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Purpose To compare the effectiveness and safety of a drug in daily practice with the outcomes of a target non‐inferiority trial by rigorously mimickingin an observational study the trial's design features. Methods This cohort study was conducted using the British Clinical Practice Research Datalink (CPRD) to emulate the ROCKET AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) trial. Patients with atrial fibrillation who were newly prescribed (>=12 months of no use) either rivaroxaban or warfarinfrom October 2008 to December 2017 were included. Non‐inferiority of rivaroxaban to warfarin in the prevention of stroke or systemic embolism was assessed in different analysis populations (intention‐to‐treat [ITT], per‐protocol [PP], and as‐treated populations) using a hazardratio (HR) of 1.46 as the non‐inferiority margin. Major bleeding (safety outcome) was also assessed and compared to that of the target trial. All outcomes were analyzed using Cox‐proportional hazard analyses. Results We included 25,473 incident users of rivaroxaban (n=4,008) or warfarin(n=21,465). Similar to the trial, non‐inferiority in the primary out come was demonstrated in all three analysis populations: HR=1.04 (95%CI 0.84 to 1.30) (ITT), HR=0.98 (95%CI 0.70 to 1.38) (PP), and HR=1.11 (95%CI 0.86 to 1.42) (as‐treated). Risk of major bleeding was also similar to the target trial. Conclusion The results of this study provide supportive evidence to the effectiveness of rivaroxaban and adds knowledge on the usefulness of emulating a non‐inferiority trial to assess drug effectiveness.

Background and Purpose: Statins are frequently initiated in patients aged 80 years and older after an ischemic stroke, even though evidence on prevention of recurrent cardiovascular disease is scarce. In this study, we seek evidence for statin prescription in the oldest old. Methods: We performed a retrospective cohort study in patients aged 65 years and older hospitalized for a first ischemic stroke between 1999 and 2016 without statin prescriptions in the year before hospitalization using the Clinical Practice Research Datalink. The age group 65 to 80 years was included to compare our results to current evidence on statin efficacy. The primary outcome was a composite of recurrent stroke, myocardial infarction, and cardiovascular mortality. The secondary outcome was all-cause mortality. A time-varying Cox model was used to account for statin prescription over time. We compared at least 2 years of statin prescription time with untreated and Results: Five thousand nine hundred ten patients, aged 65 years and older were included, of whom 3157 were 80 years and older. Two years of statin prescription in patients aged 80 years and older resulted in both a lower risk of the composite end point (adjusted hazard ratio, 0.80 [95% CI, 0.62–1.02]) and all-cause mortality (adjusted hazard ratio, 0.67 [95% CI, 0.57–0.80]). After correction for the mortality of 23.9% of the patients during the first 2 years, the number needed to treat was 64 for the primary outcome during a median follow-up of 3.9 years and 19 for all-cause mortality. Conclusions: Statins initiated in patients aged 80 and older, discharged home after hospitalization for an ischemic stroke are associated with a reduction in cardiovascular events.

Background and objectives Nonsteroidal anti-inflammatory drugs (NSAIDs) have been associated with AKI. Their association with nephrotic syndrome has not been systematically studied. This study aimed to assess the risk of nephrotic syndrome associated with NSAID use. Design, setting, participants, & measurements A matched case-control study was performed in the UK primary care database. Cases were patients with a first diagnosis of nephrotic syndrome and controls were those without nephrotic syndrome. NSAID exposure (grouped either based on cyclooxygenase enzyme selectivity and chemical groups) was classified as either current (use at the nephrotic syndrome diagnosis date and corresponding date in the control group), recent, or past use. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated using unconditional logistic regression analysis. Results We included 2620 cases and 10,454 controls. Compared with non-use, current use of 15–28 days and >28 days of conventional NSAIDs was associated with a higher relative risk of nephrotic syndrome: adjusted OR, 1.34; 95% CI, 1.06 to 1.70, and OR, 1.42; 95% CI, 0.79 to 2.55, respectively. Also, recent use (discontinuation 1–2 months before nephrotic syndrome diagnosis date; OR, 1.55; 95% CI, 1.11 to 2.15) and past use (discontinuation 2 months-2 years; OR, 1.24; 95% CI, 1.07 to 1.43), but not current use of 2 years; OR, 0.96; 95% CI, 0.85 to 1.09) were associated with a higher relative risk of nephrotic syndrome as well as past use of selective COX-2 inhibitors (discontinuation 2–24 months; OR, 1.24; 95% CI, 0.98 to 1.58). Categorization based on chemical groups showed that acetic acid and propionic acid derivatives were associated with a higher risk of nephrotic syndrome. Conclusions The use of conventional NSAIDs was associated with a higher risk of nephrotic syndrome starting from at least 2 weeks of exposure, as well as for recent and past exposure up to 2 years before the diagnosis of nephrotic syndrome. This higher risk appeared mainly attributable to acetic acid and propionic acid derivatives.

The reporting of hypersensitivity reactions (HSRs) among non-steroidal anti-inflammatory drugs (NSAIDs) according to cyclooxygenase (COX) selectivity and chemical groups has not been published yet in one study. This study assessed the reporting frequency of HSRs for NSAIDs based on their relative inhibitory potency towards COX enzymes and chemical groups, including the presence/absence of a functional sulfonamide group, in strata of 5 years after market authorization. A case/non-case study was performed among Individual Case Safety Reports (ICSRs) with NSAIDs as suspected drugs in VigiBase, the WHO spontaneous reporting database. Cases were ICSRs mentioning angioedema and anaphylactic/anaphylactoid shock conditions, while non-cases were ICSRs without HSRs. NSAIDs were categorized into (i) NSAIDs with highly COX-2 selectivity (coxibs), (ii) Non-coxib NSAIDs with COX-2 preference, (iii) NSAIDs with poor selectivity, or (iv) NSAIDs with unknown selectivity. Chemical groups were defined based on the Anatomical Therapeutic Chemical classification system and the presence/absence of a functional sulfonamide group. Reporting odds ratios (RORs) and 95% confidence intervals (95% CIs) were calculated using logistic regression analysis. We identified 13,229 cases and 106,444 non-cases. In the first 5 years after marketing, poor selectivity NSAIDs and acetic acid derivatives were associated with the highest ROR of HSRs (age- and sex-adjusted ROR 2.12, 95%CI: 1.98-2.28 and ROR 2.21, 95%CI: 1.83-2.66, respectively), all compared to coxibs, and also sulfonamide NSAIDs compared to non-sulfonamide NSAIDs (age- and sex-adjusted ROR 1.38, 95%CI: 1.29-1.47). After the first 5 years of marketing, most of the RORs returned to approximately 1. This article is protected by copyright. All rights reserved.

Aims Non-steroidal anti-inflammatory drugs (NSAIDs), particularly selective COX-2 inhibitors, are associated with an in-creased risk of cardiovascular adverse events. However, the association between these drugs and out-of-hospitalcardiac arrest with electrocardiogram-documented ventricular tachycardia/ventricular fibrillation (VT/VF-OHCA)has not been studied yet. This study was aimed to evaluate the association between the use of selective COX-2inhibitors or conventional NSAIDs and VT/VF-OHCA compared with non-use .................................................................................................................................................................................................... Methods and results A case–control study was conducted among 2483 cases with VT/VF-OHCA from the AmsteRdam REsuscitationSTudies (ARREST) registry, an ongoing Dutch registry of OHCA, and 10 441 non-VT/VF-OHCA-controls from theDutch PHARMO Database Network, containing drug dispensing records of community pharmacies, over the pe-riod July 2005–December 2011. Up to five controls were matched for age and sex to one case at the date of VT/VF-OHCA (index date). Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by conditional logis-tic regression analysis. Of the cases, 0.5% was currently exposed at the index date to selective COX-2 inhibitorsand 2.5% to conventional NSAIDs. Neither current use of selective COX-2 inhibitors nor conventional NSAIDs were associated with an increased risk of VT/VF-OHCA (adjusted OR 1.11, 95% CI: 0.79–1.56 and adjusted OR0.97, 95% CI: 0.86–1.10, respectively) compared with non-use. Stratification for VT/VF-OHCA with presence/ab-sence of acute myocardial infarction did not change these results .................................................................................................................................................................................................... Conclusion Exposure to selective COX-2 inhibitors or conventional NSAIDs was not associated with an increased risk of VT/VF-OHCA compared with non-use.

OBJECTIVES: Laboratory monitoring of patients using lithium is important to prevent harm and to increase effectiveness. The aim of this study is to determine compliance with the guidelines for laboratory monitoring of patients treated with lithium overall and within subgroups. METHODS: Patients having at least one lithium dispensing for six months or longer between January 2010 and December 2015 were identified retrospectively using data from the Dutch PHARMO Database Network. Laboratory monitoring was defined as being compliant with the Dutch Multidisciplinary Clinical Guideline Bipolar Disorders when lithium serum levels, creatinine and thyroid-stimulating hormone (TSH) had been measured at least every six months during lithium use. RESULTS: Data were analyzed from 1,583 patients with a median duration of seven six-month periods of lithium use. Results indicated that patients had been monitored over six-month periods for lithium serum levels 65% of the time, for creatinine 73% of the time and for TSH 54% of the time. Just over one seventh (16%) of patients had been monitored in compliance with the guidelines for all three parameters during total follow-up. Especially males, patients aged below 65 years, patients receiving prescriptions solely from general practitioners, prevalent users of lithium, patients without interacting co-medication, and patients without other days with laboratory measurements had been monitored less frequently in compliance with the guidelines. CONCLUSION: A considerable proportion of patients had not been monitored in accordance with the guidelines. Further research is needed to understand the reasons for noncompliance and to implement strategies with the ultimate goal of optimizing safety and effectiveness for patients treated with lithium. This article is protected by copyright. All rights reserved.

Background Patients with rheumatoid arthritis (RA) commonly use oral glucocorticoids (GCs) and proton pump inhibitors (PPIs), both associated with osteoporotic fractures. We investigated the association between concomitant use of oral GCs and PPIs and the 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 GCs and PPIs was stratified by the most recent prescription as current use (1 year); average daily and cumulative dose; and duration of use. The risk of incident osteoporotic fractures (including hip, vertebrae, humerus, forearm, pelvis and ribs) was estimated by time-dependent Cox proportional-hazards models, statistically adjusted for lifestyle parameters, comorbidities and comedications. Results Among 12 351 patients with RA (mean age of 68 years, 69% women), 1411 osteoporotic fractures occurred. Concomitant current use of oral GCs and PPIs was associated with a 1.6-fold increased risk of osteoporotic fractures compared with non-use (adjusted HR: 1.60, 95% CI: 1.35 to 1.89). This was statistically different from a 1.2-fold increased osteoporotic fracture risk associated with oral GC or PPI use alone. Most individual fracture sites were significantly associated with concomitant use of oral GCs and PPIs. Among concomitant users, fracture risk did not increase with higher daily dose or duration of PPI use. Conclusions There was an interaction in the risk of osteoporotic fractures with concomitant use of oral GCs and PPIs. Fracture risk assessment could be considered when a patient with RA is co-prescribed oral GCs and PPIs. The authors would like to acknowledge Keele University's Prognosis and Consultation Epidemiology Research Group who have given us permission to use the morbidity definitions/categorisations lists ((c) 2014). The copyright of the morbidity definitions/categorisations lists ((c) 2014) used in this paper is owned by Keele University, the development of which was supported by the Primary Care Research Consortium. For access/details relating to the morbidity definitions/categorisation lists ((c) 2014), please go to www.keele.ac.uk/mrr.The authors would also like to acknowledge Ard van Veelen from Maastricht University Medical Centre for double--checking the accuracy of tables and figures. de Vries, F (corresponding author), Univ Utrecht, Utrecht Inst Pharmaceut Sci, Div Pharmacoepidemiol & Clin Pharmacol, POB 80082, NL-3508 TB Utrecht, Netherlands. f.devries@uu.nl

Aims Drug exposure status based on routinely collected data might be misclassified when the database contains only prescriptions from 1 type of prescriber (e.g. general practitioner and not specialist). This study aims to quantify the impact of such exposure misclassification on the risk of major bleeding and stroke/transient ischaemic attack (TIA)associated with direct oral anticoagulants (DOACs) vs. vitamin K antagonists (VKAs). Methods Incident anticoagulant users (>12 mo free of anticoagulation use) in the Dutch PHARMO Database Network between 2008 and 2017 were included. Drug exposure was assessed using pharmacy dispensing information. The risks of hospital admission of major bleeding for DOAC vs. VKA users was assessed with Cox regression analysis, where exposure was based on all dispensings, on general practitioner (GP)-prescribed dispensings only or on specialist-prescribed dispensings only. Hazard ratios (HRs) were estimated also for hospitalization for gastrointestinal bleeding, intracranial bleeding and stroke/TIA. Results We included 99 182 VKA-initiators and 21 795 DOAC-initiators. Use of DOAC was associated with a lower risk of major bleeding compared to VKA use; HR 0.79 (95% confidence interval 0.70-0.90), 0.78 (0.68-0.91) and 0.62 (0.50-0.76), for exposure based on complete dispensing information, only GP- and only specialist-prescribed dispensings, respectively. Similar results were found for the other bleeding outcomes. For stroke/TIA the HRs were 0.96 (0.84-1.09), 1.00 (0.84-1.18) and 0.72 (0.58-0.90), respectively. Conclusion Including only GP-prescribed anticoagulant dispensings in this case did not materially impact the effect estimates compared to including all anticoagulant dispensings. Including only specialist-prescribed dispensings, however, strengthened the effect estimates.

Aims The introduction of direct oral anticoagulants (DOACs) has broadened the treatment arsenal for nonvalvular atrial fibrillation, but observational studies on the benefit-risk balance of DOACs compared to vitamin K antagonists (VKAs) are needed. The aim of this study was to characterize the risk of major bleeding in DOAC users using longitudinal data collected from electronic health care databases from 4 different EU-countries analysed with a common study protocol. Methods A cohort study was conducted among new users (>= 18 years) of DOACs or VKAs with nonvalvular atrial fibrillation using data from the UK, Spain, Germany and Denmark. The incidence of major bleeding events (overall and by bleeding site) was compared between current use of DOACs and VKAs. Cox regression analysis was used to calculate hazard ratios and 95% confidence intervals (CI) and adjust for confounders. Results/Conclusion Overall, 251 719 patients were included across the 4 study cohorts (mean age similar to 75 years, % females between 41.3 and 54.3%), with overall hazard ratios of major bleeding risk for DOACsvsVKAs ranging between 0.84 (95% CI: 0.79-0.90) in Denmark and 1.13 (95% CI 1.02-1.25) in the UK. When stratifying according to the bleeding site, risk of gastrointestinal bleeding was increased by 48-67% in dabigatran users and 30-50% for rivaroxaban users compared to VKA users in all data sources except Denmark. Compared to VKAs, apixaban was not associated with an increased risk of gastrointestinal bleeding in all data sources and seemed to be associated with the lowest risk of major bleeding events compared to dabigatran and rivaroxaban.

Background Antipsychotic drugs are frequently prescribed to older adults, but they may be associated with serious adverse effects. The objective was to investigate the association between use of antipsychotics in older adults and the risk of urinary tract infections (UTIs). Methods Design This study was designed as a cohort study. Setting Data were obtained from the Clinical Practice Research Datalink from January 1, 2000, to September 29, 2016. Participants Primary care patients 65 years or older in the United Kingdom with a first prescription for an oral antipsychotic were included in the study. Measurements Incidence of UTIs was calculated for periods with and without exposure to antipsychotic drugs in one cohort. Cox proportional hazard regression analysis with Andersen-Gill extension for recurrent events was used to calculate hazard ratios (HRs) with 95% confidence interval (CI). Results During the study period, 191,827 individuals with a first prescription for an oral antipsychotic drug were identified. Current use of antipsychotics was associated with an increased risk of UTI compared with past use (adjusted HR, 1.31; 95% CI, 1.28-1.34). This effect was strongest in the first 14 days of use (adjusted HR, 1.83; 95% CI, 1.73-1.95) and in individuals who used more than one antipsychotic drug concomitantly (adjusted HR, 1.64; 95% CI, 1.45-1.87). The risk was slightly higher for typical antipsychotics than for atypical antipsychotics. Stratification by sex showed that risk estimates were slightly higher in men than in women. Conclusions Use of antipsychotics was associated with an increased risk of UTIs in both men and women, particularly in the first weeks after the start of treatment.

Background: Amplitude spectrum area (AMSA) of ventricular fibrillation (VF) has been associated with survival from out-of-hospital cardiac arrest (OHCA). Ischemic heart disease has been shown to change AMSA. We studied whether the association between AMSA and survival changes with acute ST-elevation myocardial infarction (STEMI) as cause of the OHCA and/or previous MI. Methods: Multivariate logistic regression with log-transformed AMSA of first artifact-free VF segment was used to assess the association between AMSA and survival, according to presence of STEMI or previous MI, adjusting for resuscitation characteristics, medication use and comorbidities. Results: Of 716 VF-patients included from an OHCA-registry in the Netherlands, 328 (46%) had STEMI as cause of OHCA. Previous MI was present in 186 (26%) patients. Survival was 66%; neither previous MI (P = 0.11) nor STEMI (P = 0.78) altered survival. AMSA was a predictor of survival (ORadj: 1.52, 95%-CI: 1.28-1.82). STEMI was associated with lower AMSA (8.4 mV-Hz [3.7-16.5] vs. 12.3 mV-Hz [5.6-23.0]; P

Objectives The objective of the study was to identify the reasons for discontinuation of clinical drug trials and to evaluate whether efficacy-related discontinuations were adequately planned in the trial protocol. Study Design and Setting All clinical drug trials in the Netherlands, reviewed by institutional review boards in 2007, were followed until December 2015. Data were obtained through the database of the Dutch competent authority (Central Committee on Research Involving Human Subjects [CCMO]) and a questionnaire to the principal investigators. Reasons for trial discontinuation were the primary outcome of the study. Three reasons for discontinuation were analyzed separately: all cause, recruitment failure, and efficacy related (when an interim analysis had demonstrated futility or superiority). Among the efficacy-related discontinuations, we examined whether the data monitoring committee, the stopping rule, and the moment of the interim analysis in the trial progress were specified in the trial protocol. Results Of the 574 trials, 102 (17.8%) were discontinued. The most common reasons were recruitment failure (33 of 574; 5.7%) and solely efficacy related (30 of 574; 5.2%). Of the efficacy-related discontinuations, 10 of 30 (33.3%) of the trial protocols reported all three aspects in the trial protocol, and 20 of 30 (66.7%) reported at least one aspect in the trial protocol. Conclusion One out of five clinical drug trials is discontinued before the planned trial end, with recruitment failure and futility as the most common reasons. The target sample size of trials should be feasible, and interim analyses should be adequately described in trial protocols.

OBJECTIVES: To characterize reported adverse drug reactions (ADRs) in children and adolescents treated with antipsychotics and determine differences in relative reporting frequency between genders, age classes, and reporter types. METHODS: Individual case safety reports of children ages 1 - 17 years in whom an antipsychotic drug was the suspected or interacting drug from the worldwide database, VigiBase, from 1968 until March 2017, were included. Reported ADRs were categorized based on the Standardized Medical Dictionary for Regulatory Activities (MedDRA) Queries and clinical reasoning. Proportional reporting ratios (PRRs) and 95% confidence intervals (95% CIs) were calculated for genders, age classes, and reporter types. RESULTS: In total, 45,201 reported ADRs were included. The most frequently reported were ADRs related to extrapyramidal syndrome (14.7%), breast disorders or blood prolactin level changes (4.7%), and cardiac arrhythmias (4.6%). Differences in relative reporting frequencies were observed between age classes and reporter types, and less prominent between genders. For example, ADRs related to hyperglycemia/new-onset diabetes mellitus were less frequently reported in children ages 1 - 5 than in children ages 12 - 17 (PRR: 0.4, 95% CI: 0.2 - 0.5). ADRs related to cardiac arrhythmias were less frequently reported by consumers compared with health care professionals (PRR: 0.5, 95% CI: 0.5 - 0.6), whereas ADRs related to a change in weight/body mass index were more frequently reported by consumers (PRR: 3.2, 95% CI: 2.9 - 3.5). CONCLUSION: A wide spectrum of ADRs were reported in children treated with antipsychotics. The relative differences in reporting frequency between age classes and reporter types can be of help to tailor information about possible ADRs and to monitor for ADRs.

Summary What is known and objective Important risk factors and over‐the‐counter (OTC) dispensing of non‐steroidal anti‐inflammatory drugs (NSAIDs) are often not routinely recorded in electronic health records. This study aimed to assess the impact of patient's reports on these factors on the risk of acute myocardial infarction (AMI) for NSAID use. Methods A nested case‐control study was conducted among adults in the Utrecht Cardiovascular Pharmacogenetics study. Cases were patients with a first diagnosis of AMI as a hospital discharge diagnosis and controls were those without AMI. NSAID exposure was either current use of selective COX‐2 inhibitors or conventional NSAIDs. Information was collected from The Dutch PHARMO Database Network (pharmacy records of drug dispensing linked to hospitalization records) and the patient's questionnaire (lifestyle factors, body mass index and history of cardiovascular diseases). Unconditional logistic regression analysis was used to calculate odds ratios (ORs) and to control for confounding factors. Results We identified 970 AMI cases and 2974 controls. Among cases, 11 (1.1%) and 185 (19.1%) were exposed to selective COX‐2 inhibitors and conventional NSAIDs, respectively. Compared to non‐use, none of these drug classes were associated with an increased risk of AMI (adjusted OR 1.07, 95% CI: 0.52‐2.18 and 0.93, 95% CI: 0.77‐1.12, respectively). Additional adjustment for potential confounders from patient's reports did not change the risk estimates (adjusted OR 1.08, 95% CI: 0.53‐2.22 and 0.89, 95% CI: 0.73‐1.09, respectively). What is new and conclusion Additional confounding control for variables from self‐reported data or considering self‐reported OTC NSAID use did not change the risk estimates for the association between NSAIDs and AMI.

PURPOSE: To estimate the effectiveness and safety of direct oral anticoagulants (DOACs) compared with warfarin in AF patients with type 2 diabetes (T2DM). METHODS: A retrospective cohort study was designed, using the UK Clinical Practice Research Datalink (August 2011 - June 2018). Participants were 1-year naïve users of DOACs or warfarin, followed from the date of first prescription of an oral anticoagulant until the end of the study period, death, discontinuation of treatment, switching to another anticoagulant, or an outcome of interest, whichever came first. Cox regression analysis was performed to estimate the hazard ratio (HR) adjusted for potential confounders. RESULTS: A total of 8,555 patients were identified. No significant differences were found between DOACs and warfarin in the risk of stroke (adjusted HR 1.15; 95% CI 0.82 - 1.60), ischemic and unspecified stroke (adjusted HR 1.23; 95% CI 0.86 - 1.76) or haemorrhagic stroke (adjusted HR 0.75; 95% CI 0.30 - 1.85), and myocardial infarction (adjusted HR 1.39 ;95% CI 0.99 - 1.97). DOAC and warfarin users were comparable with respect to risk of major bleed (adjusted HR 0.83; 95% CI 0.68 - 1.03), intracranial bleeding (HR 0.66; 95% CI 0.34 - 1.30), gastrointestinal bleeding (HR 0.88; 95% CI 0.60 - 1.30), and bleeding on other clinically relevant sites (HR 0.89; 95% CI 0.60 - 1.31). In the subgroup analyses stratified by gender and diabetes severity, the risk for stroke and bleeding remained consistent. CONCLUSION: DOACs are effective and safe alternatives to warfarin for the prevention of stroke in AF patients with T2DM.

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 ofPharmacoepidemiology 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 5–12years 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&nbsp

The purpose of this study was to assess the impact of age and sex on the reporting of cough and angioedema related to renin angiotensin system (RAS) inhibitors. A case/non-case study was performed in VigiBase. Two case groups were identified, reports of cough and reports of angioedema and non-cases were all reports of all other adverse events. Logistic regression analysis was used to assess the association between reporting of cough and angioedema with each class of RAS inhibitors stratified by age/sex and to control for confounding. The reporting of cough with angiotensin-converting enzyme (ACE) inhibitors was significantly higher in women than in men (adjusted-ROR: 44.0, 95%CI (43.2-44.8) for women versus 29.2, 95%CI (28.5-29.9) for men). There was no difference in reporting of cough linked to angiotensin receptor blockers (ARBs) and aliskiren between men and women. In contrast, the reporting of angioedema with ACE inhibitors and ARBs was significantly higher in men than in women but for aliskiren, women had a significantly higher ROR than men (adjusted-ROR: 5.20, 95%CI (4.18-6.46) for women versus 3.04, 95%CI (2.30-4.02) for men). The reporting of cough with ACE inhibitors was increased with age until reaching a plateau at middle adulthood (40-59 years) and the reporting of angioedema with ACE inhibitors was increased with age until elderly (60-79 years). Age had only a slight effect on the reporting of cough and angioedema with ARBs and aliskiren. Both age and sex have substantial effects on the reporting of cough and angioedema with RAS inhibitors and in particular ACE inhibitors. Further study is needed to determine whether these differences mainly express different ADR risks in subgroups or also can be explained by factors influencing reporting. This article is protected by copyright. All rights reserved.

OBJECTIVES: To investigate the 5-yr prevalence and incidence rates of cardiovascular medication and cardiovascular disease before and after onset of type 1 diabetes (T1D) in children and adolescents. METHODS: Children and adolescents (

Objective To identify the occurrence and determinants of protocol-publication discrepancies in clinical drug trials. Study Design and Setting All published clinical drug trials reviewed by the Dutch institutional review boards in 2007 were analyzed. Discrepancies between trial protocols and publications were measured among key reporting aspects. We evaluated the association of trial characteristics with discrepancies in primary endpoints by calculating the risk ratio (RR) and 95% confidence interval (CI). Results Of the 334 published trials, 32 (9.6%) had a protocol/publication discrepancy in the primary endpoints. Among the subgroup of randomized controlled trials (RCTs; N = 204), 12 (5.9%) had a discrepancy in the primary endpoint. Investigator-initiated trials with and without industry (co-) funding were associated with having discrepancies in the primary endpoints compared with industry-sponsored trials (RR 3.7; 95% CI 1.4–9.9 and RR 4.4; 95% CI 2.0–9.5, respectively). Furthermore, other than phase 1–4 trials (vs. phase 1; RR 4.6; 95% CI 1.1–19.3), multicenter trials were also conducted outside the European Union (vs. single center; RR 0.2; 95% CI 0.1–0.6), not prospectively registered trials (RR 3.3; 95% CI 1.5–7.5), non-RCTs (vs. superiority RCT; RR 2.4; 95% CI 1.2–4.8) and, among the RCTs, crossover compared with a parallel group design (RR 3.7; 95% CI 1.1–12.3) were significantly associated with having discrepancies in the primary endpoints. Conclusions Improvement in completeness of reporting is still needed, especially among investigator-initiated trials and non-RCTs. To eliminate undisclosed discrepancies, trial protocols should be available in the public domain at the same time when the trial is published.

Objectives Antipsychotic drugs are frequently prescribed to elderly patients, but they are associated with serious adverse effects. The objective of the current study was to investigate the association between use of antipsychotics by elderly women and the risk of urinary tract infections (UTIs). Cohort study setting Dispensing data were obtained from the PHARMO Database Network for the period 1998–2008. Participants Ambulatory Dutch women (≥65 years) with current and past use of antipsychotics. Measurements Incidence rates of UTIs, as defined by use of nitrofurantoin, was calculated within and outside the period of exposure to antipsychotic drugs. Cox proportional hazard regression analysis with Andersen-Gill extension for recurrent events was used to calculate crude and adjusted hazard ratios (HRs). Results During the study period, 18,541 women with a first prescription of an antipsychotic were identified. Current use of antipsychotics was associated with an increased risk of UTI compared to past use: HR, adjusted for age and history of UTIs, 1.33, 95% CI 1.27–1.39. A strong temporal relationship was found: the risk of being treated for a UTI was higher in the first week after the start of the treatment (adjusted HR 3.03, 95% CI 2.63–3.50) and decreased after 3 months (adjusted HR 1.22, 95% CI 1.17–1.28). Cumulative exposure was not associated with an increased risk of UTIs. There was no difference in effect between conventional and atypical antipsychotics. Conclusion Our results show an increased risk of uncomplicated UTIs during antipsychotic use in older female patients, especially in the first week of treatment.

Background: The annual prevalence of antiepileptic drug (AED) prescribing reported in the literature differs considerably among European countries; this may be due to differences in type of data sources, time periods, population distributions, and methodology. Objectives: To assess the prevalence of AED prescribing across seven European routine health care databases in Spain, Denmark, the Netherlands, the UK, and Germany using standardised methodology and to investigate sources of variation. Methods: We used data from the Spanish Base de Datos para la Investigacion Farmacoepidemiologica en Atencion Primaria (BIFAP), the Danish national registries, the Dutch Mondriaan project (AHC, NPCRD), The Health Improvement Network (THIN) and the Clinical Practice Research Datalink (CPRD) from the UK, and the German Bavarian claims database (KVB). Analyses on annual prevalence of AEDs over the study period of 2001–2009 were stratified by sex, age, and AED type (‘old’ vs. ‘new’ depending registration year for marketing). Overall prevalences were standardised to the European 2008 reference population. Results: Prevalence of any AED varied from 79 per 10,000 persons in the Netherlands to 147 per 10,000 persons in Spain in 2001. After standardisation this range decreased to 88 per 10,000 persons in the Netherlands to 144 per 10,000 in Spain and Denmark. In all databases prevalence increased yearly since 2001 with 6% in Denmark to 15% in Spain. This increase could be entirely attributed to an increase in prescribing of ‘new’ AEDs. AED use increased with age for both females and males up to ages of 80–89 years-old and tended to be somewhat higher in females between 40 and 70 years-old. We did not find differences across databases in the number of AEDs concomitantly used. Conclusions: During the study period of 2001–2009, AED prescribing increased in all five EU countries which was mainly due to newer AEDs. Using a standardised methodology showed consistent trends across databases and countries over time. Differences in age and sex distribution explained part of the variation between countries.

The objective of this study was to investigate the occurrence and determinants of non-publication of clinical drug trials in the Netherlands.All clinical drug trials reviewed by the 28 Institutional Review Boards (IRBs) in the Netherlands in 2007 were followed-up from approval to publication. Candidate determinants were the sponsor, phase, applicant, centers, therapeutic effect expected, type of trial, approval status of the drug(s), drug type, participant category, oncology or other disease area, prospective registration, and early termination. The main outcome was publication as peer reviewed article. The percentage of trials that were published, crude and adjusted odds ratio (OR), and 95% confidence interval (CI) were used to quantify the associations between determinants and publication. In 2007, 622 clinical drug trials were reviewed by IRBs in the Netherlands. By the end of follow-up, 19 of these were rejected by the IRB, another 19 never started inclusion, and 10 were still running. Of the 574 trials remaining in the analysis, 334 (58%) were published as peer-reviewed article. The multivariable logistic regression model identified the following determinants with a robust, statistically significant association with publication: phase 2 (60% published; adjusted OR 2.6, 95% CI 1.1-5.9), phase 3 (73% published; adjusted OR 4.1, 95% CI 1.7-10.0), and trials not belonging to phase 1-4 (60% published; adjusted OR 3.2, 95% CI 1.5 to 6.5) compared to phase 1 trials (35% published); trials with a company or investigator as applicant (63% published) compared to trials with a Contract Research Organization (CRO) as applicant (50% published; adjusted OR 1.7; 95% CI 1.1-2.8); and multicenter trials also conducted in other EU countries (68% published; adjusted OR 2.2, 95% CI 1.1-4.4) or also outside the European Union (72% published; adjusted OR 2.0, 95% CI 1.0-4.0) compared to single-center trials (45% published). Trials that were not prospectively registered (48% published) had a lower likelihood of publication compared to prospectively registered trials (75% published; adjusted OR 0.5, 95% CI 0.3-0.8), as well as trials that were terminated early (33% published) compared to trials that were completed as planned (64% published; adjusted OR 0.2, 95% CI 0.1-0.3). The non-publication rate of clinical trials seems to have improved compared to previous inception cohorts, but is still far from optimal, in particular among phase 1, single-center, not prospectively registered, and early terminated trials.

Publisher's version (útgefin grein), Introduction: Several monoclonal antibodies (mAbs) have been linked to neuropsychiatric adverse efects in patients, including depression and suicidal ideation and behavior. Objective: The aim of this study was to quantify and characterize spontaneously reported adverse drug reactions (ADRs) of depression and suicidal ideation and behavior related to mAb users, and to explore a possible association with their mechanism of action. Methods: We included mAb ADRs that were reported in VigiBase, and identifed those related to depression and suicidal ideation and behavior. Reporting odds ratios (RORs) were estimated for each mAb (bevacizumab as the reference) and according to their infuence on the immune system (not directly targeting [reference], stimulating, or suppressing). Those suppressing the immune system were further divided into their intended indication (auto-immune diseases, cancer). Results: Overall, 2,924,319 ADRs for 44 mAbs were included; 9455 ADRs were related to depression and 1770 were related to suicidal ideation and behavior. The association was strongest for natalizumab and belimumab, both for depression (ROR 5.7, 95% confdence interval [CI] 5.0–6.4; and ROR 5.1, 95% CI 4.2–6.2) and suicidal ideation and behavior (ROR 12.0, 95% CI 7.9–18.3; and ROR 20.2, 95% CI 12.4–33.0). Those suppressing the immune system showed higher ROR, i.e. 1.9 (95% CI 1.8–2.0) for depression and 3.6 (95% CI 3.0–4.4) for suicidal ideation and behavior. This fnding was only seen for mAbs used for treating autoimmune diseases. Conclusion: Depression and suicidal ideation and behavior are seen in patients using mAbs, particularly mAbs used for treating autoimmune diseases that suppress the immune system. For interpretation of these data, the indications for use and other characteristics require further consideration., No external sources of funding were used to assist in the preparation of this article. The authors would like to thank the Uppsala Monitoring Centre for providing the data.

BACKGROUND: Hypochlorhydric states are an important cause of iron deficiency (ID). Nevertheless, the association between therapy with proton pump inhibitors (PPIs) and ID has long been a subject of debate. This case-control study aimed to investigate the risk of ID associated with the use of PPIs using the UK Clinical Practice Research Datalink (CRPD) database. METHODS: Cases were patients aged 19 years or older with first-time diagnosis of ID between 2005 and 2015 (n = 26,806). The dates of first diagnosis of ID in cases defined the index dates. For each case, one control was matched by age, sex and general practice. A PPI "full" user (PFU) was defined as a subject who had received PPIs for a continuous duration of at least one year prior to the index date. A PPI "limited" users (PLU) was a subject who intermittently received PPI therapy. A PPI non-user (PNU) was a subject who received no PPIs prescriptions prior to the index date. The odds ratio of ID in PFU and PLU compared to PNU was estimated using conditional logistic regression. RESULTS: Among cases, 2,960 were PFU, 6,607 PLU and 17,239 PNU. Among controls, 1,091 were PFU, 5,058 PLU and 20,657 PNU. Adjusted odds ratio of ID in PFU and PLU compared to PNU was 3.60 (95%CI, [3.32 - 3.91]) and 1.51 (95% CI, [1.44 - 1.58]). Positive dose-response and time-response relationships were observed. CONCLUSIONS: Chronic PPI use increases the risk of ID. Physicians should consider this when balancing the risks and benefits of chronic PPI prescription. This article is protected by copyright. All rights reserved.

Efficacious lowering of low-density lipoprotein cholesterol through prolonged statin therapy has become a major strategy for primary and secondary prevention of cardiovascular disease. From the perspective of patients, however, the prophylactic efficacy may be difficult to comprehend. It refers to prospective disease prevention at the population level and an uncertain risk reduction for individual patients. At the same time, actual side effects may occur and treatment entails a lifelong regimen. (aut. ref.)

Differences in incidence and prevalence of ADHD medication use between ethnic groups have been reported. Goal of this study was to determine whether there are also differences in usage patterns of ADHD medication among native Dutch children and adolescents and those with a Moroccan, Turkish and Surinam cultural background in the Netherlands between 1999 and 2010. In a cohort of ADHD patients

Aims Out-of-hospital cardiac arrest (OHCA) remains a major cause of death. We aimed to determine whether type-2 diabetes mellitus (T2DM) is associated with reduced pre-hospital and in-hospital survival rates after OHCA. Methods and results An observational community-based cohort study was performed among 1549 OHCA patients with ECG-documented ventricular tachycardia/ventricular fibrillation (VT/VF). We compared pre-hospital and in-hospital survival rates between T2DM patients and non-diabetic patients. Analyses among T2DM patients were stratified according to current T2DM treatment, used as proxy for T2DM severity. Proportions of neurologically intact survival were analysed. Pre-hospital survival rates were lower in T2DM patients (n = 275) than in non-diabetic patients (n = 1274); 48.7 vs. 55.8% (univariate P = 0.032). Type-2 diabetes mellitus was associated with lower pre-hospital survival [OR 0.75 (0.58-0.98); after evaluation of the risk factors, we found no relevant confounding]. Patients treated with insulin only had lower pre-hospital survival rates than patients treated with oral glucose-lowering drugs only (37.3 vs. 53.3%, univariate P = 0.034), partially explained by location of OHCA and EMS response time [ORadj 0.62 (0.33-1.17)]. In-hospital survival rates were also lower in T2DM patients (n = 134) than in non-diabetic patients (n = 711); 40.3 vs. 57.7%, univariate P < 0.001. In those patients whose cause of OHCA was retrieved (n = 771), T2DM was significantly associated with lower in-hospital survival [ORadj 0.57 (0.37-0.87)]. Neurologically intact status at discharge was similarly high among T2DM and non-diabetic patients (94.4 vs. 94.6%, P = 0.954). Conclusion T2DM is associated with lower pre-hospital and in-hospital survival rates after OHCA. Neurologically intact status at hospital discharge is high both among T2DM and non-diabetic patients.

Introduction: Responsible conduct of research implies that results of clinical trials should be completely and adequately reported. This article describes the design of a cohort study that aims to investigate the occurrence and the determinants of selective reporting in an inception cohort of all clinical drug trials that were reviewed by the Dutch Institutional Review Boards (IRBs) in 2007. It also describes the characteristics of the study cohort. Methods and analysis: In 2007, Dutch IRBs reviewed 622 clinical drug trials. For each trial, we assessed the stages of progress. We discriminated five intermediate stages and five definite stages. Intermediate stages of progress are: approved by an IRB; started inclusion; completed as planned; terminated early; published as article. The definite stages of progress are: rejected by an IRB; never started inclusion; not published as article; completely reported; selectively reported. We will use univariate and multivariate Cox regression models to identify trial characteristics associated with non-publication. We will identify seven trial-specific discrepancy items, including the objectives, inclusion and exclusion criteria, end points, sample size, additional analyses, type of population analysis and sponsor acknowledgement. The percentage of trials with discrepancies between the protocol and the publication will be scored. We will investigate the association between trial characteristics and the occurrence of discrepancies. Ethics and dissemination: No IRB-approval is required for this study. Access to confidential research protocols was provided by the Central Committee on Research Involving Human Subjects. We plan to finish data collection in June 2015, and expect to complete data cleaning, analysis and manuscript preparation within the next 3 months. Hence, a first draft of an article containing the results is expected before the end of October 2015.

ObjectiveTo determine the incidence of chronic comorbidities among children with type 1 diabetes (T1D) and to compare incidences with a group of children without diabetes.DesignPopulation-based cohort study.SettingDutch PHARMO database (1998–2010).PatientsAll patients (Main outcome measureThe incidence of nine common chronic comorbidities was assessed on the basis that they were treated pharmacologically and/or resulted in hospital admission. Cox proportional hazard analysis was used to estimate the strength of the association between T1D and comorbidities, expressed as HRs and 95% CIs.ResultsA total of 915 patients with T1D and 3590 children in the reference cohort (51% boys, mean age of 10.1 (SD 4.5) years) were included. T1D was associated with an increased risk (HR; 95% CI) of hospitalisation for any comorbidity (3.7; 2.5 to 5.5), thyroid disease (14.2; 6.7 to 31.0), non-infectious enteritis and colitis (5.9; 3.0 to 11.5), cardiovascular disorders (3.1; 2.3 to 4.2), mental disorders (2.0; 1.4 to 3.1), epilepsy (2.0; 1.1 to 3.7) and (obstructive) pulmonary disease (1.5; 1.2 to 2.0). There was no significant difference in the incidences of other comorbidities (malignant disorders, anaemia and migraine) between the two cohorts.ConclusionsOur longitudinal study showed that incidences of six chronic diseases were significantly higher in T1D children during the early years of developing this disease compared with the reference children.

BACKGROUND: Electronic prescribing records can enable exploration of medication adherence, but analysis decisions may influence estimates and require alignment to new consensus-based definitions.OBJECTIVE: To compare different computations of inhaled corticosteroid (ICS) implementation in a primary care asthma population initiating ICS therapy when assessed within episodes of persistent use, and examine longitudinal variation in implementation.METHODS: A historical cohort study was conducted on UK's Optimum Patient Care Research Database. Eligible patients had physician-diagnosed asthma, initiated ICS therapy, and had 3 or more years of continuous registration. ICS treatment episodes were constructed on the basis of 3 definitions, permitting 30-, 90-, and 182-day gaps between prescriptions. Implementation was estimated using 2 continuous medication availability (CMA I and II) definitions to explore effects of carryover of previous prescriptions in 4 observation windows: 6, 8, 12, and 24 months. Impact of methodology was assessed by descriptive statistics, linear mixed models, and measures of agreement.RESULTS: A total of 13,922 eligible patients (mean age, 39.9 years; 48.7% men) were identified. For CMA I, permitting a 90-day gap, mean ICS implementation for the 2-year period was 89.3% (±16.0%; range, 14.4%-100%). Sensitivity analyses with 30- and 182-day gaps resulted in increased (97.0% ± 7.2%) and decreased (81.1% ± 21.6%) estimates. CMA II produced estimates with varying concordance (0.69-0.87). Substantial variance was found between and within patients (intraclass coefficient, 0.30-0.36).CONCLUSIONS: Different analysis choices resulted in substantial variation in implementation estimates, highlighting the need for transparent and clinically relevant methododology. Distinguishing between (non)persistence and implementation is important in clinical practice, and may require different interventions in routine consultations.

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.

Background Treatment with vitamin K antagonists (coumarins) is associated with an increased risk of bleeding. Because use of selective serotonin reuptake inhibitors (SSRIs) is also associated with an increased risk of bleeding, we assessed the odds ratio (OR) of abnormal bleeding associated with SSRI use in users of the coumarins acenocoumarol or phenprocoumon and compared this with the OR of bleeding as a result of use of nonsteroidal anti-inflammatory drugs. Methods We used data from a Dutch linkage system including pharmacy and linked hospitalization records for approximately 2 million subjects to conduct a case-control study in a cohort of new users of coumarins. Cases were patients who were hospitalized having a primary diagnosis of abnormal major bleeding while taking a coumarin and were matched with up to 4 control subjects. Conditional logistic regression analysis was used to determine ORs and 95% confidence intervals (CIs) for the risk of hospitalization because of abnormal bleeding associated with concurrent use of SSRIs or nonsteroidal anti-inflammatory drugs. Results We identified 1848 case patients with abnormal bleeding. Users of SSRIs were at significantly increased risk of hospitalization because of nongastrointestinal tract bleeding (hereafter referred to as “nongastrointestinal bleeding”) (adjusted OR, 1.7; 95% CI, 1.1-2.5) but not because of gastrointestinal tract bleeding (hereafter referred to as “gastrointestinal bleeding”) (adjusted OR, 0.8; 95% CI, 0.4-1.5). Users of nonsteroidal anti-inflammatory drugs had a similar increased risk of nongastrointestinal bleeding (adjusted OR, 1.7; 95% CI, 1.3-2.2), whereas the risk of gastrointestinal bleeding was higher (adjusted OR, 4.6; 95% CI, 3.3-6.5). Conclusion In users of coumarins, SSRI usage was associated with increased risk of hospitalization because of nongastrointestinal bleeding but not because of gastrointestinal bleeding.

OBJECTIVES: Because of the high risk of pneumonia in patients with diabetes, we aimed to assess the effect of angiotensin-converting enzyme (ACE) inhibitor use on the occurrence of pneumonia in a general population of patients with diabetes.METHODS: The study population comprised all patients in the UK General Practice Research Database who had a diagnosis of diabetes (both type 1 and type 2) between 1987 and 2001. Cases were defined as patients with a first diagnosis of pneumonia. For each case, up to four controls were matched by age, gender, practice, and index date. Patients were classified as current ACE inhibitor user when the index date was between the start and end date of ACE inhibitor therapy. Conditional logistic regression analysis was used to estimate the strength of the association between ACE inhibitor use and pneumonia risk.RESULTS: ACE inhibitors were used in 12.7% of 4719 cases and in 13.7% of 15,322 matched controls [crude odds ratio (OR)=0.92, 95% confidence interval (CI)=0.82-1.01]. After adjusting for confounding, ACE inhibitor therapy was associated with a significant reduction in pneumonia risk (adjusted OR=0.72, 95% CI=0.64-0.80). The protective association was consistent across different relevant subgroups with the strongest association in patients with a history of stroke. There was a significant dose-effect relationship (P for trend < 0.001).CONCLUSIONS: The use of ACE inhibitors is associated with a significant reduction in pneumonia risk and, apart from blood pressure-lowering properties, may be useful in the prevention of pneumonia in patients with diabetes.

A population-based cohort study was conducted in the Dutch PHARMO database to investigate prevalence and patterns of anti-infective medication use in children and adolescents with type 1 diabetes (T1D) before and after the onset of this disease. All patients P < 0.001) and average number of prescriptions (2.71 compared to 1.42 per child, P < 0.001) in the T1D cohort were significantly higher than those in the reference cohort after the onset of diabetes. This pattern was consistent across sex and age categories and already observed in the year before the onset of type 1 diabetes. Patients in the T1D cohort received more antibacterials (49.8 compared to 40%, P < 0.001), antimycotics (4.0 compared to 1.3%, P < 0.001), antivirals (2.5 compared to 0.4%, P < 0.001), and second-line antibiotics, such as aminoglycosides, quinolones, and third-generation cephalosporins and carbapenems. Our findings that elevated anti-infective use in the T1D cohort exists in the period before the onset of type 1 diabetes and the consumption of more second-line anti-infective compounds in this time period warrant further research.

Response to: 'Correspondence on 'Concomitant use of oral glucocorticoids and proton pump inhibitors and risk of osteoporotic fractures among patients with rheumatoid arthritis: a population-based cohort study'' by Zheng We thank Dr Zheng for his comments on our recently published article in the Annals of the Rheumatic Diseases entitled 'Concom-itant use of oral glucocorticoids and proton pump inhibitors and risk of osteoporotic fractures among patients with rheumatoid arthritis: a population-based cohort study'. 1 2 Our main goal in this study was to bring more clinical insight into the simultaneous use of these two common medications in patients with rheumatoid arthritis (RA), that is, oral glucocorticoids (GCs) and proton pump inhibitors (PPIs), using data from a large primary care database and pharmacoepidemiological methodologies. Our results showed that there was an interaction in the risk of osteoporotic (OP) fractures with concomitant use of oral GCs and PPIs in patients with RA. Based on the adjusted hazard ratios and according to the formula proposed by Rothman et al, 3 the relative excess risk due to interaction (RERI) was: 1.60-1.23 − 1.22 + 1 = 0.15. We now have also calculated the CIs and the statistical significance of this index using the method proposed by Hosmer and Lemeshow. 4 5 The lower and upper limits of the 95% CI of the RERI were −0.16 and 0.45, respectively, and the p value was 0.36. This means, although we observed a 15% more risk of OP fracture with concomitant use of oral GCs and PPIs in addition to the single use of each drug versus non-use of both, this additive interaction was not statistically significant. As we discussed in our paper, there is currently no proven biological mechanism for an action of PPIs on bone or falling, 6 while the effects of GCs on bone and the musculoskeletal system are quite established. Our secondary analyses (ie, lower fracture risk with long-term or higher daily doses of PPIs compared with short-term or lower daily doses) did not support the few proposed potential mechanisms, such as hypochlorhydria and calcium malabsorption, or an increased fall risk due to malab-sorption of magnesium or vitamin B 12. This is important to consider when interpreting a potential additive interaction between oral GCs and PPIs on fracture risk. Without this basic knowledge, it would be extremely difficult to confer any conclusions on a plausible synergistic action of these two drugs, since it would sound more as a methodological reasoning rather than a clinical explanation.

Objectives: Clinical trials have shown that low-dose glucocorticoid therapy in patients with rheumatoid arthritis (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 1997-2017. Exposure to oral glucocorticoids was stratified by the most recent prescription in current (1 year) use, and average daily and cumulative doses. Risk of incident osteoporotic fractures (including hip, vertebrae, humerus, forearm, pelvis, and ribs) were estimated by time-dependent Cox proportional-hazards models, adjusted for life-style 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/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., Rheumatology, 61 (4)