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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.

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.

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.

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 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 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 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 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 To identify single nucleotide polymorphisms (SNPs) associated with switching from an angiotensin-converting enzyme (ACE)-inhibitor to an angiotensin receptor blocker. Methods Two cohorts of patients starting ACE-inhibitors were identified within the Rotterdam Study in the Netherlands and the Genetics of Diabetes Audit and Research in Tayside Scotland study in Scotland. Cases were intolerant patients who switched from an ACE-inhibitor to an angiotensin receptor blocker and controls were individuals who used ACE-inhibitors continuously for at least 2 years and did not switch. Genome-wide association study (GWAS) using an additive model was run in these sets and the results were meta-analysed using Genome-Wide Association Meta Analysis software. Results A total of 972 cases out of 5161 ACE-inhibitor starters were identified. Eight SNPs within four genes reached the genome-wide association study significance level (P

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.

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.

Aims The aims of the present study were to assess antiplatelet drug use patterns after a first myocardial infarction (MI) and to evaluate the determinants of antiplatelet nonpersistence. Methods The present study was conducted in 4690 patients from the Utrecht Cardiovascular Pharmacogenetics cohort with a first MI between 1986 and 2010, who were followed for a maximum of 10 years. Medication use and event diagnosis were obtained from the Dutch PHARMO Record Linkage System. Antiplatelet drug users were classified as persistent users (gap between prescriptions ≤90 days), nonpersistent users (>90‐day gap and no refills), and restarters (a new prescription after a >90‐day gap). The association between potential determinants and antiplatelet nonpersistence was analysed using Cox regression. Results The proportions of persistent users decreased from 84.0% at the 1‐year follow‐up to 32.8% at 10 years for any antiplatelet drug, and 77.3% to 27.5% for aspirin; and 39.0% to 6.4% for clopidogrel at 6 years. Most nonpersistent users restarted antiplatelet drugs later, leading to 89.3% overall antiplatelet drug users at 10 years after MI. Diabetes (hazard ratio [HR] 0.44; 0.32–0.60), hypertension (HR 0.77; 0.60–0.99), hypercholesterolaemia (HR 0.49; 0.39–0.62) and more recent MI diagnosis period (2003–2007: HR 0.69, 0.61–0.79; 2008–2010: HR 0.38, 0.19–0.77, compared to ≤ 2002 period) lowered the risk of antiplatelet nonpersistence, while vitamin K antagonist (VKA) comedication (HR 18.97; 16.91–21.28) increased this risk. Conclusions A large proportion of patients with a first MI still used antiplatelet drugs after 10 years. The frequent discontinuations during this time frame are expected to reduce the effectiveness of antiplatelet drugs as secondary prevention of cardiovascular diseases. Diabetes, hypertension, hypercholesterolaemia, VKA comedication and MI diagnosis period were determinants of antiplatelet nonpersistence.

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.

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 (

Purpose To assess the risk of gastrointestinal perforation, ulcers, or bleeding (PUB) associated with the use of conventional nonsteroidal anti‐inflammatory drugs (NSAIDs) with proton pump inhibitors (PPIs) and selective COX‐2 inhibitors, with or without PPIs compared with conventional NSAIDs. Methods A case–control study was performed within conventional NSAIDs and/or selective COX‐2 inhibitors users identified from the Dutch PHARMO Record Linkage System in the period 1998–2012. Cases were patients aged ≥18 years with a first hospital admission for PUB. For each case, up to four controls were matched for age and sex at the date a case was hospitalized (index date). Logistic regression analysis was used to calculate odds ratios (ORs). Results At the index date, 2634 cases and 5074 controls were current users of conventional NSAIDs or selective COX‐2 inhibitors. Compared with conventional NSAIDs, selective COX‐2 inhibitors with PPIs had the lowest risk of PUB (adjusted OR 0.51, 95% confidence interval [CI]: 0.35–0.73) followed by selective COX‐2 inhibitors (adjusted OR 0.66, 95%CI: 0.48–0.89) and conventional NSAIDs with PPIs (adjusted OR 0.79, 95%CI: 0.68–0.92). Compared with conventional NSAIDs, the risk of PUB was lower for those aged ≥75 years taking conventional NSAIDs with PPIs compared with younger patients (adjusted interaction OR 0.79, 95%CI: 0.64–0.99). However, those aged ≥75 years taking selective COX‐2 inhibitors, the risk was higher compared with younger patients (adjusted interaction OR 1.22, 95%CI: 1.01–1.47). Conclusions Selective COX‐2 inhibitors with PPIs, selective COX‐2 inhibitors, and conventional NSAIDs with PPIs were associated with lower risks of PUB compared with conventional NSAIDs. These effects were modified by age. © 2017 The Authors. Pharmacoepidemiology & Drug Safety Published by John Wiley & Sons Ltd.

PURPOSE: To evaluate the association between the use of streptomycin, amikacin, kanamycin and capreomycin in tuberculosis (TB) treatment and the pharmacovigilance reporting of ototoxicity (deafness or hearing loss, tinnitus and vertigo). Second, to analyze patient demographic and geographic factors that influence the reporting of ototoxicity in TB treatment. METHODS: A case/non-case disproportionality analysis of the VigiBase® individual case safety reports (ICSRs) of patients treated for TB using multidrug regimens that contain either of streptomycin, amikacin, kanamycin or capreomycin. Cases were reports of ototoxicity; non-cases were other adverse drug reactions (ADRs). The unit of analysis was the drug-ADR pair. We calculated reporting odds ratios (RORs) and their 95% confidence intervals (CI). The referent drug was streptomycin. RESULTS: By June 2014, there were 3361 drug-ADR pairs in VigiBase® (1693 ICSRs) where the parenteral administration of the four drugs for TB treatment was suspected of causing the reported ADRs. Deafness, tinnitus and vertigo were reported in 576 drug-ADR pairs (cases), the rest being other ADRs (non-cases). Reporting of deafness was most disproportionately associated with amikacin use (ROR 9.3; 95%CI 3.8-23.0), followed by kanamycin use (ROR 4.3; 95%CI 1.3-14.2). Reporting of vertigo was inversely associated with capreomycin use (ROR 0.1; 95%CI 0.01-0.4). Geographic region affected the reporting of ototoxicity while age and sex did not. CONCLUSION: Spontaneous reporting of deafness cases within VigiBase® was most disproportionately associated with amikacin use, followed by kanamycin. There were regional variations in the global reporting of ototoxicity. These findings should be verified through a follow up study. Copyright © 2016 John Wiley & Sons, Ltd.

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.

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.

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

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

AIM: The aim of the present study was to describe the occurrence and determinants of angiotensin-converting enzyme (ACE) inhibitor (ACEI) intolerance and angioedema (AE) among patients initiating ACEI therapy in a real-world primary care population. METHODS: Two nested case-control studies were conducted in a cohort of 276 977 patients aged ≥45 years initiating ACEIs from 2007 to 2014 in the UK Clinical Practice Research Datalink (CPRD). Cases of AE occurring for the first time during ACEI therapy (n = 416) were matched with AE-free controls (n = 4335) on the duration of ACEI treatment. Documented switches to angiotensin-II receptor blockers in the prescription records were used to identify ACEI-intolerance cases (n = 24 709), and these were matched with continuous ACEI users (n = 84 238) on the duration of ACEI therapy. Conditional logistic regression was used to assess the associations of demographic factors, comorbidities and comedication with AE and ACEI intolerance. RESULTS: AE during ACEI therapy was associated with age over 65 years [odds ratio (OR) 1.36, 95% confidence interval (CI) 1.07, 1.73], history of allergy (OR 1.53, 95% CI 1.19, 1.96), use of calcium channel blockers (OR 1.57, 95% CI 1.23; 2.01), use of antihistamines (OR 21.25, 95% CI 16.44, 27.46) and use of systemic corticosteroids (OR 4.52, 95% CI 3.26, 6.27). ACEI intolerance was significantly associated with more comorbidities and comedication compared with AE, including allergy (OR 2.02, 95% CI 1.96, 2.09), use of antiasthmatic drugs (OR 1.51, 95% CI 1.42, 1.61) and use of antihistamines (OR 1.53, 95% CI 1.43, 1.63). CONCLUSIONS: Among ACEI users developing AE or ACEI intolerance, several comorbidities and comedication classes were significantly more prevalent compared with ACEI users not developing these adverse reactions.

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.

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.

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 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.

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)