Descriptive analysis on disproportionate medication errors and associated patient characteristics in the Food and Drug Administration's Adverse Event Reporting System.

BACKGROUND: Medication errors (MEs) are a major public health concern which can cause harm and financial burden within the healthcare system. Characterizing MEs is crucial to develop strategies to mitigate MEs in the future. OBJECTIVES: To characterize ME-associated reports, and investigate signals of disproportionate reporting (SDRs) on MEs in the Food and Drug Administration's Adverse Event Reporting System (FAERS). METHODS: FAERS data from 2004 to 2020 was used. ME reports were identified with the narrow Standardised Medical Dictionary for Regulatory Activities® (MedDRA®) Query (SMQ) for MEs. Drug names were converted to the Anatomical Therapeutic Chemical (ATC) classification. SDRs were investigated using the reporting odds ratio (ROR). RESULTS: In total 488 470 ME reports were identified, mostly (59%) submitted by consumers and mainly (55%) associated with females. Median age at time of ME was 57 years (interquartile range: 37-70 years). Approximately 1 out of 3 reports stated a serious health outcome. The most prevalent reported drug class was "antineoplastic and immunomodulating agents" (25%). The most common ME type was "incorrect dose administered" (9%). Of the 1659 SDRs obtained, adalimumab was the most common drug associated with MEs, noting a ROR of 1.22 (95% confidence interval: 1.21-1.24). CONCLUSION: This study offers a first of its kind characterization of MEs as reported to FAERS. Reported MEs are frequent and may be associated with serious health outcomes. This FAERS data provides insights on ME prevention and offers possibilities for additional in-depth analyses.

Epidemiology of chronic inflammatory demyelinating polyradiculoneuropathy in The Netherlands.

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a rare but disabling disorder that often requires long-term immunomodulatory treatment. Background incidence rates and prevalence and risk factors for developing CIDP are still poorly defined. In the current study, we used a longitudinal population-based cohort study in The Netherlands to assess these rates and demographic factors and comorbidity associated with CIDP. We determined the incidence rate and prevalence of CIDP between 2008 and 2017 and the occurrence of potential risk factors in a retrospective Dutch cohort study using the Integrated Primary Care Information (IPCI) database. Cases were defined as CIDP if the diagnosis of CIDP was described in the electronic medical file. In a source population of 928 030 persons with a contributing follow-up of 3 525 686 person-years, we identified 65 patients diagnosed with CIDP. The overall incidence rate was 0.68 per 100 000 person-years (95% CI 0.45-0.99). The overall prevalence was 7.00 per 100 000 individuals (95% CI 5.41-8.93). The overall incidence rate was higher in men compared to woman (IRR 3.00, 95% CI 1.27-7.11), and higher in elderly of 50 years or older compared with people <50 years of age (IRR 17 95% CI 4-73). Twenty percent of CIDP cases had DM and 9% a co-existing other auto-immune disease. These background rates are important to monitor changes in the frequency of CIDP following infectious disease outbreaks, identify potential risk factors, and to estimate the social and economic burden of CIDP.

The use and safety of corticosteroid injections for shoulder pain in general practice: a retrospective cohort study.

BACKGROUND: Guidelines for shoulder pain in general practice recommend treatment with corticosteroid injections (CSI) if initial pain management fails. However, little is known about the actual use and safety of CSIs in treatment by general practitioners (GP). OBJECTIVE: The objective of this study was to gain insight into the use and safety of CSIs for patients with a new episode of shoulder pain in general practice. METHODS: A retrospective cohort study was conducted using a healthcare database containing the electronic medical records of approximately 200,000 patients in general practice. A search algorithm was constructed to identify patients with a new episode of shoulder pain between January 2012 and December 2017. Data on the use of CSIs in 2 random samples (n = 1,000) were manually validated for a 12-month period after the diagnosis. RESULTS: In total, 26% of the patients with a new episode of shoulder pain received a CSI. The patient's age (OR 1.03, 95% CI 1.02-1.04) and a history of shoulder pain (OR 1.52, 95% CI 1.13-2.12) were significantly associated with the administration of a CSI. Half of the patients received the CSI in the first consultation. The patient's age was positively associated with the likelihood of receiving the CSI in the first consultation (OR 1.01, 95% CI 1.00-1.02). No serious adverse reactions were recorded by the GP. CONCLUSION: In contrast to the guidelines, CSIs were frequently administered in the first consultation. Older patients and patients with a history of shoulder pain were more likely to receive a CSI for shoulder pain.

Antidepressant and anticonvulsant prescription rates in patients with osteoarthritis: a population-based cohort study.

OBJECTIVES: There are signs that antidepressants and anticonvulsants are being prescribed more often for OA patients, despite limited evidence. Our objectives were to examine prescription rates and time trends for antidepressants and anticonvulsants in OA patients, to assess the percentage of long-term prescriptions, and to determine patient characteristics associated with antidepressant or anticonvulsant prescription. METHODS: A population-based cohort study was conducted using the Integrated Primary Care Information database. First, episodic and prevalent prescription rates for antidepressants (amitriptyline, nortriptyline and duloxetine) and anticonvulsants (gabapentinoids) in OA patients were calculated for the period 2008-17. Logistic regression was used to assess which patient characteristics were associated with prescriptions. RESULTS: In total, 164 292 OA patients were included. The prescription rates of amitriptyline, gabapentin and pregabalin increased over time. The increase in prescription rates for pregabalin was most pronounced. Episodic prescription rate increased from 7.1 to 13.9 per 1000 person-years between 2008 and 2017. Amitriptyline was prescribed most (15.1 episodic prescriptions per 1000 person-years in 2017). Prescription rates of nortriptyline and duloxetine remained stable at 3.0 and 2.0 episodic prescriptions per 1000 person-years, respectively. For ≤3% of patients with incident OA, medication was prescribed long-term (≥3 months). In general, all medication was prescribed more frequently for older patients (except duloxetine), women, patients with OA in ≥2 joints, patients with spinal OA and patients with musculoskeletal disorders. CONCLUSION: Prescription rates of amitriptyline, gabapentin and pregabalin increased over time. Since there is little evidence to support prescription in OA, caution is necessary when prescribing.

Appendicitis in children with acute abdominal pain in primary care, a retrospective cohort study.

BACKGROUND: General practitioners (GPs) face a diagnostic challenge when assessing acute abdominal pain in children. However, no information is available on the current diagnostic process or the diagnostic accuracy of history and physical examination in primary care settings. OBJECTIVE: To describe the diagnostic process for acute abdominal pain among children in primary care, focusing on appendicitis, and to assess the diagnostic accuracy of individual clinical features. METHODS: A retrospective cohort study in Dutch primary care, using the Integrated Primary Care Information database. Children aged 4-18 years were included if they had no history of appendicitis and presented with acute abdominal pain during 2010-2016. We evaluated GP management and the diagnostic accuracy of clinical features for appendicitis. Pre- and post-test probabilities were calculated for each clinical feature and compared with the probability of appendicitis after GP assessment. RESULTS: Out of 5691 children, 944 (16.6%) were referred and 291 (5.1%) had appendicitis, of whom 55 (18.9%) were initially misdiagnosed. The pre-test probability (i.e. of appendicitis in evaluated children) varied from 3% (rigidity) to 28% (migratory pain). Concerning post-test probabilities, positive values for rebound pain (32.1%) and guarding (35.8%) and the negative value for right lower quadrant tenderness (0.6%) were superior to overall GP assessment (29.6% and 1.1%, respectively). CONCLUSIONS: GP assessment will miss almost one-fifth of children with appendicitis at their first presentation, and about two-third of GP referrals will be negative. The presence of specific signs can increase or decrease the likelihood of appendicitis, emphasising the importance of a physical examination.

It can be difficult for general practitioners (GPs) to assess acute abdominal pain in children because they must decide whether it is a common minor problem or an uncommon serious problem. However, unlike their hospital counterparts, GPs must often rely on only the history and examination. We, therefore, wanted to gain a better understanding of how GPs assess abdominal pain and the accuracy of the different parts of their assessment. To do this, we looked back at clinical records for children who presented to a GP with acute abdominal pain between 2010 and 2016. The effect of examination on the probability of detecting appendicitis was calculated for several clinical features, and these were compared with the probability of appendicitis after a full GP assessment. Approximately 1 in 20 of the included children was diagnosed with appendicitis, one in five were initially misdiagnosed, and one in four were ultimately referred to the hospital. We show that some signs and symptoms were not particularly useful for assessment, but when they were, signs detected by the GP examining the patient were more useful than symptoms reported by patients or parents. We recommend that GPs provide safety netting advice and examine the abdomen.

The incidence and management of shoulder complaints in general practice: a retrospective cohort study.

BACKGROUND: Shoulder pain is the third most common musculoskeletal complaint in primary care. The international guidelines for general practitioners (GPs) recommend a stepwise treatment of shoulder pain. Little is known about the actual distribution of these treatments in current practice. OBJECTIVE: To gain insight in the incidence and current management of shoulder complaints in Dutch general practice. METHODS: A retrospective cohort study was conducted using a health care database containing the full electronic medical records of approximately 200 000 patients in Dutch general practice. A search algorithm was constructed to identify incident cases of shoulder complaints from January 2012 to December 2017. Data on the management of shoulder complaints were manually validated in a random sample of 1000 cases. RESULTS: The overall incidence of shoulder complaints was 30.3 (95% confidence interval 29.9-30.7) per 1000 person-years. More than half of the patients (58.6%) consulted their GP only once, 44.4% two times or more and 19.7% three times or more. For most patients (58.1%), the GP applied a wait-and-see policy or prescription of oral medication in the first consultation. However, no less than 42.9% of the patients were referred or received an injection already in the first consultation. CONCLUSIONS: There is a wide variety of treatments for shoulder complaints applied by the GP. Some patients are referred or received an injection already in the first consultation. The stepwise approach recommended by the guideline, might not always be applicable due to the diversity of patient- and shoulder characteristics presented in general practice.

Treatment pathway analysis of newly diagnosed dementia patients in four electronic health record databases in Europe.

PURPOSE: Real-world studies to describe the use of first, second and third line therapies for the management and symptomatic treatment of dementia are lacking. This retrospective cohort study describes the first-, second- and third-line therapies used for the management and symptomatic treatment of dementia, and in particular Alzheimer's Disease. METHODS: Medical records of patients with newly diagnosed dementia between 1997 and 2017 were collected using four databases from the UK, Denmark, Italy and the Netherlands. RESULTS: We identified 191,933 newly diagnosed dementia patients in the four databases between 1997 and 2017 with 39,836 (IPCI (NL): 3281, HSD (IT): 1601, AUH (DK): 4474, THIN (UK): 30,480) fulfilling the inclusion criteria, and of these, 21,131 had received a specific diagnosis of Alzheimer's disease. The most common first line therapy initiated within a year (± 365 days) of diagnosis were Acetylcholinesterase inhibitors, namely rivastigmine in IPCI, donepezil in HSD and the THIN and the N-methyl-D-aspartate blocker memantine in AUH. CONCLUSION: We provide a real-world insight into the heterogeneous management and treatment pathways of newly diagnosed dementia patients and a subset of Alzheimer's Disease patients from across Europe.

Evaluation of a clinical decision rule to guide antibiotic prescription in children with suspected lower respiratory tract infection in The Netherlands: A stepped-wedge cluster randomised trial.

BACKGROUND: Optimising the use of antibiotics is a key component of antibiotic stewardship. Respiratory tract infections (RTIs) are the most common reason for antibiotic prescription in children, even though most of these infections in children under 5 years are viral. This study aims to safely reduce antibiotic prescriptions in children under 5 years with suspected lower RTI at the emergency department (ED), by implementing a clinical decision rule. METHODS AND FINDINGS: In a stepped-wedge cluster randomised trial, we included children aged 1-60 months presenting with fever and cough or dyspnoea to 8 EDs in The Netherlands. The EDs were of varying sizes, from diverse geographic and demographic regions, and of different hospital types (tertiary versus general). In the pre-intervention phase, children received usual care, according to the Dutch and NICE guidelines for febrile children. During the intervention phase, a validated clinical prediction model (Feverkidstool) including clinical characteristics and C-reactive protein (CRP) was implemented as a decision rule guiding antibiotic prescription. The intervention was that antibiotics were withheld in children with a low or intermediate predicted risk of bacterial pneumonia (≤10%, based on Feverkidstool). Co-primary outcomes were antibiotic prescription rate and strategy failure. Strategy failure was defined as secondary antibiotic prescriptions or hospitalisations, persistence of fever or oxygen dependency up to day 7, or complications. Hospitals were randomly allocated to 1 sequence of treatment each, using computer randomisation. The trial could not be blinded. We used multilevel logistic regression to estimate the effect of the intervention, clustered by hospital and adjusted for time period, age, sex, season, ill appearance, and fever duration; predicted risk was included in exploratory analysis. We included 999 children (61% male, median age 17 months [IQR 9 to 30]) between 1 January 2016 and 30 September 2018: 597 during the pre-intervention phase and 402 during the intervention phase. Most children (77%) were referred by a general practitioner, and half of children were hospitalised. Intention-to-treat analyses showed that overall antibiotic prescription was not reduced (30% to 25%, adjusted odds ratio [aOR] 1.07 [95% CI 0.57 to 2.01, p = 0.75]); strategy failure reduced from 23% to 16% (aOR 0.53 [95% CI 0.32 to 0.88, p = 0.01]). Exploratory analyses showed that the intervention influenced risk groups differently (p < 0.01), resulting in a reduction in antibiotic prescriptions in low/intermediate-risk children (17% to 6%; aOR 0.31 [95% CI 0.12 to 0.81, p = 0.02]) and a non-significant increase in the high-risk group (47% to 59%; aOR 2.28 [95% CI 0.84 to 6.17, p = 0.09]). Two complications occurred during the trial: 1 admission to the intensive care unit during follow-up and 1 pleural empyema at day 10 (both unrelated to the study intervention). Main limitations of the study were missing CRP values in the pre-intervention phase and a prolonged baseline period due to logistical issues, potentially affecting the power of our study. CONCLUSIONS: In this multicentre ED study, we observed that a clinical decision rule for childhood pneumonia did not reduce overall antibiotic prescription, but that it was non-inferior to usual care. Exploratory analyses showed fewer strategy failures and that fewer antibiotics were prescribed in low/intermediate-risk children, suggesting improved targeting of antibiotics by the decision rule. TRIAL REGISTRATION: Netherlands Trial Register NTR5326.

Opioid prescriptions in patients with osteoarthritis: a population-based cohort study.

OBJECTIVES: To examine the incidence, prevalence and trends for opioid prescriptions in patients with OA. Furthermore, types of opioids prescribed and long-term prescription rates were examined. Finally, the patient characteristics associated with the prescription of opioids were assessed. METHODS: A population-based cohort study was conducted using the Integrated Primary Care Information database. Incidence and prevalence of opioid prescriptions were calculated for the period 2008-2017. Logistic regression was used to assess which patient characteristics were associated with opioid prescriptions. RESULTS: In total, 157 904 OA patients were included. The overall prescription rate remained fairly stable, at around 100 incident and 170 prevalent prescriptions per 1000 person years. However, the incident prescription rate for oxycodone increased from 7.1 to 40.7 per 1000 person years and for fentanyl from 4.2 to 7.4 per 1000 person years. The incident prescription rate for paracetamol/codeine decreased from 63.0 to 13.3 per 1000 person years. Per follow-up year, long-term use was found in 3% of the patients with incident OA. Finally, factors associated with more prescriptions were increasing age, OA in ≥2 joint groups [odds ratio (OR) 1.56; 95% CI: 1.51, 1.65] and the presence of other musculoskeletal disorders (OR 4.91; 95% CI: 4.76, 5.05). Men were less likely to be prescribed opioids (OR 0.78; 95% CI: 0.76, 0.80). CONCLUSION: Prescription rates for opioids remained stable, but types of opioids prescribed changed. Oxycodone and fentanyl were increasingly prescribed, while prescriptions of paracetamol/codeine decreased. Since the benefit of opioids for OA pain is questionable and side effects are common, opioids should be prescribed with caution.

Real-world evidence in Alzheimer's disease: The ROADMAP Data Cube.

INTRODUCTION: The ROADMAP project aimed to provide an integrated overview of European real-world data on Alzheimer's disease (AD) across the disease spectrum. METHODS: Metadata were identified from data sources in catalogs of European AD projects. Priority outcomes for different stakeholders were identified through systematic literature review, patient and public consultations, and stakeholder surveys. RESULTS: Information about 66 data sources and 13 outcome domains were integrated into a Data Cube. Gap analysis identified cognitive ability, functional ability/independence, behavioral/neuropsychiatric symptoms, treatment, comorbidities, and mortality as the outcomes collected most. Data were most lacking in caregiver-related outcomes. In general, electronic health records covered a broader, less detailed data spectrum than research cohorts. DISCUSSION: This integrated real-world AD data overview provides an intuitive visual model that facilitates initial assessment and identification of gaps in relevant outcomes data to inform future prospective data collection and matching of data sources and outcomes against research protocols.

Risks and clinical predictors of cirrhosis and hepatocellular carcinoma diagnoses in adults with diagnosed NAFLD: real-world study of 18 million patients in four European cohorts.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a common condition that progresses in some patients to steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma (HCC). Here we used healthcare records of 18 million adults to estimate risk of acquiring advanced liver disease diagnoses in patients with NAFLD or NASH compared to individually matched controls. METHODS: Data were extracted from four European primary care databases representing the UK, Netherlands, Italy and Spain. Patients with a recorded diagnosis of NAFLD or NASH (NAFLD/NASH) were followed up for incident cirrhosis and HCC diagnoses. Each coded NAFLD/NASH patient was matched to up to 100 "non-NAFLD" patients by practice site, gender, age ± 5 years and visit recorded within ± 6 months. Hazard ratios (HR) were estimated using Cox models adjusted for age and smoking status and pooled across databases by random effects meta-analyses. RESULTS: Out of 18,782,281 adults, we identified 136,703 patients with coded NAFLD/NASH. Coded NAFLD/NASH patients were more likely to have diabetes, hypertension and obesity than matched controls. HR for cirrhosis in patients compared to controls was 4.73 (95% CI 2.43-9.19) and for HCC, 3.51 (95% CI 1.72-7.16). HR for either outcome was higher in patients with NASH and those with high-risk Fib-4 scores. The strongest independent predictor of a diagnosis of HCC or cirrhosis was baseline diagnosis of diabetes. CONCLUSIONS: Real-world population data show that recorded diagnosis of NAFLD/NASH increases risk of life-threatening liver outcomes. Diabetes is an independent predictor of advanced liver disease diagnosis, emphasising the need to identify specific groups of patients at highest risk.

Real-world data reveal a diagnostic gap in non-alcoholic fatty liver disease.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is the most common cause of liver disease worldwide. It affects an estimated 20% of the general population, based on cohort studies of varying size and heterogeneous selection. However, the prevalence and incidence of recorded NAFLD diagnoses in unselected real-world health-care records is unknown. We harmonised health records from four major European territories and assessed age- and sex-specific point prevalence and incidence of NAFLD over the past decade. METHODS: Data were extracted from The Health Improvement Network (UK), Health Search Database (Italy), Information System for Research in Primary Care (Spain) and Integrated Primary Care Information (Netherlands). Each database uses a different coding system. Prevalence and incidence estimates were pooled across databases by random-effects meta-analysis after a log-transformation. RESULTS: Data were available for 17,669,973 adults, of which 176,114 had a recorded diagnosis of NAFLD. Pooled prevalence trebled from 0.60% in 2007 (95% confidence interval: 0.41-0.79) to 1.85% (0.91-2.79) in 2014. Incidence doubled from 1.32 (0.83-1.82) to 2.35 (1.29-3.40) per 1000 person-years. The FIB-4 non-invasive estimate of liver fibrosis could be calculated in 40.6% of patients, of whom 29.6-35.7% had indeterminate or high-risk scores. CONCLUSIONS: In the largest primary-care record study of its kind to date, rates of recorded NAFLD are much lower than expected suggesting under-diagnosis and under-recording. Despite this, we have identified rising incidence and prevalence of the diagnosis. Improved recognition of NAFLD may identify people who will benefit from risk factor modification or emerging therapies to prevent progression to cardiometabolic and hepatic complications.

Validation of the Feverkidstool and procalcitonin for detecting serious bacterial infections in febrile children.

BackgroundTo validate the Feverkidstool, a prediction model consisting of clinical signs and symptoms and C-reactive protein (CRP) to identify serious bacterial infections (SBIs) in febrile children, and to determine the incremental diagnostic value of procalcitonin.MethodsThis prospective observational study that was carried out at two Dutch emergency departments included children with fever, aged 1 month to 16 years. The prediction models were developed with polytomous logistic regression differentiating "pneumonia" and "other SBIs" from "non-SBIs" using standardized, routinely collected data on clinical signs and symptoms, CRP, and procalcitonin.ResultsA total of 1,085 children were included with a median age of 1.6 years (interquartile range 0.8-3.4); 73 children (7%) had pneumonia and 98 children (9%) had other SBIs. The Feverkidstool showed good discriminative ability in this new population. After adding procalcitonin to the Feverkidstool, c-statistic for "pneumonia" increased from 0.85 (95% confidence interval (CI) 0.76-0.94) to 0.86 (0.77-0.94) and for "other SBI" from 0.81 (0.73-0.90) to 0.83 (0.75- 0.91). A model with clinical features and procalcitonin performed similar to the Feverkidstool.ConclusionThis study confirms the external validity of the Feverkidstool, with CRP and procalcitonin being equally valuable for predicting SBI in our population of febrile children. Our findings do not support routine dual use of CRP and procalcitonin.

Dementia prevalence and incidence in a federation of European Electronic Health Record databases: The European Medical Informatics Framework resource.

INTRODUCTION: The European Medical Information Framework consortium has assembled electronic health record (EHR) databases for dementia research. We calculated dementia prevalence and incidence in 25 million persons from 2004 to 2012. METHODS: Six EHR databases (three primary care and three secondary care) from five countries were interrogated. Dementia was ascertained by consensus harmonization of clinical/diagnostic codes. Annual period prevalences and incidences by age and gender were calculated and meta-analyzed. RESULTS: The six databases contained 138,625 dementia cases. Age-specific prevalences were around 30% of published estimates from community samples and incidences were around 50%. Pooled prevalences had increased from 2004 to 2012 in all age groups but pooled incidences only after age 75 years. Associations with age and gender were stable over time. DISCUSSION: The European Medical Information Framework initiative supports EHR data on unprecedented number of people with dementia. Age-specific prevalences and incidences mirror estimates from community samples in pattern at levels that are lower but increasing over time.

Implementation of clinical decision support in young children with acute gastroenteritis: a randomized controlled trial at the emergency department.

Acute gastroenteritis (AGE) is one of the most frequent reasons for young children to visit emergency departments (EDs). We aimed to evaluate (1) feasibility of a nurse-guided clinical decision support system for rehydration treatment in children with AGE and (2) the impact on diagnostics, treatment, and costs compared with usual care by attending physician. A randomized controlled trial was performed in 222 children, aged 1 month to 5 years at the ED of the Erasmus MC-Sophia Children's hospital in The Netherlands ( 2010-2012). Outcome included (1) feasibility, measured by compliance of the nurses, and (2) length of stay (LOS) at the ED, the number of diagnostic tests, treatment, follow-up, and costs. Due to failure of post-ED weight measurement, we could not evaluate weight difference as measure for dehydration. Patient characteristics were comparable between the intervention (N = 113) and the usual care group (N = 109). Implementation of the clinical decision support system proved a high compliance rate. The standardized use of oral ORS (oral rehydration solution) significantly increased from 52 to 65%(RR2.2, 95%CI 1.09-4.31 p < 0.05). We observed no differences in other outcome measures. CONCLUSION: Implementation of nurse-guided clinical decision support system on rehydration treatment in children with AGE showed high compliance and increase standardized use of ORS, without differences in other outcome measures. What is Known: • Acute gastroenteritis is one of the most frequently encountered problems in pediatric emergency departments. • Guidelines advocate standardized oral treatment in children with mild to moderate dehydration, but appear to be applied infrequently in clinical practice. What is New: • Implementation of a nurse-guided clinical decision support system on treatment of AGE in young children showed good feasibility, resulting in a more standardized ORS use in children with mild to moderate dehydration, compared to usual care. • Given the challenges to perform research in emergency care setting, the ED should be experienced and adequately equipped, especially during peak times.

Risk of upper gastrointestinal bleeding from different drug combinations.

BACKGROUND & AIMS: Concomitant use of nonsteroidal anti-inflammatory drugs (NSAIDs) and low-dose aspirin increases the risk of upper gastrointestinal bleeding (UGIB). Guidelines suggest avoiding certain drug combinations, yet little is known about the magnitude of their interactions. We estimated the risk of UGIB during concomitant use of nonselective (ns)NSAIDs, cyclooxygenase -2 selective inhibitors (COX-2 inhibitors), and low-dose aspirin with other drugs. METHODS: We performed a case series analysis of data from 114,835 patients with UGIB (930,888 person-years of follow-up) identified from 7 population-based health care databases (approximately 20 million subjects). Each patient served as his or her own control. Drug exposure was determined based on prescriptions of nsNSAIDs, COX-2 inhibitors, or low-dose aspirin, alone and in combination with other drugs that affect the risk of UGIB. We measured relative risk (incidence rate ratio [IRR] during drug exposure vs nonexposure) and excess risk due to concomitant drug exposure (relative excess risk due to interaction [RERI]). RESULTS: Monotherapy with nsNSAIDs increased the risk of diagnosis of UGIB (IRR, 4.3) to a greater extent than monotherapy with COX-2 inhibitors (IRR, 2.9) or low-dose aspirin (IRR, 3.1). Combination therapy generally increased the risk of UGIB; concomitant nsNSAID and corticosteroid therapies increased the IRR to the greatest extent (12.8) and also produced the greatest excess risk (RERI, 5.5). Concomitant use of nsNSAIDs and aldosterone antagonists produced an IRR for UGIB of 11.0 (RERI, 4.5). Excess risk from concomitant use of nsNSAIDs with selective serotonin reuptake inhibitors (SSRIs) was 1.6, whereas that from use of COX-2 inhibitors with SSRIs was 1.9 and that for use of low-dose aspirin with SSRIs was 0.5. Excess risk of concomitant use of nsNSAIDs with anticoagulants was 2.4, of COX-2 inhibitors with anticoagulants was 0.1, and of low-dose aspirin with anticoagulants was 1.9. CONCLUSIONS: Based on a case series analysis, concomitant use of nsNSAIDs, COX-2 inhibitors, or low-dose aspirin with SSRIs significantly increases the risk of UGIB. Concomitant use of nsNSAIDs or low-dose aspirin, but not COX-2 inhibitors, with corticosteroids, aldosterone antagonists, or anticoagulants produces significant excess risk of UGIB.

The role of electronic healthcare record databases in paediatric drug safety surveillance: a retrospective cohort study.

AIM: Electronic healthcare record (EHR)-based surveillance systems are increasingly being developed to support early detection of safety signals. It is unknown what the power of such a system is for surveillance among children and adolescents. In this paper we provide estimates of the number and classes of drugs, and incidence rates (IRs) of events, that can be monitored in children and adolescents (0-18 years). METHODS: Data were obtained from seven population-based EHR databases in Denmark, Italy, and the Netherlands during the period 1996-2010. We estimated the number of drugs for which specific adverse events can be monitored as a function of actual drug use, minimally detectable relative risk (RR) and IRs for 10 events. RESULTS: The population comprised 4 838 146 individuals (25 575 132 person years (PYs)), who were prescribed 2170 drugs (1 610 631 PYs drug-exposure). Half of the total drug-exposure in PYs was covered by only 18 drugs (0.8%). For a relatively frequent event like upper gastrointestinal bleeding there were 39 drugs for which an association with a RR ≥4, if present, could be investigated. The corresponding number of drugs was eight for a rare event like anaphylactic shock. CONCLUSION: Drug use in children is rare and shows little variation. The number of drugs with enough exposure to detect rare adverse events in children and adolescents within an EHR-based surveillance system such as EU-ADR is limited. Use of additional sources of paediatric drug exposure information and global collaboration are imperative in order to optimize EHR data for paediatric safety surveillance.

Adverse drug reactions in a primary care population prescribed non-steroidal anti-inflammatory drugs.

OBJECTIVE: To determine how often patients with musculoskeletal (MSK) complaints prescribed a non-steroidal anti-inflammatory drug (NSAID) subsequently consult their general practitioner (GP) with a non-serious adverse drug reaction (ADR). DESIGN: Cohort study. SETTING: A healthcare database containing the electronic GP medical records of over 1.5 million patients throughout the Netherlands. PATIENTS: A total of 16 626 adult patients with MSK complaints prescribed an NSAID. MAIN OUTCOME MEASURES: The patients' medical records were manually assessed for the duration of NSAID use for a maximum of two months, and consultations for complaints predefined as potential ADRs were identified. Subsequently, the likelihood of an association with the NSAID use was assessed and these potential ADRs were categorized as likely, possible, or unlikely ADRs. RESULTS: In total, 961 patients (6%) consulted their GP with 1227 non-serious potential ADRs. In 174 patients (1%) at least one of these was categorized as a likely ADR, and in a further 408 patients (2.5%) at least one was categorized as a possible ADR. Dyspepsia was the most frequent likely ADR, followed by diarrhoea and dyspnoea (respectively 34%, 8%, and 8% of all likely ADRs). CONCLUSION: Of the patients with MSK complaints prescribed an NSAID, almost one in 30 patients re-consulted their GP with a complaint likely or possibly associated with the use of this drug. The burden of such consultations for non-serious ADRs should be taken into account by GPs when deciding whether treatment with an NSAID is appropriate.

The EU-ADR Web Platform: delivering advanced pharmacovigilance tools.

PURPOSE: Pharmacovigilance methods have advanced greatly during the last decades, making post-market drug assessment an essential drug evaluation component. These methods mainly rely on the use of spontaneous reporting systems and health information databases to collect expertise from huge amounts of real-world reports. The EU-ADR Web Platform was built to further facilitate accessing, monitoring and exploring these data, enabling an in-depth analysis of adverse drug reactions risks. METHODS: The EU-ADR Web Platform exploits the wealth of data collected within a large-scale European initiative, the EU-ADR project. Millions of electronic health records, provided by national health agencies, are mined for specific drug events, which are correlated with literature, protein and pathway data, resulting in a rich drug-event dataset. Next, advanced distributed computing methods are tailored to coordinate the execution of data-mining and statistical analysis tasks. This permits obtaining a ranked drug-event list, removing spurious entries and highlighting relationships with high risk potential. RESULTS: The EU-ADR Web Platform is an open workspace for the integrated analysis of pharmacovigilance datasets. Using this software, researchers can access a variety of tools provided by distinct partners in a single centralized environment. Besides performing standalone drug-event assessments, they can also control the pipeline for an improved batch analysis of custom datasets. Drug-event pairs can be substantiated and statistically analysed within the platform's innovative working environment. CONCLUSIONS: A pioneering workspace that helps in explaining the biological path of adverse drug reactions was developed within the EU-ADR project consortium. This tool, targeted at the pharmacovigilance community, is available online at https://bioinformatics.ua.pt/euadr/.

Development and validation of a clinical prediction rule for acute appendicitis in children in primary care.

BACKGROUND: Recognising acute appendicitis in children presenting with acute abdominal pain in primary care is challenging. General practitioners (GPs) may benefit from a clinical prediction rule. OBJECTIVES: To develop and validate a clinical prediction rule for acute appendicitis in children presenting with acute abdominal pain in primary care. METHODS: In a historical cohort study data was retrieved from GP electronic health records included in the Integrated Primary Care Information database. We assigned children aged 4-18 years presenting with acute abdominal pain (≤ 7 days) to development (2010-2012) and validation (2013-2016) cohorts, using acute appendicitis within six weeks as the outcome. Multiple logistic regression was used to develop a prediction model based on predictors with > 50% data availability derived from existing rules for secondary care. We performed internal and external temporal validation and derived a point score to stratify risk of appendicitis into three groups, i.e. low-risk, medium-risk and high-risk. RESULTS: The development and validation cohorts included 2,041 and 3,650 children, of whom 95 (4.6%) and 195 (5.3%) had acute appendicitis. The model included male sex, pain duration (<24, 24-48, > 48 h), nausea/vomiting, elevated temperature (≥ 37.3 °C), abnormal bowel sounds, right lower quadrant tenderness, and peritoneal irritation. Internal and temporal validation showed good discrimination (C-statistics: 0.93 and 0.90, respectively) and excellent calibration. In the three groups, the risks of acute appendicitis were 0.5%, 7.5%, and 41%. CONCLUSION: Combined with further testing in the medium-risk group, the prediction rule could improve clinical decision making and outcomes.