Questionnaire to assess necessity beliefs and concerns about ICS, four questions about ICS use to measure self-reported adherence, and the Asthma Control Questionnaire to assess asthma symptoms. Proportion of days covered was used to determine pharmacy refill adherence.Results: Data from 93 patients with asthma were analyzed. Necessities were positively related to self-reported adherence (P = 0.01). No other associations were found between beliefs and subjective or objective adherence. There was no correlation between self-reported and refill adherence. Participants were significantly (P < 0.001) less adherent according to self-report data (24.4%) than according to pharmacy data (57.8%). No relationship was found between adherence and asthma symptoms.Conclusion: Higher necessities are associated with higher self-reported adherence, suggesting that it could be more important to focus on necessities than on concerns in an attempt to improve adherence. Self-reported and refill adherence measurements cannot be used interchangeably. No relationship between adherence and asthma symptoms was found.Keywords: asthma, inhaled corticosteroids, adherence, medication beliefs, asthma symptoms

BACKGROUND: Age-dependent changes in lithium pharmacokinetic and pharmacodynamic properties can influence lithium use in an aging population, especially as newer treatment options are available. OBJECTIVE: We compared lithium use patterns between middle-aged and elderly outpatients in the Netherlands. METHODS: Data for this study were obtained from the Dutch PHARMO Record Linkage System. Incident lithium users 40 years or older were identified in the period 1996-2008. The following lithium use patterns were defined: continuation, add on, switch, and discontinuation. Differences were assessed for the following age groups: 40 to 49 years, 50 to 59 years, 60 to 69 years, and 70 years or older. The youngest group was the reference group. Patient baseline characteristics and potential determinants of changes in lithium use patterns were assessed. RESULTS: We identified 2081 incident lithium users. Use of antidepressants was not different at baseline between age groups, but elderly patients starting lithium treatment used baseline antipsychotics less frequently (P < 0.05). Older patients were less likely to receive psychotropic drugs as add on to ongoing lithium therapy (P < 0.05). Frequency of discontinuation and switch events did not differ between the age groups. In the whole study group, age was associated with any change in lithium use patterns. CONCLUSIONS: Older patients are less likely to receive psychotropic drugs as add on to ongoing lithium therapy. Despite pharmacokinetic and pharmacodynamic changes in the elderly, lithium is not more often discontinued and not more often switched in older patients. [ABSTRACT FROM AUTHOR]

Purpose: To limit misuse and save costs, on January 1, 2009, benzodiazepines were excluded from the Dutch reimbursement list when used as anxiolytic, hypnotic, or sedative. This study aims to assess the impact of this reimbursement restriction on benzodiazepine use in patients with newly diagnosed anxiety or sleeping disorder in general practice.Methods: Was conducted a retrospective observational database study deriving data on diagnoses and prescriptions from the electronic health records-based Netherlands Information Network of General Practice (LINH). We looked for patients aged 18 years and older with an incident diagnosis of sleeping disturbance (International Classification of Primary Care code: P06) or anxiety (P74, P01) between January 2008 and December 2009. Incidence of these diagnoses, benzodiazepine use, and initiation of selective serotonin reuptake inhibitor (SSRI) treatment was compared between 2008 and 2009.Results: In total, we identified 13,596 patients with an incident diagnosis of anxiety (3,769 in 2008 and 3,710 in 2009) or sleeping disorder (3,254 in 2008 and 2,863 in 2009). The proportion of patients being prescribed a benzodiazepine after a diagnosis was lower in 2009 than in 2008 for both anxiety (30.1% vs. 33.7% P < .05) and sleeping disorder (59.1% vs. 67.0%, P < .05), as was the proportion of patients with more than 1 benzodiazepine prescription for both anxiety (36.4% vs. 42.6%, P < .05) and sleeping disorder (35.0% vs. 42.6%, P < .05). We found no increase in the use of alternative treatment for anxiety with SSRIs.Conclusions: The reimbursement restriction has led to a moderate decrease in the number of incident diagnoses and initiation of benzodiazepine use in patients with newly diagnosed anxiety or sleeping disorder. This finding indicates that in settings where no such reimbursement opportunities exist, physicians have room to reduce benzodiazepine prescribing. [ABSTRACT FROM AUTHOR]

Background: Hyponatraemia due to antipsychotic use is a potentially serious problem; however, it is not known whether it is an adverse drug reaction (ADR) to antipsychotic use or is due to the underlying psychiatric disease.Objective: To estimate the strength of the association between antipsychotics and hyponatraemia or syndrome of inappropriate antidiuretic hormone secretion (SIADH), using information reported to the WHO Collaborating Centre for International Drug Monitoring, the Uppsala Monitoring Centre (UMC).Setting: The WHO global individual case safety report database system (VigiBase) maintained by the UMC.Study Design: Case-control study, with cases being reports of hyponatraemia/SIADH, and controls being reports of other ADRs. Each case was sampled with ten controls sequencing in time from the date the corresponding case was entered into the database. The potential contribution of the chemical structures and receptor affinity (dopaminergic and/or serotonergic) of the antipsychotics was studied, as was the influence of concomitant use of other medications known to cause hyponatraemia.Main Outcome Measures: The strength of the association between antipsychotic use and hyponatraemia in comparison with other drugs was expressed as reporting odds ratio (ROR), a measure of disproportionality, with corresponding 95% CIs, adjusted for age, sex and concomitant medication associated with hyponatraemia. In addition, stratification by the presence or absence of concomitant medication was performed.Results: Up to August 2008, 3 881 518 suspected ADRs were reported and filed in VigiBase, with 912 reports on hyponatraemia related to antipsychotics. The adjusted ROR for the association between antipsychotic use and hyponatraemia was 1.58 (95% CI 1.46, 1.70). The adjusted RORs did not vary for the different chemical structures or dopamine D(2) and serotonin 5-HT(2A) receptor affinity profiles. The ROR was 3.00 (95% CI 2.65, 3.39) for the association between hyponatraemia and antipsychotic use in the absence of concomitant medication associated with hyponatraemia, and 1.16 (95% CI 1.06, 1.28) in the presence of concomitant medication associated with hyponatraemia.Conclusions: Antipsychotic use may be associated with reporting of hyponatraemia. Moreover, the concomitant use of medication associated with hyponatraemia potentially leads to under-reporting of antipsychotic-associated hyponatraemia. We advise testing patients whose psychiatric and/or physical condition deteriorates while on antipsychotics for hyponatraemia. [ABSTRACT FROM AUTHOR]

Background: Drug-induced ototoxicity is a subject of interest because many diseases are treated with drugs that have potential toxic effects on the ear. There is evidence that both inner ear and kidney tissue are immunologically, biochemically and functionally related. It has been suggested that drugs that influence the transport of sodium and/or potassium change ionic homeostasis in the inner ear and, hence, induce functional disturbances such as hearing loss, tinnitus and vertigo.Objectives: To assess whether renal suspected adverse drug reactions (sADRs) have predictive value for ear and labyrinth adverse drug reactions (ADRs) and whether drug classes involved have influence ion transport systems.Study Design: Data were obtained from the Netherlands Pharmacovigilance Centre Lareb. The study base comprised all reports of sADRs up until 1 January 2007. Cases were all sADRs for relevant renal disorders and all sADRs for relevant ear disorders. All other reported sADRs were selected as 'non-cases'. The relationship between drug classes and renal, ear and labyrinth sADRs was evaluated by calculating reporting odds ratios (RORs). An ROR > or = 1.50 was regarded as a cut-off value for an association. Drug classes were classified into four groups: (A) ROR kidney <1.50 and ROR ear <1.50 or no reports on ear sADRs (reference group); (B) ROR kidney <1.50 and ROR ear > or = 1.50; (C) ROR kidney > or = 1.50 and ROR ear <1.50 or no reports on ear sADRs; and (D) ROR kidney > or = 1.50 and ROR ear > or = 1.50. For each group, we calculated odds ratios (ORs) for the association between the group classification and the effect on ion channels/ion transport systems in kidney and ear tissues.Results: Of 193 drug classes with relevant ADRs for renal disorders, 120 drug classes also had reports on ototoxic reactions. Fourteen out of 120 drug classes had an ROR > or = 1.50 for the association between the drug class and both renal and ear sADRs. Among these drug classes were several with a well known ability to induce renal (adverse) effects and ear and labyrinth disorders, such as loop diuretics, aminoglycosides and quinine. We found that one mechanistic commonality of the drug classes mentioned in the reports was the ability to affect ion transport systems. The percentage of drugs having this property differed between the four groups. The ORs for groups D and B were significantly higher compared with the reference group (OR 12.2, 95% CI 3.0, 30.5 and OR 8.7, 95% CI 2.4, 18.7, respectively), whereas there was no association for group C.Conclusion: Our data suggest that renal sADRs as such are not a marker for drug-induced ear and labyrinth disorders. However, the ability of drugs to act on ion channels or ion transport systems and, therefore, have an influence on ionic homeostasis in the kidney and ear might be a predictor for the possible occurrence of drug-related ototoxicity. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To assess whether use of oral glucocorticoids is associated with cardiovascular and cerebrovascular morbidity. DESIGN AND SETTING: Nested case-control study within a cohort of patients (> or = 50 years old) with at least one prescription for oral or non-systemic glucocorticoids. Data were from the general practice research database. PATIENTS: 50 656 patients were identified with a first record for ischaemic heart disease (International classification of diseases, ninth revision (ICD-9) codes 410, 411, 413, and 414), ischaemic stroke or transient ischaemic attack (ICD-9 codes 430-436), or heart failure (ICD-9 code 428) between 1988 and 1998. One control was matched to each case by sex, age, general practice, underlying disease, and calendar time. MAIN OUTCOME MEASURE: Odds ratio (OR) of cardiovascular or cerebrovascular events in patients using oral glucocorticoids compared with non-users. RESULTS: There was a significant association between ever use of oral glucocorticoids and any cardiovascular or cerebrovascular outcome (adjusted OR 1.25, 95% confidence interval (CI) 1.21 to 1.29). The association was stronger for current use of oral glucocorticoids than for recent or past use. Among current users, the highest ORs were observed in the group with the highest average daily dose, although the dose-response relation was not continuous. Current use was associated with an increased risk of heart failure (adjusted OR 2.66, 95% CI 2.46 to 2.87), which was consistent between patients with rheumatoid arthritis, patients with chronic obstructive pulmonary disease, and patients without either of the two conditions. Also, current use was associated with a smaller increased risk of ischaemic heart disease (OR 1.20, 95% CI 1.11 to 1.29). CONCLUSIONS: Oral glucocorticoid use was identified as a risk factor for heart failure. However, the evidence remains observational and only a randomised controlled trial of glucocorticoid treatment versus other disease modifying agents is likely to distinguish the importance of the underlying disease activity from its treatment in predicting cardiovascular outcomes. [ABSTRACT FROM AUTHOR]

Objective: To study the association between use of alpha-blockers and risk of hip/femur fractures.Design: Population-based case-control study.Setting: General Practice Research Database.Subjects: Cases were defined as men, aged 40 years and older with a first diagnosis for hip/femur fracture. Controls were matched 1 : 1 on gender, year of birth and general practitioner-practice.Results: In all, 4571 cases and an equal number of controls were identified. Current use of alpha-blockers (prazosin, doxazosin, indoramin, terazosin, alfuzosin and tamsulosin) was compared with non-use of alpha-blockers. Current use of alpha-blockers on the index date was associated with an increased risk of hip/femur fracture [adjusted odds ratio (OR) 1.9, 95% confidence interval (CI): 1.1-3.0] in the overall analysis. The effect was particularly strong for first prescriptions within a treatment episode (adjusted OR 5.1, 95% CI: 1.0-31.7) and during the first month of treatment (adjusted OR 4.1, 95% CI: 0.7-23.9). Stratification according to indication of use showed that current use of alpha-blockers was not associated with hip/femur fracture in men with a diagnosis of benign prostatic hyperplasia (adjusted OR 1.0, 95% CI: 0.4-2.5), but was associated in men who used alpha-blockers for cardiovascular disease (adjusted OR 2.8, 95% CI: 1.4-5.4).Conclusion: Current use of alpha-blockers was associated with an increased risk of hip/femur fracture and with the start of a new treatment episode. The effect seemed to be confined to patients who used alpha-blockers for cardiovascular disease. Caution with respect to first-dose effects related to the initiation of a new episode of alpha-blocker treatment is advised. [ABSTRACT FROM AUTHOR]

Aim: To determine the association of diabetes-related characteristics with fractures at different sites in individuals with type 2 diabetes (T2D)., Materials and Methods: We conducted a cohort study using the Clinical Practice Research Datalink (CPRD) GOLD. Patients aged over 30 years with T2D were identified within the CPRD. Patients were followed from the start of diabetes treatment until the end of data collection, death, or the occurrence of a fracture. Cox proportional hazards models were used to estimate the hazard ratios for the association of the individual characteristics (diabetes duration, glycated haemoglobin [HbA1c] level, and microvascular complications) with fracture risk, adjusted for demographics, comorbidities and comedication., Results: A diabetes duration of >10 years was associated with an increased risk of any fracture and major osteoporotic fractures (MOFs), while a diabetes duration of >8 years was associated with an increased hip fracture risk, compared to a duration <2 years. An HbA1c level <6% was associated with an increased fracture risk compared to HbA1c values of 6% to <7%. The presence of one or two microvascular complications was associated with an increased risk of any fracture and MOFs and the presence of two microvascular complications was associated with an increased hip fracture risk, compared to no microvascular complications., Conclusion: In conclusion, our study shows that a diabetes duration of 10 years or more, strict glycaemic control resulting in HbA1c levels below 6%, and/or the presence of at least one microvascular complication increased the risk of any fracture, hip fractures, MOFs, and humerus fractures, but not ankle, scapula or skull fractures., (© 2024 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aim: To investigate the effect of dipeptidyl peptidase-4 inhibitors (DPP4-Is) and glucagon-like peptide-1 receptor agonists (GLP1-RAs) on diabetic foot ulcer (DFU) and DFU-related outcomes (lower limb amputation [LLA], DFU-related hospitalization and mortality)., Methods: We performed a cohort study with data from the Clinical Practice Research Datalink Aurum database with linkage to hospital data. We included people with type 2 diabetes starting treatment with metformin. Then we propensity score matched new users of DPP4-Is and sulphonylureas (N = 98 770), and new users of GLP1-RAs and insulin (N = 25 422). Cox proportional hazards models estimated the hazard ratios (HRs) for the outcomes., Results: We observed a lower risk of DFU with both DPP4-I use versus sulphonylurea use (HR 0.88, 95% confidence interval [CI]: 0.79-0.97) and GLP1-RA use versus insulin use (HR 0.44, 95% CI: 0.32-0.60) for short-term exposure (≤ 400 days) and HR 0.74 (95% CI: 0.60-0.92) for long-term exposure (>400 days). Furthermore, the risks of hospitalization and mortality were lower with both DPP4-I use and GLP1-RA use. The risk of LLA was lower with GLP1-RA use. The results remained consistent across several sensitivity analyses., Conclusions: Incretin-based therapy was associated with a lower risk of DFU and DFU-related outcomes. This suggests benefits for the use of this treatment in people at risk of DFU., (© 2024 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aims: Sodium-glucose cotransporter-2 inhibitors (SGLT-2is) have a direct cardiac effect that is likely to be independent of its glucose lowering renal effect. Previous research has shown that SGLT2-is mitigate heart failure and prevent arrhythmic cardiac death. Our objective is to determine whether SGLT-2is reduce atrial fibrillation (AF) in comparison to other second-to third-line antidiabetic drugs in type 2 diabetes., Methods and Results: We conducted a population-based, new-user active comparator cohort study using data from the UK Clinical Practice Research Datalink. We identified a cohort of patients initiating a new antidiabetic drug class between January 2013 and September 2020. This cohort included patients initiating their first ever non-insulin antidiabetic drug, as well as those who switched to or added-on an antidiabetic drug class not previously used in their treatment history. Individuals with a diagnosis of AF or atrial flutter at any time before cohort entry were excluded. Cox regression analysis with time-dependent covariates was used to estimate hazard ratios (HRs) and 95% confidence intervals (95% CIs) of AF comparing SGLT-2-is with other second-line to third-line antidiabetic drugs. Stratified analyses were performed according to sex, diabetes duration (<5 or ≥ 5 years), body mass index (BMI), HbA1c, and presence of heart failure.The cohort comprised 142 447 patients. SGLT-2is were associated with a statistically significant reduced hazard of AF compared to other second-line to third-line antidiabetic drugs (adjusted HR: 0.77 [95% CI: 0.68-0.88]). This reduced risk was present in both sexes but was more prominently among women (adjusted HRwomen: 0.60 [95% CI: 0.45-0.79]; HRmen: 0.85 [95% CI: 0.73-0.98]; P-value interaction: 0.012). There was no evidence for effect modification when stratifying on duration of diabetes, BMI, HbA1c, or presence of heart failure., Conclusion: SGLT-2is were associated with a reduced risk of AF in patients with type 2 diabetes compared to other second-line to third-line antidiabetic drugs. This reduced risk occurs in both sexes but more prominently among women., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Antimicrobial stewardship interventions mainly focus on initial antibiotic prescriptions, with few considering within-episode repeat prescriptions. We aimed to describe the magnitude, type and determinants of within-episode repeat antibiotic prescriptions in patients presenting to primary care with respiratory tract infections (RTIs)., Methods: We conducted a population-based cohort study among 530 sampled English general practices within the Clinical Practice Research Datalink (CPRD). All individuals with a primary care RTI consultation for which an antibiotic was prescribed between March 2018 and February 2022. Main outcome measurement was repeat antibiotic prescriptions within 28 days of a RTI visit stratified by age (children vs. adults) and RTI type (lower vs. upper RTI). Multivariable logistic regression and principal components analyses were used to identify risk factors and patient clusters at risk for within-episode repeat prescriptions., Findings: 905,964 RTI episodes with at least one antibiotic prescription were identified. In adults, 19.9% (95% CI 19.3-20.5%) had at least one within-episode repeat prescription for a lower RTI, compared to 10.5% (95% CI 10.3-10.8%) for an upper RTI. In children, this was around 10% irrespective of RTI type. The majority of repeat prescriptions occurred a median of 10 days after the initial prescription and was the same antibiotic class in 48.3% of cases. Frequent RTI related GP visits and prior within-RTI-episode repeat antibiotic prescriptions were main factors associated with repeat prescriptions in both adults and children irrespective of RTI type. Young (<2 years) and older (65+) age were associated with repeat prescriptions. Among those aged 2-64 years, allergic rhinitis, COPD and oral corticosteroids were associated with repeat prescriptions., Interpretations: Repeat within-episode antibiotic use accounts for a significant proportion of all antibiotics prescribed for RTIs, with same class antibiotics unlikely to confer clinical benefit and is therefore a prime target for future antimicrobial stewardship interventions., Competing Interests: Declaration of Competing Interest No conflicts of interest to declare., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: People with pediatric and early adulthood type 1 diabetes (T1D) might have a higher fracture risk at several sites compared to the general population. Therefore, we assessed the hazard ratios (HR) of various fracture sites and determined the risk factors associated with fractures among people with newly diagnosed childhood and adolescence T1D., Methods: All people from the UK Clinical Practice Research Datalink GOLD (1987-2017), below 20 years of age with a T1D diagnosis code (n = 3100) and a new insulin prescription, were included and matched 1:1 by sex, age, and practice to a control without diabetes. Cox regression was used to estimate HRs of any, major osteoporotic fractures (MOFs) and peripheral fractures (lower-arm and lower-legs) for people with T1D compared to controls. The analyses were adjusted for sex, age, diabetic complications, medication (glucocorticoids, anti-depressants, anxiolytics, bone medication, anti-convulsive), Charlson-comorbidity-index (CCI), hypoglycemia, falls and alcohol. T1D was further stratified by diabetes duration, presence of diabetic microvascular complications (retinopathy, nephropathy, and neuropathy) and boys versus girls., Results: The crude HRs for any fracture (HR: 1.30, CI95%: 1.11-1.51), lower-arm (HR: 1.22, CI95%: 1.00-1.48), and lower-leg fractures (HR: 1.54, CI95%: 1.11-2.13) were statistically significant increase in T1D compared to controls, but the effect disappeared in the adjusted analyses. For MOFs, no significant differences were seen. Risk factors in the T1D cohort were few, but the most predominantly one was a previous fracture (any fracture: HR: 2.00, CI95%: 1.70-2.36; MOFs: HR: 1.89, CI95%: 1.44-2.48, lower- arm fractures: HR: 2.08, CI95%: 1.53-2.82 and lower-leg fractures: HR: 2.08, CI95%: 1.34-3.25). Others were a previous fall (any fracture: HR: 1.54, CI95%: 1.20-1.97), hypoglycemia (Any fracture: HR: 1.46, CI95%: 1.21-1.77 and lower-leg fractures: HR: 2.34, CI95%: 1.47-3.75), and anxiolytic medication (Any fracture: HR: 1.52, CI95%: 1.10-2.11). Whereas girls had a lower risk compared to boys (Any fracture: HR: 0.78, CI95%: 0.67-0.90 and lower-arm fractures; HR: 0.51, CI95%: 0.38-0.68). The risk of any fracture in T1D did not increase with longer diabetes duration compared to controls (0-4 years: HR: 1.20, CI95%: 1.00-1.44; 5-9 years: HR: 1.17, CI95%: 0.91-1.50; <10 years: HR: 0.83, CI95%: 0.54-1.27). Similar patterns were observed for other fracture sites. Furthermore, one complication compared to none in T1D correlated with a higher fracture risk (1 complication: HR: 1.42, CI95%: 1.04-1.95)., Conclusion: The overall fracture risk was not increased in pediatric and early adulthood T1D; instead, it was associated with familiar risk factors and specific diabetes-related ones., Competing Interests: Declaration of competing interest Peter Vestergaard is head of research in the Steno Diabetes Center North Denmark sponsored by the Novo Nordisk Foundation. Joop van den Bergh: unrestricted research grant and lecture fee from Amgen and UCB, is consultant for PoroUS. Nicklas H. Rasmussen holds shares in Novo Nordisk, has lecture fees from Boehringer Ingelheim and travel expenses from UCB. The other authors Johanna Driessen, Patrick Souverein and Annika Kvist declare that they have no conflict of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: This study aimed to determine the hazard ratios (HR) for various fracture sites and identify associated risk factors in a cohort of relatively healthy adult people with newly diagnosed type 1 diabetes (T1D)., Methods: The study utilized data from the UK Clinical Practice Research Datalink GOLD (1987-2017). Participants included people aged 20 and above with a T1D diagnosis code (n = 3281) and a new prescription for insulin. Controls without diabetes were matched based on sex, year of birth, and practice. Cox regression analysis was conducted to estimate HRs for any fracture, major osteoporotic fractures (MOFs), and peripheral fractures (lower-arm and lower-leg) in people with T1D compared to controls. Risk factors for T1D were examined and included sex, age, diabetic complications, medication usage, Charlson comorbidity index (CCI), hypoglycemia, previous fractures, falls, and alcohol consumption. Furthermore, T1D was stratified by duration of disease and presence of microvascular complications., Results: The proportion of any fracture was higher in T1D (10.8 %) than controls (7.3). Fully adjusted HRs for any fracture (HR: 1.43, CI95%: 1.17-1.74), MOFs (HR: 1.46, CI95%: 1.04-2.05), and lower-leg fractures (HR: 1.37, CI95%: 1.01-1.85) were statistically significantly increased in people with T1D compared to controls. The primary risk factor across all fracture sites in T1D was a previous fracture. Additional risk factors at different sites included previous falls (HR: 1.64, CI95%: 1.17-2.31), antidepressant use (HR: 1.34, CI95%: 1.02-1.76), and anxiolytic use (HR: 1.54, CI95%: 1.08-2.29) for any fracture; being female (HR: 1.65, CI95%: 1.14-2.38) for MOFs; the presence of retinopathy (HR: 1.47, CI95%: 1.02-2.11) and previous falls (HR: 2.04, CI95%: 1.16-3.59) for lower-arm and lower-leg fractures, respectively. Lipid-lowering medication use decreased the risk of MOFs (HR: 0.66, CI95%: 0.44-0.99). Stratification of T1D by disease duration showed that the relative risk of any fracture in T1D did not increase with longer diabetes duration (0-4 years: HR: 1.52, CI95%: 1.23-1.87; 5-9 years: HR: 1.30, CI95%: 0.99-1.71; <10 years: HR: 1.07, CI95%: 0.74-1.55). Similar patterns were observed for other fracture sites. Moreover, the occurrence of microvascular complications in T1D was linked to a heightened risk of fractures in comparison to controls. However, when considering the T1D cohort independently, the association was not statistically significant., Conclusion: In a cohort of relatively healthy and newly diagnosed people with T1D HRs for any fracture, MOFs, and lower-leg fractures compared to controls were increased. A previous fracture was the most consistent risk factor for a subsequent fracture, whereas retinopathy was the only diabetes related one. We postulate a potential initial fracture risk, succeeded by a subsequent risk reduction, which might potentially increase in later years due to the accumulation of complications and other factors., Competing Interests: Declaration of competing interest Peter Vestergaard is head of research in the Steno Diabetes Center North Denmark sponsored by the Novo Nordisk Foundation. Joop van den Bergh: unrestricted research grant and lecture fee from Amgen and UCB, is consultant for PoroUS. Nicklas H. Rasmussen holds shares in Novo Nordisk, has lecture fees from Boehringer Ingelheim and travel expenses from UCB. The other authors Johanna Driessen, Patrick Souverein and Annika Kvist declare that they have no conflict of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Aim: To investigate whether sodium-glucose cotransporter-2 (SGLT2) inhibitor use as compared to dipeptidyl peptidase-4 (DPP-4) inhibitor use as add-on to metformin is associated with the risk of any fracture or major osteoporotic fractures (MOFs)., Methods: A cohort study using the Clinical Practice Research Datalink (CPRD) Aurum database was conducted. All patients aged 18 years and older with a first-ever prescription for a DPP-4 inhibitor or an SGLT2 inhibitor as add-on to metformin between January 1, 2013 and June 30, 2020 were selected. Patients starting with SGLT2 inhibitors were matched (up to 1:3) on propensity scores to patients starting with DPP-4 inhibitors. Propensity scores were calculated based on sex, age, body mass index, comorbidities, comedication and lifestyle factors. Cox proportional hazard models were used to estimate the risk of fracture with SGLT2 inhibitor use as compared to DPP-4 inhibitor use., Results: A total of 13 807 SGLT2 inhibitor users (age 55.4 ± 10.6 years, 36.7% female) were included in this study, matched with 28 524 DPP-4 inhibitor users (age 55.4 ± 8.0 years, 36.4% female). The risk of any fracture with current SGLT2 inhibitor use was similar compared with current DPP-4 inhibitor use (adjusted hazard ratio [aHR] 1.09, 95% confidence interval [CI] 0.91-1.31), as was the risk of MOFs (aHR 0.89, 95% CI 0.64-1.22) and the risk of fractures at any of the individual MOF sites. Additionally, no association was found with duration of SGLT2 inhibitor use (longest duration >811 days) for any of the individual SGLT2 inhibitor agents, or after stratification by sex and age., Conclusion: Use of SGLT2 inhibitors was not associated with the risk of any fracture, MOFs or fracture at the individual MOF sites when compared to DPP-4 inhibitor use., (© 2023 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aims: In clinical practice, factors associated with cardiovascular disease (CVD) like albuminuria, education level, or coronary artery calcium (CAC) are often known, but not incorporated in cardiovascular risk prediction models. The aims of the current study were to evaluate a methodology for the flexible addition of risk modifying characteristics on top of SCORE2 and to quantify the added value of several clinically relevant risk modifying characteristics., Methods and Results: Individuals without previous CVD or DM were included from the UK Biobank; Atherosclerosis Risk in Communities (ARIC); Multi-Ethnic Study of Atherosclerosis (MESA); European Prospective Investigation into Cancer, The Netherlands (EPIC-NL); and Heinz Nixdorf Recall (HNR) studies (n = 409 757) in whom 16 166 CVD events and 19 149 non-cardiovascular deaths were observed over exactly 10.0 years of follow-up. The effect of each possible risk modifying characteristic was derived using competing risk-adjusted Fine and Gray models. The risk modifying characteristics were applied to individual predictions with a flexible method using the population prevalence and the subdistribution hazard ratio (SHR) of the relevant predictor. Risk modifying characteristics that increased discrimination most were CAC percentile with 0.0198 [95% confidence interval (CI) 0.0115; 0.0281] and hs-Troponin-T with 0.0100 (95% CI 0.0063; 0.0137). External validation was performed in the Clinical Practice Research Datalink (CPRD) cohort (UK, n = 518 015, 12 675 CVD events). Adjustment of SCORE2-predicted risks with both single and multiple risk modifiers did not negatively affect calibration and led to a modest increase in discrimination [0.740 (95% CI 0.736-0.745) vs. unimproved SCORE2 risk C-index 0.737 (95% CI 0.732-0.741)]., Conclusion: The current paper presents a method on how to integrate possible risk modifying characteristics that are not included in existing CVD risk models for the prediction of CVD event risk in apparently healthy people. This flexible methodology improves the accuracy of predicted risks and increases applicability of prediction models for individuals with additional risk known modifiers., Competing Interests: Conflict of interest: Dr. Matsushita received funding from the National Institutes of Health during the study and personal fees from Fukuda Denshi, Kowa Company, and the American Medical Group Association outside of the submitted work. L.P. is funded by a BHF Programme Grant (RG/18/13/33946) S.K. is funded by a BHF Chair award (CH/12/2/29428)., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Rationale: Adults with a recent fracture have a high imminent risk of a subsequent fracture. We hypothesise that, like subsequent fracture risk, fall risk is also highest immediately after a fracture. This study aims to assess if fall risk is time-dependent in subjects with a recent fracture compared to subjects without a fracture., Methods: This retrospective matched cohort study used data from the UK Clinical Practice Research Datalink GOLD. All subjects ≥50 years with a fracture between 1993 and 2015 were identified and matched one-to-one to fracture-free controls based on year of birth, sex and practice. The cumulative incidence and relative risk (RR) of a first fall was calculated at various time intervals, with mortality as competing risk. Subsequently, analyses were stratified according to age, sex and type of index fracture., Results: A total of 624,460 subjects were included; 312,230 subjects with an index fracture, matched to 312,230 fracture-free controls (71% females, mean age 70 ± 12, mean follow-up 6.5 ± 5 years). The RR of falls was highest in the first year after fracture compared to fracture-free controls; males had a 3-fold and females a 2-fold higher risk. This imminent fall risk was present in all age and fracture types and declined over time. A concurrent imminent fracture and mortality risk were confirmed., Conclusion/discussion: This study demonstrates an imminent fall risk in the first years after a fracture in all age and fracture types. This underlines the need for early fall risk assessment and prevention strategies in 50+ adults with a recent fracture., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Introduction: In recent years, the number of general practices contributing to the Clinical Practice Research Datalink (CPRD) database GOLD is decreasing. Therefore, for research questions addressing for instance novel treatments requiring up-to-date data, sample size will become an important consideration in study feasibility. In recent years, CPRD Aurum, containing information of practices that use EMIS software, has become an additional data source that is being used for CPRD studies. In order to establish whether Aurum is suited to act as data source for future studies in the field of lung cancer research, we aimed to compare characteristics between patients with lung cancer in Aurum and GOLD., Methods: A retrospective study was performed comparing characteristics and overall survival (OS) of patients with lung cancer in Aurum and GOLD. To further evaluate similarity, hypothetical eligibility of these patients in Aurum and GOLD was compared for 11 randomized clinical trials (RCTs)., Results: Baseline characteristics registered in Aurum and GOLD were largely similar, with some clinically irrelevant differences for previous malignancies, deviant laboratory values and drug use. Median OS was 9.8 and 9.0 months for patients in Aurum and GOLD, respectively. Potential RCT eligibility varied between 49.4% and 79.5% and 49.1% and 78.1% for patients in Aurum and GOLD, respectively. Mortality rates and the comparison of the obtained HRs per hypothetical eligibility cohort per RCT were similar in Aurum and GOLD., Conclusion: This study showed that data of patients with lung cancer in Aurum and GOLD are largely comparable, suggesting that Aurum is suitable for future epidemiological lung cancer research., (© 2023 The Authors. Pharmacoepidemiology and Drug Safety published by John Wiley & Sons Ltd.)

Aims: Previous studies suggest relatively increased cardiovascular risk after COVID-19 infection. This study assessed incidence and explored individual risk and timing of cardiovascular disease occurring post-COVID-19 in a large primary care database., Methods and Results: Data were extracted from the UK's Clinical Practice Research Datalink. Incidence rates within 180 days post-infection were estimated for arterial or venous events, inflammatory heart disease, and new-onset atrial fibrillation or heart failure. Next, multivariable logistic regression models were developed on 220 751 adults with COVID-19 infection before 1 December 2020 using age, sex and traditional cardiovascular risk factors. All models were externally validated in (i) 138 034 vaccinated and (ii) 503 404 unvaccinated adults with a first COVID-19 infection after 1 December 2020. Discriminative performance and calibration were evaluated with internal and external validation. Increased incidence rates were observed up to 60 days after COVID-19 infection for venous and arterial cardiovascular events and new-onset atrial fibrillation, but not for inflammatory heart disease or heart failure, with the highest rate for venous events (13 per 1000 person-years). The best prediction models had c -statistics of 0.90 or higher. However, <5% of adults had a predicted 180-day outcome-specific risk larger than 1%. These rare outcomes complicated calibration., Conclusion: Risks of arterial and venous cardiovascular events and new-onset atrial fibrillation are increased within the first 60 days after COVID-19 infection in the general population. Models' c -statistics suggest high discrimination, but because of the very low absolute risks, they are insufficient to inform individual risk management., Competing Interests: Conflict of interest: none declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: Low-dose rivaroxaban has been indicated for the management of atherosclerotic cardiovascular disease (ASCVD) after recent (2019-2020) updates to European guidelines. We aimed to describe prescription trends of low-dose rivaroxaban in ASCVD patients over the period 2015-2022 in two European countries, to compare the trends before and after guideline changes, and to determine the characteristics of users., Methods: In a cross-sectional interrupted time series analysis, utilization of low-dose rivaroxaban (2.5 mg, twice daily) was measured in Clinical Practice Research Datalink Aurum (United Kingdom [UK]) and the PHARMO Database Network (the Netherlands) from 1 January 2015 to 28 February 2022 in patients with an ASCVD diagnosis. Incidence rates (IRs) and incidence rate ratios (IRRs) of new use (within 182 days) compared to the reference period, 2015-2018, were calculated. Age, sex and comorbidities of users were compared to those of nonusers., Results: In the UK, from 721 271 eligible subjects the IR of new use of low-dose rivaroxaban in the period 2015-2018, before guideline changes, was 12.4 per 100 000 person-years and after guideline changes in 2020-2022 was 124.0 (IRR 10.0, 95% confidence interval [CI] 8.5, 11.8). In the Netherlands from 394 851 subjects, the IR in 2015-2018 was 2.4 per 100 000 person-years and in 2020 was 16.3 (IRR 6.7, 95% CI 4.0, 11.4). Users were younger (UK mean difference [MD] -6.1 years, Netherlands -2.4 years; P < .05) and more likely to be male (UK difference 11.5%, Netherlands 13.4%; P < .001) than nonusers., Conclusions: There was a statistically significant increase in the use of low-dose rivaroxaban for the management of ASCVD after guideline changes in the UK and the Netherlands. There were international differences, but low-dose rivaroxaban has not been put into widespread practice., (© 2023 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Introduction: Since being designated as medicines by World Health Organization (WHO), blood components are subject to pharmacovigilance reporting. Using VigiBase, the WHO global database of individual case safety reports (ICSRs), we characterized reports of adverse reactions for all blood products., Study Design and Methods: ICSRs involving blood products as the suspected medicine in VigiBase between 1968 and 2021 were extracted. MedDRA preferred terms and the International Society of Blood Transfusion haemovigilance definitions were used to stratify adverse reactions. Descriptive statistics were used to characterize ICSR demographics., Results: A total of 111,033 ICSRs containing 577,577 suspected adverse reactions with 6152 MedDRA preferred terms were reported for 34 blood products. There were 12,153 (10.9%) reports for blood components, 98,135 (88.4%) reports for plasma-derived medicines, and 745 (0.7%) reports for recombinant products. The majority of reports (21.0% and 19.7%, respectively) were from patients aged 45-64 and over 65 years. The Americas contributed the most ICSRs (49.7%). Top reported suspected adverse reactions were for the following MedDRA preferred terms: headache (3.5%), pyrexia (2.8%), chills (2.8%), dyspnoea (1.8%), and nausea (1.8%)., Conclusion: VigiBase already has a large number of reports on blood products. When compared to other existing haemovigilance databases, our study found reports from a broader range of countries and reporters. This may provide us with new perspectives, but for VigiBase to reach its full potential in haemovigilance some alterations in what is captured in reports are required., (© 2023 The Authors. Transfusion published by Wiley Periodicals LLC on behalf of AABB.)

Pharmacogenomic testing is a method to prevent adverse drug reactions. Pharmacogenomics could be relevant to optimize statin treatment, by identifying patients at high risk for adverse drug reactions. We aim to investigate the clinical validity and utility of pre-emptive pharmacogenomics screening in primary care, with SLCO1B1 c.521T>C as a risk factor for statin-induced adverse drug reactions. The focus was on changes in therapy as a proxy for adverse drug reactions observed in statin-users in a population-based Dutch cohort. In total, 1136 statin users were retrospectively genotyped for the SLCO1B1 c.521T>C polymorphism (rs4149056) and information on their statin dispensing was evaluated as cross-sectional research. Approximately half of the included participants discontinued or switched their statin treatment within three years. In our analyses, we could not confirm an association between the SLCO1B1 c.521T>C genotype and any change in statin therapy or arriving at a stable dose sooner in primary care. To be able to evaluate the predictive values of SLCO1B1 c.521T>C genotype on adverse drug reactions from statins, prospective data collection of actual adverse drug reactions and reasons to change statin treatment should be facilitated.

Aims: Sodium-glucose cotransporter-2 inhibitors (SGLT-2is) are antidiabetic agents that can have direct cardiac effects by impacting on cardiac ion transport mechanisms that control cardiac electrophysiology. We studied the association between SGLT-2i use and all-cause mortality and the risk of sudden cardiac arrest (SCA) in patients with type 2 diabetes., Methods: Using data from the UK Clinical Practice Research Datalink, a cohort study among patients initiating a new antidiabetic drug class on or after January 2013 through September 2020 was conducted. A Cox regression with time-dependent covariates was performed to estimate the hazard ratios (HRs) of SCA and all-cause mortality comparing SGLT-2is with other second- to third-line antidiabetic drugs. Stratified analyses were performed according to sex, diabetes duration (<5 or ≥5 years), and the presence of cardiovascular disease., Results: A total of 152 591 patients were included. Use of SGLT-2i was associated with a reduced HR of SCA when compared with other second- to third-line antidiabetic drugs after adjustment for common SCA risk factors, although this association marginally failed to reach statistical significance [HR: 0.62, 95% confidence interval (95% CI): 0.38-1.01]. The HR of all-cause mortality associated with SGLT-2i use when compared with other second- to third-line antidiabetics was 0.43 (95% CI: 0.39-0.48) and did not vary by sex, diabetes duration, or the presence of cardiovascular disease. SGLT-2i use remained associated with lower all-cause mortality in patients without concomitant insulin use (HR: 0.56, 95% CI: 0.50-0.63)., Conclusion: SGLT-2i use was associated with reduced all-cause mortality in patients with type 2 diabetes. The association between use of SGLT-2i and reduced risk of SCA was not statistically significant., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: People with multiple sclerosis (pwMS) have an increased risk of infections; risk factors include underlying disease, physical impairment and use of some disease-modifying treatments., Objective: To quantify changes in population-level infection rates among pwMS and compare these to the general population and people with rheumatoid arthritis (pwRA), and identify patient characteristics predictive of infections after MS diagnosis., Methods: We conducted a multi-database study using data on 23,226 people with MS diagnosis from the UK Clinical Practice Research Datalink Aurum and GOLD (January 2000-December 2020). PwMS were matched to MS-free controls and pwRA. We calculated infection rates, and estimated incidence rate ratios (IRR) and 95% confidence intervals (CI) of predictors for infections ⩽ 5 years after MS diagnosis using Poisson regression., Results: Among pwMS, overall infection rates remained stable - 1.51-fold (1.49-1.52) that in MS-free controls and 0.87-fold (0.86-0.88) that in pwRA - although urinary tract infection rate per 1000 person-years increased from 98.7 (96.1-101) (2000-2010) to 136 (134-138) (2011-2020). Recent infection before MS diagnosis was most predictive of infections (1 infection: IRR 1.92 (1.86-1.97); ⩾2 infections: IRR 3.00 (2.89-3.10))., Conclusion: The population-level elevated risk of infection among pwMS has remained stable despite the introduction of disease-modifying treatments.

Purpose: National regulators in Australia and the United Kingdom issued safety advisories on the association between pioglitazone use and bladder cancer in July 2011. The Australian advisory noted that males were at higher risk of bladder cancer than females, while the UK advisory highlighted a new recommendation, suggest careful consideration in the elderly due to increasing risk with age. This study examined whether these differences in the advisories had different age- and sex-based impacts in each country., Methods: Interrupted time series analysis was used to compare pioglitazone use (prescriptions/100000 population) in Australia and the United Kingdom for the 24 months before and 11 months after the July 2011 safety advisories (study period July 2009-June 2012). Separate models were used to compare use by sex and age group (≥65 years vs. <65 years) in each country., Results: Pioglitazone use fell in Australia (17%) and the United Kingdom (24%) following the safety advisories. Use of pioglitazone fell more for males (18%) than females (16%) in Australia, and more for females (25%) than males (23%) in the United Kingdom; however, neither difference was statistically significant (Australia p = 0.445, United Kingdom p = 0.462). Pioglitazone use fell to a similar extent among older people than younger people in the United Kingdom (23% vs. 26%, p = 0.354), and did not differ between age groups in Australia (both 18%, p = 0.772)., Conclusions: The results indicate that differences in the Australian and UK safety advisories resulted in substantial reductions in pioglitazone use at the population level in both countries, however, differences by sub-groups were not observed., (© 2022 The Authors. Pharmacoepidemiology and Drug Safety published by John Wiley & Sons Ltd.)

Purpose: In this descriptive study, we examined the incidence of fractures in patients with newly treated type 2 diabetes mellitus (T2D) compared to matched reference population., Methods: Participants from the UK Clinical Practice research datalink (CPRD) GOLD (1987-2017), aged ≥30 years, with a T2D diagnosis code and a first prescription for a non-insulin anti-diabetic drug (n = 124,328) were included. Cases with T2D were matched by year of birth, sex and practice to a reference population (n = 124,328), the mean follow-up was 7.7 years. Crude fracture incidence rates (IRs) and incidence rate ratios (IRRs) were calculated. Analyses were stratified by fracture site and sex and additionally adjusted for BMI, smoking status, alcohol use and history of any fracture at index date., Results: The IR of all fractures and major osteoporotic fractures was lower in T2D compared to the reference population (IRR 0.97; 95%CI 0.94-0.99). The IRs were lower for clavicle (IRR 0.67; 0.56-0.80), radius/ulna (IRR 0.81; 0.75-0.86) and vertebral fractures (0.83; 0.75-0.92) and higher for ankle (IRR 1.16; 95%CI 1.06-1.28), foot (1.11; 1.01-1.22), tibia/fibula (1.17; 1.03-1.32) and humerus fractures (1.11; 1.03-1.20). Differences in IRs at various fracture sites between T2D and the reference population were more pronounced in women than in men. In contrast, BMI adjusted IRs for all fractures (IRR 1.07; 1.04-1.10) and most individual fracture sites were significantly higher in T2D, especially in women., Conclusion: The crude incidence of all fractures was marginally lower in patients with newly treated T2D compared to the matched reference population but differed according to fracture site, especially in women. BMI adjusted analyses resulted in higher incidence rates in T2D at almost all fracture sites compared to crude incidence rates and this was more pronounced in women than in men. This implies that BMI may have a protective impact on the crude incidence of fractures, especially in women with newly treated T2D., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Joop van den Bergh is involved in research that is sponsored by Amgen, Eli Lilly and UCB. Peter Vestergaard is head of research in the Steno Diabetes Center North Jutland sponsored by the Novo Nordisk Foundation. The other authors, Cindy Sarodnik, Nicklas Rasmussen, Sandrine Bours, Nicolaas Schaper, Patrick Souverein, Morten Jensen, and Johanna Driessen, declare that they have no conflict of interest., (© 2022 The Authors.)

Aim: Activated blood platelet products facilitate myocardial intracellular Ca2+ overload, thereby provoking afterdepolarizations and increasing susceptibility of ischemic myocardium to ventricular fibrillation (VF). These effects are counteracted in vitro by acetylsalicylic acid (ASA), but no prior study investigated whether ASA is associated with decreased out-of-hospital cardiac arrest (OHCA) risk on a population level. Therefore, we studied whether ASA and other antiplatelet drugs (carbasalate calcium, clopidogrel) are associated with decreased risk of OHCA., Methods: We conducted a population-based case-control study among individuals (772 OHCA-cases with documented VT/VF, 2444 non-OHCA-controls) who had used antiplatelet drugs in the year before index-date (OHCA-date), and studied the association between current antiplatelet drug use and OHCA-risk with multivariable logistic regression analysis., Results: ASA use was associated with reduced OHCA-risk (adjusted odds ratio (ORadj) 0.6 [0.5-0.8]), and more so in women (ORadj 0.3 [0.2-0.6]) than in men (ORadj 0.7 [0.5-0.95], Pinteraction 0.021). Carbasalate calcium was associated with decreased OHCA-risk in women (ORadj 0.5 [0.3-0.9]), but not in men (ORadj 1.3 [0.96-1.7], Pinteraction 0.005). Clopidogrel was not associated with reduction in OHCA-risk. Risk reduction associated with ASA in patients with OHCA was similar in the presence of acute myocardial infarction (AMI) (ORadj 0.6 [0.4-0.9]) and in the absence of AMI (ORadj 0.7 [0.4-1.2])., Conclusion: ASA use was associated with reduced OHCA-risk in both sexes, and more so in women, while carbasalate calcium only protected women. Clopidogrel was not associated with reduced OHCA-risk., Competing Interests: The authors have declared that no competing interests exist.

Introduction: Regulatory advisories on hydroxyzine and risk of QT prolongation and Torsade de pointes (TdP) were issued in the UK in April 2015 and Canada in June 2016. We hypothesized patients with risk factors for QT prolongation and TdP, compared with those without risk factors, would be less likely to initiate hydroxyzine in the UK and in British Columbia (BC), Canada, following advisories., Methods: We conducted a longitudinal study with repeated measures, and evaluated hydroxyzine initiation in a UK cohort and a concurrent BC control cohort (April 2013-March 2016) as well as in a BC advisory cohort (June 2014-May 2017)., Results: This study included 247,665 patients in the UK cohort, 297,147 patients in the BC control cohort, and 303,653 patients in the BC advisory cohort. Over a 12-month post-advisory period, hydroxyzine initiation decreased by 21% in the UK (rate ratio 0.79, 95% confidence interval 0.66-0.96) relative to the expected level of initiation based on the pre-advisory trend. Hydroxyzine initiation did not change in the BC control cohort or following the Canadian advisory in the BC advisory cohort. The decrease in hydroxyzine initiation in the UK in the 12 months after the advisories was not significantly different for patients with risk factors compared with those without risk factors., Conclusion: Hydroxyzine initiation decreased in the UK, but not in BC, in the 12 months following safety advisories. The decrease in hydroxyzine initiation in the UK was not significantly different for patients with versus without risk factors for QT prolongation and TdP., (© 2022. The Author(s).)

Aims: Opioid use has substantially increased in the last decade and is associated with overdose mortality, but also with increased mortality from cardiovascular causes. This finding may partly reflect an association between opioids and out-of-hospital cardiac arrest (OHCA). Therefore, we aimed to investigate OHCA-risk of opioids in the community., Methods: We conducted 2 population-based case-control studies separately in the Netherlands (2009-2018) and Denmark (2001-2015). Cases were individuals who experienced OHCA of presumed cardiac cause. Each case was matched with up to 5 non-OHCA-controls according to age, sex and OHCA-date. Conditional logistic regression analysis was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs)., Results: We included 5473 OHCA-cases matched with 21 866 non-OHCA-controls in the Netherlands, and 35 017 OHCA-cases matched with 175 085 non-OHCA-controls in Denmark. We found that use of opioids (the Netherlands: cases: 5.4%, controls: 1.8%; Denmark: cases: 11.9%, controls: 4.4%) was associated with increased OHCA-risk in both regions (the Netherlands: OR 2.1 [95% CI 1.8-2.5]; Denmark: OR 1.8 [95% CI 1.5-2.1]). The association was observed in both sexes, and in individuals with cardiovascular disease (the Netherlands: OR 1.8 [95% CI 1.5-2.1]; Denmark: OR 1.6 [95% CI 1.5-1.7]) or without (the Netherlands: OR 3.4 [95% CI: 2.4-4.8], P interaction  < .0001; Denmark: OR 2.3 [95% CI: 2.0-2.5], P interaction  < .0001)., Conclusion: Use of opioids is associated with increased OHCA-risk in both sexes, independently of concomitant cardiovascular disease. These findings should be considered when evaluating the harms and benefits of treatment with opioids., (© 2021 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Background: Dopamine receptor agonist drugs, which are used, for example, to treat Parkinson's disease (PD), increase the risk for impulse control disorders (ICDs), potentially resulting in devastating psychosocial consequences. It is unknown whether other drugs with dopaminergic properties also increase the risk for ICDs. This study assesses the disproportionality of reporting ICDs between drugs with dopaminergic properties and selected non-dopaminergic drugs., Methods: A case/non-case disproportionality analysis was performed, using data from VigiBase (1968-2020). Reports on ICDs as suspected adverse drug reactions (ADRs) were cases (n=852), and those with ADRs other than ICDs were non-cases (n=281,720). Relative reporting frequencies were expressed as adjusted reporting odds ratios (aRORs). Within the dopamine receptor agonists, the relationship between reporting odds ratios and dopamine receptor occupancy was explored., Results: A high disproportionality was found for reporting ICDs for all dopaminergic drugs (aROR 20.4 [95% CI 17.4-24.1]) compared to non-dopaminergic drugs. In pharmacotherapeutic subgroups, a high disproportionality was found for primary dopaminergic agents used in PD (aROR 52.1 [95% CI 44.1-61.5]), and to a lesser extent for ADHD psychostimulants and antidepressants (aROR 5.8 [95% 4.1-8.3] and aROR 3.9 [95% CI 2.9-5.6], respectively). There was no difference in reporting by consumers and healthcare professionals. The highest disproportionality was found for the dopamine receptor agonists pramipexole and ropinirole., Conclusions: A signal of disproportion in ICD occurrence was found among all investigated drugs with dopaminergic properties, highlighting the importance of counselling and monitoring for ICDs when prescribing dopaminergic drugs., Competing Interests: Declaration of Competing Interest drs. L.E. De Wit has nothing to disclose, dr. I. Wilting has nothing to disclose, dr. P.C. Souverein has nothing to disclose, dr. P. van der Pol has nothing to disclose, prof.dr. A.C.G. Egberts has nothing to disclose, (Copyright © 2022. Published by Elsevier B.V.)

Background: Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), commonly used antihypertensive drugs, may have a protective effect against depression in older individuals, but evidence in humans is limited., Aims: We evaluated the risk of depression, among older individuals with hypertension, comparing ACE or ARB initiators to thiazide(-like) diuretic initiators. Thiazide(-like) diuretics were used as control because these drugs are not associated with mood disorders., Methods: We used a propensity score-matched new user cohort design with routinely collected data from general practices in England from the Clinical Practice Research Datalink database. We matched 12,938 pairs of new users of ACEIs/ARBs and thiazide(-like) diuretics with hypertension (mean age 67.6 years; 54.7% women). Follow-up time started on the date of drug initiation and ended on the date of treatment discontinuation plus 30 days, or switch to a comparator, occurrence of a study event, death, date of patient's transfer out of practice, or end of the study period. The primary outcome was a composite endpoint of treated depression and nonfatal and fatal self-harm., Results/outcomes: Compared to the thiazide(-like) diuretic group, ACEIs/ARBs use was not associated with a lower risk of the primary outcome (hazard ratio 0.96 (95% confidence interval: 0.79; 1.15)). Results did not differ according to lipophilicity, duration of use, and average daily dose, or class (ACEIs or ARBs)., Conclusions/interpretation: New use of ACEIs or ARBs is not associated with a lower risk of depression among individuals with hypertension.

Background: Antidepressant drug consumption has increased, mainly in the elderly. This trend could be explained by the use for indications other than depression. We aimed to describe the indications related to antidepressant drug new users in two primary care settings., Methods: A longitudinal study of new antidepressant users aged ≥65 was conducted, with data from the Nivel-PCD (The Netherlands) and SIDIAP (Catalonia) databases (2010-2015). As a proxy for indication, diagnoses registered around the 3 months of antidepressant prescribing were collected. Indications were classified in seven categories and an additional one of non-selected indications. The percentage and incidence calculated over the total population registered was described., Results: A total of 16,537 and 199,168 new antidepressant users were identified in the Nivel-PCD and SIDIAP databases, respectively (women aged 65-69 were the most prevalent). Depression was the most frequent indication (24.0% and 31.3%), followed by anxiety (12.5% and 19.5%) and sleep disorders (10.2% and 26.4%). Tricyclic antidepressants were the most commonly prescribed in Nivel-PCD (48.7%), mainly associated with neuropathic pain, and selective serotonin reuptake inhibitor antidepressants in SIDIAP (63.1%), associated with depression. The non-selected indications category showed an upward trend in the Nivel-PCD database while in the SIDIAP database it decreased., Limitations: It is not mandatory for physicians to register a diagnosis with each prescription., Conclusions: Depression was the most common prescribing indication in The Netherlands and Spain, followed by anxiety and sleep disorders. The most commonly prescribed antidepressant differed between the countries and is likely explained by differences in local guidelines., (Copyright © 2022. Published by Elsevier B.V.)

Objectives: Clinical trials have shown that low-dose glucocorticoid therapy in patients with RA reduces bone loss in hands or hip, but the effect on osteoporotic fractures is not yet clear. Therefore, we investigated the use of low-dose oral glucocorticoids and risk of osteoporotic fractures among patients with RA., Methods: This was a cohort study including patients with RA aged 50+ years from the Clinical Practice Research Datalink between 1997 and 2017. Exposure to oral glucocorticoids was stratified by the most recent prescription in current (<6 months), recent (7-12 months) and past (>1 year) use, and average daily and cumulative doses. Risk of incident osteoporotic fractures (including hip, vertebrae, humerus, forearm, pelvis and ribs) was estimated by time-dependent Cox proportional-hazards models, adjusted for lifestyle parameters, comorbidities and comedications. Secondary analyses assessed osteoporotic fracture risk with a combination of average daily and cumulative doses of oral glucocorticoids., Results: Among 15 123 patients with RA (mean age 68.8 years, 68% females), 1640 osteoporotic fractures occurred. Current low-dose oral glucocorticoid therapy (≤7.5 mg prednisolone equivalent dose/day) in patients with RA was not associated with overall risk of osteoporotic fractures (adjusted hazard ratio 1.14, 95% CI 0.98, 1.33) compared with past glucocorticoid use, but was associated with an increased risk of clinical vertebral fracture (adjusted hazard ratio 1.59, 95% CI 1.11, 2.29). Results remained unchanged regardless of a short-term or a long-term use of oral glucocorticoids., Conclusion: Clinicians should be aware that even in RA patients who receive low daily glucocorticoid doses, the risk of clinical vertebral fracture is increased., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Aim: Drugs causing QT-prolongation as off-target effect [non-cardiac QT-prolonging drugs (QT-drugs)] increase the risk of out-of-hospital cardiac arrest (OHCA). Such drugs are categorized in multiple clinically widely used CredibleMeds.org lists. Category 1 ('known risk of Torsade de Pointes') and category 2 ('possible risk of Torsade de Pointes') are of particular clinical relevance. However, a category-stratified analysis of OHCA-risk is presently unavailable., Methods and Results: We conducted a case-control study with OHCA-cases from presumed cardiac causes included from the ARREST registry in the Netherlands (2009-2018) that was specifically designed to study OHCA, and age/sex/OHCA-date matched non-OHCA-controls. Adjusted odds ratios for OHCA (ORadj) of QT-drugs from categories 1 or 2 were calculated, using conditional logistic regression. Stratified analysis was performed according to sex, age, and presence of cardiovascular drugs (proxy for cardiovascular disease). We included 5473 OHCA-cases (68.8 years, 69.9% men) and matched them to 20 866 non-OHCA-controls. Compared with no use of non-cardiac QT-drugs, drugs of both categories were associated with increased OHCA-risk, but seemingly weaker for category 2 {category 1: case 3.2%, control 1.4%, ORadj 1.7 [95% confidence interval (CI): 1.3-2.1]}; [category 2: case 7.3%, control 4.0%, ORadj 1.4 (95% CI: 1.2-1.6)]. The increased risk occurred in men and women, at all ages (highest in patients aged ≤50 years), and both in the presence or absence of cardiovascular drug use., Conclusion: Both category 1 and category 2 QT-drugs are associated with increased OHCA-risk in both sexes, at all ages, and in patients taking or not taking cardiovascular drugs., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)