Prevalence and incidence rate of hospital admissions related to medication between 2008 and 2013 in The Netherlands.

PURPOSE: In 2009 a Dutch guideline was published containing recommendations to reduce Hospital Admissions Related to Medications (HARMs). This study aims to examine time-trends of HARMs and their potential preventability between 2008 and 2013 in The Netherlands. METHODS: A retrospective prevalence study was conducted using the Dutch PHARMO Database Network. A semi-automated pre-selection was used to make a crude identification of possible HARMs of which four samples were selected. These were independently assessed with respect to causality and potential preventability by a physician and pharmacist. The results were stratified by age into 18-64 years and 65 years and older. For these groups the net prevalences and incidence rates of HARMs and potentially preventable HARMs were calculated for the years 2008, 2009, 2011 and 2013. RESULTS: Four samples of 467 (2008), 447 (2009), 446 (2011) and 408 (2013) admissions were assessed. The net prevalence of HARMs in the 18-64 years group was approximately four times smaller compared to the older group with a mean prevalence of 2.7% (95% confidence interval [CI]:2.4%-3.0%) and 10.2% (95%CI: 9.7%-10.7%) respectively. The potential preventability was 25.1% (18.4%-31.8%) and 48.3% (95%CI: 44.8%-51.8%), respectively. The prevalence of HARMs in both groups did not change significantly between 2008 and 2013 with 2.4% (95%CI: 1.9%-3.0%) and 10.0% (95%CI: 9.0%-11.0%) in 2008 and 3.1% (2.7%-3.5%) and 10.4% (95%CI: 9.4%-11.4%) in 2013, respectively. CONCLUSION: Despite efforts to reduce HARMs, the prevalence did not decrease over time. Additional measures are therefore necessary, especially in the elderly population.

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.

Time-trends in the prescribing of gastroprotective agents to primary care patients initiating low-dose aspirin or non-steroidal anti-inflammatory drugs: a population-based cohort study.

AIMS: Low-dose aspirin (LDA) and non-steroidal-anti-inflammatory drugs (NSAIDs) both increase the risk of upper gastrointestinal events (UGIEs). In the Netherlands, recommendations regarding the prescription of gastroprotective agents (GPAs) in LDA users were first issued in 2009 in the HARM-Wrestling consensus. National guidelines on gastroprotective strategies (GPSs) in NSAID users were issued in the first part of the preceding. The aim of the present study was to examine time-trends in GPSs in patients initiating LDA and those initiating NSAIDs between 2000 and 2012. METHODS: Within a large electronic primary healthcare database, two cohorts were selected: (i) patients newly prescribed LDA and (ii) patients newly prescribed NSAIDs between 2000 and 2012. Patients who had been prescribed a GPA in the previous six months were excluded. For both cohorts, patients' risk of a UGIE was classified as low, moderate or high, based on the HARM-Wrestling consensus, and the presence of an adequate GPSwas determined. RESULTS: A total of 37 578 patients were included in the LDA cohort and 352 025 patients in the NSAID cohort. In both cohorts, an increase in GPSs was observed over time, but prescription of GPAs was lower in the LDA cohort. By 2012, an adequate GPS was present in 31.8% of high-risk LDA initiators, vs. 48.0% of high-risk NSAID initiators. CONCLUSIONS: Despite a comparable risk of UGIEs, GPSs are prescribed less in high-risk LDA initiators than in high-risk NSAID initiators. For both groups of patients, there is still room for improvement in guideline adherence.

Quick assessment of drug-related admissions over time (QUADRAT study).

PURPOSE: To develop a computerized prescreening procedure for the identification of possible/probably Hospital Admissions potential Related to Medications (HARMs). METHOD: Pairs of drugs and reasons for hospitalization (generated automatically from the PHARMO record linkage database by using two data mining techniques) were assessed manually to determine whether they represented pharmacologically plausible adverse drug events (PP-ADEs). Two crude samples of these PP-ADEs (from 2005 and 2008) were examined manually to establish causality and preventability on the basis of hospital discharge letters plus medication dispensing data. The results were used to calculate the positive predictive value (PPV) of the crude causality PP-ADEs, the net percentage of possible/probably HARMs, and their potential preventability. RESULTS: Data mining by Gamma Poisson Shrinkage and trend analysis produced 1330 and 2941 significant drug-event pairs, respectively. After manual assessment, 307 different PP-ADEs remained. The annual prevalence of these PP-ADEs was stable at approximately 8% throughout 2000-2009. Manual assessment of two samples of crude PP-ADEs showed that their causality PPV was 53.7% (95%CI: 52.7%-54.7%) in 2005 and 47.9% (95%CI: 46.9%-49.0%) in 2008. The net contribution of possible/probably HARMs to all acute admissions was 4.6% (95%CI: 4.5%-4.8%) in 2005 and 3.9% (95%CI: 3.8%-4.0%) in 2008. The potential preventability of all possible/probably HARMs in the two samples was 19.3% (95%CI: 18.5-20.1). CONCLUSION: Automated pre-selection of PP-ADEs is an efficient way to monitor crude trends. Further validation and manual assessment of the automatically selected hospitalizations is necessary to get a more detailed and precise picture.

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.

New oral anticoagulants increase risk for gastrointestinal bleeding: a systematic review and meta-analysis.

BACKGROUND & AIMS: A new generation of oral anticoagulants (nOAC), which includes thrombin and factor Xa inhibitors, has been shown to be effective, but little is known about whether these drugs increase patients' risk for gastrointestinal bleeding (GIB). Patients who require OAC therapy frequently have significant comorbidities and may also take aspirin and/or thienopyridines. We performed a systematic review and meta-analysis of the risk of GIB and clinically relevant bleeding in patients taking nOAC. METHODS: We queried MEDLINE, EMbase, and the Cochrane library (through July 2012) without language restrictions. We analyzed data from 43 randomized controlled trials (151,578 patients) that compared nOAC (regardless of indication) with standard care for risk of bleeding (19 trials on GIB). Odds ratios (ORs) were estimated using a random-effects model. Heterogeneity was assessed with the Cochran Q test and the Higgins I(2) test. RESULTS: The overall OR for GIB among patients taking nOAC was 1.45 (95% confidence interval [CI], 1.07-1.97), but there was substantial heterogeneity among studies (I2, 61%). Subgroup analyses showed that the OR for atrial fibrillation was 1.21 (95% CI, 0.91-1.61), for thromboprophylaxis after orthopedic surgery the OR was 0.78 (95% CI, 0.31-1.96), for treatment of venous thrombosis the OR was 1.59 (95% CI, 1.03-2.44), and for acute coronary syndrome the OR was 5.21 (95% CI, 2.58-10.53). Among the drugs studied, the OR for apixaban was 1.23 (95% CI, 0.56-2.73), the OR for dabigatran was 1.58 (95% CI, 1.29-1.93), the OR for edoxaban was 0.31 (95% CI, 0.01-7.69), and the OR for rivaroxaban was 1.48 (95% CI, 1.21-1.82). The overall OR for clinically relevant bleeding in patients taking nOAC was 1.16 (95% CI, 1.00-1.34), with similar trends among subgroups. CONCLUSIONS: Studies on treatment of venous thrombosis or acute coronary syndrome have shown that patients treated with nOAC have an increased risk of GIB, compared with those who receive standard care. Better reporting of GIB events in future trials could allow stratification of patients for therapy with gastroprotective agents.

Ischaemic cardiovascular risk and prescription of non-steroidal anti-inflammatory drugs for musculoskeletal complaints.

OBJECTIVE: To determine the influence of ischaemic cardiovascular (CV) risk on prescription of non-steroidal anti-inflammatory drugs (NSAIDs) by general practitioners (GPs) in patients with musculoskeletal complaints. DESIGN: Cohort study. SETTING: A healthcare database containing the electronic GP medical records of over one million patients throughout the Netherlands. PATIENTS: A total of 474 201 adults consulting their GP with a new musculoskeletal complaint between 2000 and 2010. Patients were considered at high CV risk if they had a history of myocardial infarction, angina pectoris, stroke, transient ischaemic attack, or peripheral arterial disease, and at low CV risk if they had no CV risk factors. MAIN OUTCOME MEASURES: Frequency of prescription of non-selective (ns)NSAIDs and selective cyclooxygenase-2 inhibitors (coxibs). RESULTS: Overall, 24.4% of patients were prescribed an nsNSAID and 1.4% a coxib. Of the 41,483 patients with a high CV risk, 19.9% received an nsNSAID and 2.2% a coxib. These patients were more likely to be prescribed a coxib than patients with a low CV risk (OR 1.9, 95% CI 1.8-2.0). Prescription of nsNSAIDs decreased over time in all risk groups and was lower in patients with a high CV risk than in patients with a low CV risk (OR 0.8, 95% CI 0.7-0.8). CONCLUSION: Overall, patients with a high CV risk were less likely to be prescribed an NSAID for musculoskeletal complaints than patients with a low CV risk. Nevertheless, one in five high CV risk patients received an NSAID, indicating that there is still room for improvement.

Proton pump inhibitors reduce the risk of neoplastic progression in patients with Barrett's esophagus.

BACKGROUND & AIMS: Acid exposure contributes to the development of Barrett's esophagus (BE) and its progression toward esophageal adenocarcinoma. Patients with BE are frequently treated with acid suppressants, but it is unclear whether these prevent the development of BE-related cancer. We investigated whether acid suppression reduces the risk of neoplastic progression in patients with BE. METHODS: We performed a multicenter prospective cohort study of 540 patients with BE. We collected information on medication use at each surveillance visit, which was cross-checked with pharmacy records. Patients also completed a questionnaire about their use of over-the-counter medication. Incident cases of high-grade dysplasia and esophageal adenocarcinoma were identified during a median follow-up period of 5.2 years. Time-dependent Cox regression models were used to investigate the effect of acid suppression on the risk of neoplastic progression. RESULTS: Forty patients (7%) developed high-grade dysplasia or esophageal adenocarcinoma during the follow-up period. Use of histamine-2 receptor antagonists did not affect the incidence of neoplastic progression. However, use of proton pump inhibitors (PPIs) at inclusion in the study or during the follow-up period reduced the risk of neoplastic progression (hazard ratio, 0.41; 95% confidence interval, 0.18-0.93 and hazard ratio, 0.21; 95% confidence interval, 0.07-0.66). Prolonged use of PPIs and good adherence were associated with an additional protective effect. The prevalence of esophagitis decreased during PPI use, but length of BE was not affected. CONCLUSIONS: In a multicenter prospective cohort study, PPI use was associated with a reduced risk of neoplastic progression in patients with BE.

Adherence to gastroprotection during cyclooxygenase 2 inhibitor treatment and the risk of upper gastrointestinal tract events: a population-based study.

OBJECTIVE: Guidelines recommend coprescription of gastroprotective agents (GPAs) in patients receiving cyclooxygenase 2 inhibitors (coxibs) who are at high risk of upper gastrointestinal (UGI) tract complications (i.e., patients with a previous complicated ulcer or with multiple risk factors). Suboptimal GPA adherence has been shown to diminish the gastroprotective effect during use of nonselective nonsteroidal antiinflammatory drugs, but little is known about the effect of GPA adherence during coxib treatment. We undertook this study to determine the association between GPA adherence and UGI tract events among patients receiving coxibs. METHODS: Using primary care data from 3 databases, we conducted a case-control study in a cohort of patients age ≥50 years who were newly starting treatment with coxibs and concomitantly taking GPAs. Patients who had a UGI tract event (bleeding or symptomatic ulcer) were matched to event-free controls for age, sex, database, and calendar date. Coxib treatment intervals were defined as consecutive coxib prescriptions with intervening gaps not exceeding the duration of the previous coxib prescription. Adherence to GPAs was calculated as the proportion of days of coxib treatment covered by a GPA prescription. Odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated using conditional logistic regression analysis. RESULTS: The coxib plus GPA-treated cohort consisted of 14,416 coxib-treated patients who received GPAs for at least 1 day, yielding 16,442 coxib treatment intervals in which a GPA was coprescribed. Most patients were treated with coxibs for <30 days. Seventy-four patients had a UGI tract event during or shortly after a coxib treatment interval in which a GPA was coprescribed, with an incidence rate of 11.9 (95% CI 9.4-14.8) per 1,000 years of coxib treatment. The risk of UGI tract events was 1.97 (95% CI 0.84-4.60) for patients with <20% adherence to GPAs compared to patients with >80% adherence to GPAs. For every 10% decrease in GPA adherence, the risk of UGI tract events increased by 9% (OR 1.09 [95% CI 1.00-1.18]). CONCLUSION: Decreasing GPA adherence among coxib-treated patients is associated with an increased risk of UGI tract events.

Population-based analysis of non-steroidal anti-inflammatory drug use among children in four European countries in the SOS project: what size of data platforms and which study designs do we need to assess safety issues?

BACKGROUND: Data on utilization patterns and safety of non-steroidal anti-inflammatory drugs (NSAIDs) in children are scarce. The purpose of this study was to investigate the utilization of NSAIDs among children in four European countries as part of the Safety Of non-Steroidal anti-inflammatory drugs (SOS) project. METHODS: We used longitudinal patient data from seven databases (GePaRD, IPCI, OSSIFF, Pedianet, PHARMO, SISR, and THIN) to calculate prevalence rates of NSAID use among children (0-18 years of age) from Germany, Italy, Netherlands, and United Kingdom. All databases contained a representative population sample and recorded demographics, diagnoses, and drug prescriptions. Prevalence rates of NSAID use were stratified by age, sex, and calendar time. The person-time of NSAID exposure was calculated by using the duration of the prescription supply. We calculated incidence rates for serious adverse events of interest. For these adverse events of interest, sample size calculations were conducted (alpha = 0.05; 1-beta = 0.8) to determine the amount of NSAID exposure time that would be required for safety studies in children. RESULTS: The source population comprised 7.7 million children with a total of 29.6 million person-years of observation. Of those, 1.3 million children were exposed to at least one of 45 NSAIDs during observation time. Overall prevalence rates of NSAID use in children differed across countries, ranging from 4.4 (Italy) to 197 (Germany) per 1000 person-years in 2007. For Germany, United Kingdom, and Italian pediatricians, we observed high rates of NSAID use among children aged one to four years. For all four countries, NSAID use increased with older age categories for children older than 11. In this analysis, only for ibuprofen (the most frequently used NSAID), enough exposure was available to detect a weak association (relative risk of 2) between exposure and asthma exacerbation (the most common serious adverse event of interest). CONCLUSIONS: Patterns of NSAID use in children were heterogeneous across four European countries. The SOS project platform captures data on more than 1.3 million children who were exposed to NSAIDs. Even larger data platforms and the use of advanced versions of case-only study designs may be needed to conclusively assess the safety of these drugs in children.

Suboptimal gastroprotective coverage of NSAID use and the risk of upper gastrointestinal bleeding and ulcers: an observational study using three European databases.

BACKGROUND: Gastro-protective agents (GPA) are co-prescribed with non-steroidal anti-inflammatory drugs (NSAID) to lower the risk of upper gastrointestinal (UGI) events. It is unknown to what extent the protective effect is influenced by therapy adherence. AIM: To study the association between GPA adherence and UGI events among non-selective (ns) NSAID users. METHODS: The General Practice Research Database (UK 1998-2008), the Integrated Primary Care Information database (the Netherlands 1996-2007) and the Health Search/CSD Longitudinal Patient Database (Italy 2000-2007) were used. A nested case-control design was employed within a cohort of nsNSAID users aged ≥50 years, who also used a GPA. UGI event cases (UGI bleeding and/or symptomatic ulcer with/without obstruction/perforation) were matched to event-free members of the cohort for age, sex, database and calendar time. Adherence to GPA was calculated as the proportion of nsNSAID treatment days covered by a GPA prescription. Adjusted OR with 95% CI were calculated. RESULTS: The cohort consisted of 618 684 NSAID users, generating 1 107 266 nsNSAID episodes. Of these, 117 307 (10.6%) were (partly) covered by GPA, 4.9% of which with a GPA coverage <20% (non-adherence), and 68.1% with a GPA coverage >80% (full adherence). 339 patients experienced an event. Among non-adherers, the OR was 2.39 (95% CI 1.66 to 3.44) for all UGI events and 1.89 (95% CI 1.09 to 3.28) for UGI bleeding alone, compared to full adherers. CONCLUSIONS: The risk of UGI events was significantly higher in nsNSAID users with GPA non-adherence. This underlines the importance of strategies to improve GPA adherence.

NHERF1 and NHERF2 are necessary for multiple but usually separate aspects of basal and acute regulation of NHE3 activity.

Na(+)/H(+) exchanger 3 (NHE3) is expressed in the brush border (BB) of intestinal epithelial cells and accounts for the majority of neutral NaCl absorption. It has been shown that the Na(+)/H(+) exchanger regulatory factor (NHERF) family members of multi-PDZ domain-containing scaffold proteins bind to the NHE3 COOH terminus and play necessary roles in NHE3 regulation in intestinal epithelial cells. Most studies of NHE3 regulation have been in cell models in which NHERF1 and/or NHERF2 were overexpressed. We have now developed an intestinal Na(+) absorptive cell model in Caco-2/bbe cells by expressing hemagglutinin (HA)-tagged NHE3 with an adenoviral infection system. Roles of NHERF1 and NHERF2 in NHE3 regulation were determined, including inhibition by cAMP, cGMP, and Ca(2+) and stimulation by EGF, with knockdown (KD) approaches with lentivirus (Lenti)-short hairpin RNA (shRNA) and/or adenovirus (Adeno)-small interfering RNA (siRNA). Stable infection of Caco-2/bbe cells by NHERF1 or NHERF2 Lenti-shRNA significantly and specifically reduced NHERF protein expression by >80%. NHERF1 KD reduced basal NHE3 activity, while NHERF2 KD stimulated NHE3 activity. siRNA-mediated (transient) and Lenti-shRNA-mediated (stable) gene silencing of NHERF2 (but not of NHERF1) abolished cGMP- and Ca(2+)-dependent inhibition of NHE3. KD of NHERF1 or NHERF2 alone had no effect on cAMP inhibition of NHE3, but KD of both simultaneously abolished the effect of cAMP. The stimulatory effect of EGF on NHE3 was eliminated in NHERF1-KD but occurred normally in NHERF2-KD cells. These findings show that both NHERF2 and NHERF1 are involved in setting NHE3 activity. NHERF2 is necessary for cGMP-dependent protein kinase (cGK) II- and Ca(2+)-dependent inhibition of NHE3. cAMP-dependent inhibition of NHE3 activity requires either NHERF1 or NHERF2. Stimulation of NHE3 activity by EGF is NHERF1 dependent.

Risk of acute myocardial infarction during use of individual NSAIDs: A nested case-control study from the SOS project.

BACKGROUND: Use of selective COX-2 non-steroidal anti-inflammatory drugs (NSAIDs) (coxibs) has been associated with an increased risk of acute myocardial infarction (AMI). However, the risk of AMI has only been studied for very few NSAIDs that are frequently used. OBJECTIVES: To estimate the risk of AMI for individual NSAIDs. METHODS: A nested case-control study was performed from a cohort of new NSAID users ≥18 years (1999-2011) matching cases to a maximum of 100 controls on database, sex, age, and calendar time. Data were retrieved from six healthcare databases. Adjusted odds ratios (ORs) of current use of individual NSAIDs compared to past use were estimated per database. Pooling was done by two-stage pooling using a random effects model (ORmeta) and by one-stage pooling (ORpool). RESULTS: Among 8.5 million new NSAID users, 79,553 AMI cases were identified. The risk was elevated for current use of ketorolac (ORmeta 2.06;95%CI 1.83-2.32, ORpool 1.80; 1.49-2.18) followed, in descending order of point estimate, by indometacin, etoricoxib, rofecoxib, diclofenac, fixed combination of diclofenac with misoprostol, piroxicam, ibuprofen, naproxen, celecoxib, meloxicam, nimesulide and ketoprofen (ORmeta 1.12; 1.03-1.22, ORpool 1.00;0.86-1.16). Higher doses showed higher risk estimates than lower doses. CONCLUSIONS: The relative risk estimates of AMI differed slightly between 28 individual NSAIDs. The relative risk was highest for ketorolac and was correlated with COX-2 potency, but not restricted to coxibs.

Development and application of indicators for the reduction of potentially preventable hospital admissions related to medications.

OBJECTIVE: The Dutch HARM-Wrestling (HW) Task Force issued general and drug-specific recommendations aimed at reducing hospital admissions related to medication (HARMs). This study examines if the drug-specific recommendations could be converted into indicators that could be monitored in existing databases of general practitioner (GP) or community pharmacy (CP) data. The study also assesses the performance of these indicators before and during the official release of HW recommendations. METHODS: HW recommendations were divided into sub-recommendations. We studied to what extent these were measurable as indicators based on available information in both databases. For each measurable indicator, performance between 2007 and 2010 was determined and possibilities for further improvement were estimated. RESULTS: Thirty-four drug-specific HW recommendations were divided into 69 sub-recommendations, 32 of which were measurable as indicator in at least one of the databases. Application of these indicators between 2007 and 2010 showed that many of the indicators did not change over time. Possibilities for further improvement were estimated as moderate to major for 16/31 (52%) indicators measured in the GP database and 6/15 (40%) HW indicators measured in the CP database. CONCLUSIONS: Further implementation of the HW recommendations and development of additional monitoring methods are warranted to improve drug safety in outpatients.

Validation study in four health-care databases: upper gastrointestinal bleeding misclassification affects precision but not magnitude of drug-related upper gastrointestinal bleeding risk.

OBJECTIVE: To evaluate the accuracy of disease codes and free text in identifying upper gastrointestinal bleeding (UGIB) from electronic health-care records (EHRs). STUDY DESIGN AND SETTING: We conducted a validation study in four European electronic health-care record (EHR) databases such as Integrated Primary Care Information (IPCI), Health Search/CSD Patient Database (HSD), ARS, and Aarhus, in which we identified UGIB cases using free text or disease codes: (1) International Classification of Disease (ICD)-9 (HSD, ARS); (2) ICD-10 (Aarhus); and (3) International Classification of Primary Care (ICPC) (IPCI). From each database, we randomly selected and manually reviewed 200 cases to calculate positive predictive values (PPVs). We employed different case definitions to assess the effect of outcome misclassification on estimation of risk of drug-related UGIB. RESULTS: PPV was 22% [95% confidence interval (CI): 16, 28] and 21% (95% CI: 16, 28) in IPCI for free text and ICPC codes, respectively. PPV was 91% (95% CI: 86, 95) for ICD-9 codes and 47% (95% CI: 35, 59) for free text in HSD. PPV for ICD-9 codes in ARS was 72% (95% CI: 65, 78) and 77% (95% CI: 69, 83) for ICD-10 codes (Aarhus). More specific definitions did not have significant impact on risk estimation of drug-related UGIB, except for wider CIs. CONCLUSIONS: ICD-9-CM and ICD-10 disease codes have good PPV in identifying UGIB from EHR; less granular terminology (ICPC) may require additional strategies. Use of more specific UGIB definitions affects precision, but not magnitude, of risk estimates.

High-risk use of over-the-counter non-steroidal anti-inflammatory drugs: a population-based cross-sectional study.

BACKGROUND: The use of non-steroidal anti-inflammatory drugs (NSAIDs) is associated with serious adverse drug events (ADEs). AIM: To determine the prevalence of over-the-counter (OTC) NSAID use in the general population and in patients with a high risk of developing a serious NSAID-related ADE. DESIGN AND SETTING: Cross-sectional study in four general practices in the Netherlands. METHOD: Two patient samples were selected: a random sample of adults (general population sample); and adult patients with a high risk of developing a serious ADE in case of NSAID use (high-risk sample). All included patients were sent a questionnaire regarding their use of OTC NSAIDs in the 4 weeks prior to participation. RESULTS: In the general population sample, 118 of 456 (26%) invited patients completed the questionnaire. Of these, 35 (30%) had used an OTC NSAID. In the high-risk sample, 264 of 713 (37%) invited patients completed the questionnaire, and of these high-risk patients 33 (13%) had used an OTC NSAID. Over 20% of OTC NSAID users in the general population sample and over 30% in the high-risk sample had used the OTC NSAID for >7 days. OTC NSAIDs were used in a dosage exceeding the recommended daily maximum by 9% and 3% of OTC NSAID users in the general population and the high-risk sample respectively. CONCLUSION: OTC NSAIDs are used by almost one-third of the general population. In the high-risk patients selected, one in eight patients used an OTC NSAID. Continued efforts by health authorities and healthcare professionals to inform patients of the risks of these drugs are warranted.

Low-dose acetylsalicylic acid use and the risk of upper gastrointestinal bleeding: a meta-analysis of randomized clinical trials and observational studies.

BACKGROUND: Low-dose acetylsalicylic acid (LDA, 75 mg/day to 325 mg/day) is recommended for primary and secondary prevention of cardiovascular events, but has been linked to an increased risk of upper gastrointestinal bleeding (UGIB). OBJECTIVE: To analyze the magnitude of effect of LDA use on UGIB risk. METHODS: The PubMed and Embase databases were searched for randomized controlled trials (RCTs) reporting UGIB rates in individuals receiving LDA, and observational studies of LDA use in patients with UGIB. Studies were pooled for analysis of UGIB rates. RESULTS: Eighteen studies were included. Seven RCTs reported UGIB rates in individuals randomly assigned to receive LDA (n=22,901) or placebo (n=22,923). Ten case-control studies analyzed LDA use in patients with UGIB (n=10,816) and controls without UGIB (n=30,519); one cohort study reported 207 UGIB cases treated with LDA only. All studies found LDA use to be associated with an increased risk of UGIB. The mean number of extra UGIB cases associated with LDA use in the RCTs was 1.2 per 1000 patients per year (95% CI 0.7 to 1.8). The number needed to harm was 816 (95% CI 560 to 1500) for RCTs and 819 (95% CI 617 to 1119) for observational studies. Meta-analysis of RCT data showed that LDA use was associated with a 50% increase in UGIB risk (OR 1.5 [95% CI 1.2 to 1.8]). UGIB risk was most pronounced in observational studies (OR 3.1 [95% CI 2.5 to 3.7]). CONCLUSIONS: LDA use was associated with an increased risk of UGIB.

Identification of acute myocardial infarction from electronic healthcare records using different disease coding systems: a validation study in three European countries.

OBJECTIVE: To evaluate positive predictive value (PPV) of different disease codes and free text in identifying acute myocardial infarction (AMI) from electronic healthcare records (EHRs). DESIGN: Validation study of cases of AMI identified from general practitioner records and hospital discharge diagnoses using free text and codes from the International Classification of Primary Care (ICPC), International Classification of Diseases 9th revision-clinical modification (ICD9-CM) and ICD-10th revision (ICD-10). SETTING: Population-based databases comprising routinely collected data from primary care in Italy and the Netherlands and from secondary care in Denmark from 1996 to 2009. PARTICIPANTS: A total of 4 034 232 individuals with 22 428 883 person-years of follow-up contributed to the data, from which 42 774 potential AMI cases were identified. A random sample of 800 cases was subsequently obtained for validation. MAIN OUTCOME MEASURES: PPVs were calculated overall and for each code/free text. 'Best-case scenario' and 'worst-case scenario' PPVs were calculated, the latter taking into account non-retrievable/non-assessable cases. We further assessed the effects of AMI misclassification on estimates of risk during drug exposure. RESULTS: Records of 748 cases (93.5% of sample) were retrieved. ICD-10 codes had a 'best-case scenario' PPV of 100% while ICD9-CM codes had a PPV of 96.6% (95% CI 93.2% to 99.9%). ICPC codes had a 'best-case scenario' PPV of 75% (95% CI 67.4% to 82.6%) and free text had PPV ranging from 20% to 60%. Corresponding PPVs in the 'worst-case scenario' all decreased. Use of codes with lower PPV generally resulted in small changes in AMI risk during drug exposure, but codes with higher PPV resulted in attenuation of risk for positive associations. CONCLUSIONS: ICD9-CM and ICD-10 codes have good PPV in identifying AMI from EHRs; strategies are necessary to further optimise utility of ICPC codes and free-text search. Use of specific AMI disease codes in estimation of risk during drug exposure may lead to small but significant changes and at the expense of decreased precision.

Idiopathic acute liver injury in paediatric outpatients: incidence and signal detection in two European countries.

BACKGROUND: Acute liver failure is idiopathic and drug-related in, respectively, around 50 and 15 % of children. Population-based, epidemiologic data about the pattern of disease manifestation and incidence of less severe acute liver injury, either idiopathic or potentially drug-attributed are limited in children and adolescents. OBJECTIVES: (i) To assess the incidence of idiopathic acute liver injury (ALI) and its clinical features in children and adolescent outpatients; and (ii) to investigate the role of the drug as a potential cause of ALI which is considered idiopathic. METHODS: A retrospective cohort study was performed during the years 2000-2008. Data were retrieved from three longitudinal electronic healthcare databases in two European countries: Pedianet and Health Search/CSD Longitudinal Patient Database from Italy and the Integrated Primary Care Information database from The Netherlands. Cases of idiopathic acute liver injury in population aged <18 years were identified by exclusion of all competing causes of liver injury (e.g. viral, autoimmune hepatitis), according to CIOMS criteria. The potential role of drug exposure as actual underlying cause of idiopathic ALI was detected through signal detection mining techniques. Both pooled and country-specific incidence rates [IR/100,000 person-years (PYs)] of idiopathic ALI and pooled adjusted rate ratios (RR) of drugs identified as a potential cause of idiopathic ALI, plus 95 % confidence intervals (CI) were estimated using the custom-built software Jerboa. RESULTS: Among 785 definite cases of idiopathic ALI, the pooled IR was 62.4/100,000 PYs (95 % CI 58.1-66.8). The country-specific IR was higher in Italy (73.0/100,000 PYs, 95 % CI 67.8-78.4) than in The Netherlands (21.0/100,000 PYs, 95 % CI 16.0-27.2) and increased with age in both countries. Isolated elevations of liver enzymes were reported in around two-thirds of cases in Italy, while in The Netherlands the cases were more often identified by a combination of signs/symptoms. Among drugs detected as potential underlying cause of idiopathic ALI, clarithromycin (RR 25.9, 95 % CI 13.4-50), amoxicillin/clavulanic acid (RR 18.6, 95 % CI 11.3-30.6), and amoxicillin (RR 7.5, 95 % CI 3.4-16.8) were associated with the highest risk compared to non-use. CONCLUSION: The incidence of idiopathic ALI in paediatrics is relatively low and comparable with adults. Clinical presentations differ between the two European countries. Signal detection in healthcare databases allowed identifying antibiotics as the drugs mostly associated with ALI with apparently unknown aetiology.