BACKGROUND AND PURPOSE:A multi-country European study using data from six healthcare databases from four countries was performed to evaluate in a large study population (>32 million) the risk of ischemic stroke (IS) associated with individual NSAIDs and to assess the impact of risk factors of IS and co-medication.METHODS:Case-control study nested in a cohort of new NSAID users. For each case, up to 100 sex- and age-matched controls were selected and confounder-adjusted odds ratios for current use of individual NSAIDs compared to past use calculated.RESULTS:49,170 cases of IS were observed among 4,593,778 new NSAID users. Use of coxibs (odds ratio 1.08, 95%-confidence interval 1.02-1.15) and use of traditional NSAIDs (1.16, 1.12-1.19) were associated with an increased risk of IS. Among 32 individual NSAIDs evaluated, the highest significant risk of IS was observed for ketorolac (1.46, 1.19-1.78), but significantly increased risks (in decreasing order) were also found for diclofenac, indomethacin, rofecoxib, ibuprofen, nimesulide, diclofenac with misoprostol, and piroxicam. IS risk associated with NSAID use was generally higher in persons of younger age, males, and those with a prior history of IS.CONCLUSIONS:Risk of IS differs between individual NSAIDs and appears to be higher in patients with a prior history of IS or transient ischemic attack (TIA), in younger or male patients. Co-medication with aspirin, other antiplatelets or anticoagulants might mitigate this risk. The small to moderate observed risk increase (by 13-46%) associated with NSAIDs use represents a public health concern due to widespread NSAID usage.

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.

OBJECTIVES:To investigate the cardiovascular safety of non-steroidal anti-inflammatory drugs (NSAIDs) and estimate the risk of hospital admission for heart failure with use of individual NSAIDs.DESIGN:Nested case-control study.SETTING:Five population based healthcare databases from four European countries (the Netherlands, Italy, Germany, and the United Kingdom).PARTICIPANTS:Adult individuals (age ≥18 years) who started NSAID treatment in 2000-10. Overall, 92 163 hospital admissions for heart failure were identified and matched with 8 246 403 controls (matched via risk set sampling according to age, sex, year of cohort entry).MAIN OUTCOME MEASURE:Association between risk of hospital admission for heart failure and use of 27 individual NSAIDs, including 23 traditional NSAIDs and four selective COX 2 inhibitors. Associations were assessed by multivariable conditional logistic regression models. The dose-response relation between NSAID use and heart failure risk was also assessed.RESULTS:Current use of any NSAID (use in preceding 14 days) was found to be associated with a 19% increase of risk of hospital admission for heart failure (adjusted odds ratio 1.19; 95% confidence interval 1.17 to 1.22), compared with past use of any NSAIDs (use >183 days in the past). Risk of admission for heart failure increased for seven traditional NSAIDs (diclofenac, ibuprofen, indomethacin, ketorolac, naproxen, nimesulide, and piroxicam) and two COX 2 inhibitors (etoricoxib and rofecoxib). Odds ratios ranged from 1.16 (95% confidence interval 1.07 to 1.27) for naproxen to 1.83 (1.66 to 2.02) for ketorolac. Risk of heart failure doubled for diclofenac, etoricoxib, indomethacin, piroxicam, and rofecoxib used at very high doses (≥2 defined daily dose equivalents), although some confidence intervals were wide. Even medium doses (0.9-1.2 defined daily dose equivalents) of indomethacin and etoricoxib were associated with increased risk. There was no evidence that celecoxib increased the risk of admission for heart failure at commonly used doses.CONCLUSIONS:The risk of hospital admission for heart failure associated with current use of NSAIDs appears to vary between individual NSAIDs, and this effect is dose dependent. This risk is associated with the use of a large number of individual NSAIDs reported by this study, which could help to inform both clinicians and health regulators.

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.

To develop a computerized prescreening procedure for the identification of possible/probably Hospital Admissions potential Related to Medications (HARMs).

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.

It is a cause for serious concern that many at-risk patients in Holland use OTC NSAIDs, presumably without knowing the risk they take.1 However, …

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.

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.

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.

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.

Two strategies for prevention of upper gastrointestinal (UGI) events for nonselective nonsteroidal anti‐inflammatory drug (nsNSAID) users are replacement of the nsNSAID by a cyclo‐oxygenase‐2‐selective inhibitor (coxib) or co‐prescription of a gastroprotective agent (GPA).

Aim: Concomitant use of non-steroidal anti-inflammatory drugs (NSAIDs) and low-dose aspirin (LDA) increases the risk of upper gastrointestinal bleeding (UGIB).Although clinical guidelines suggest to avoid certain drug combinations, little is known about the magnitude of interaction between different NSAIDs and specific drug groups.This is partly due to the need of a large sample for studying drug interactions.Understanding drug synergism is important to develop strategies to minimize the risk of UGIB.Design: A self-controlled case series analysis was performed using data from seven population-based healthcare databases located in three countries (Denmark, Italy, and the Netherlands).UGIB cases were identified based on disease classification codes.Drug exposure was classified into mutually exclusive groups.Interaction of the three main groups (non-selective (ns)NSAIDs, coxibs and LDA) with other drugs was examined.Incidence rate ratios (IRRs) of UGIB during exposure (and corresponding 95% CI) were obtained by Poisson regression modeling.Interaction was assessed on additive (with relative excess risk due to interaction, RERI) and multiplicative scale.Results: In total 114,835 UGIB cases, with corresponding follow-up of 930,888 personyears, were analyzed.Monotherapy with nsNSAIDs was associated with a higher IRR than monotherapy with coxibs or LDA (IRR 4.3; 2.9 and 3.1 respectively).The IRR was highest for concomitant use of nsNSAIDs and steroids (IRR 12.8; 95% CI: 11.2-14.7),which also demonstrated the highest additive interaction (RERI 5.5)(Figure 1).The IRR for nsNSAIDs and aldosterone antagonists was 11.0 (95%CI 8.6 -14.0) and RERI 4.5.Selective serotonin re-uptake inhibitors (SSRIs) and anticoagulants combined with either nsNSAIDs, coxibs or LDA increased the risk of UGIB significantly and also to a greater extent than expected based on the sum of the individual drugs (RERI 1.6;1.9 and 0.5 for SSRIs and 2.4;0.1 and 1.9 for anticoagulants, respectively).Only for the combination of LDA and antiplatelets was apart from additive, also multiplicative interaction observed (IRR 5.4; 95%CI: 4.7-6.4;RERI 1.7).Increasing age was associated with a higher IRR.Stratifying by age showed that for all drugs older persons (.60 years) had a higher IRR compared to younger persons ( ,60 years), except for combinations of nsNSAIDs+anticoagulants and coxibs+steroids.Conclusion: Concomitant use of SSRIs with nsNSAIDs, coxibs or LDA significantly increases the risk of UGIB up to seven-fold.Concomitant use of steroids, anticoagulants or antiplatelets with nsNSAIDs or LDA, but not with coxibs, showed an increased risk of UGIB, up to thirteen-fold.These increased risks were greater than the sum of the risks of individual drugs.This knowledge is of clinical relevance and can help clinicians in tailoring therapy to minimize UGI adverse events.

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.

Background The use of non-steroidal anti-inflammatory drugs (NSAIDs) is associated with serious adverse drug events (ADEs)1. In many countries, including the Netherlands, NSAIDs are available over-the-counter (OTC). Objectives To determine the prevalence of OTC NSAID use in the general population and in patients with a high risk of developing a serious NSAID-related ADE. Methods We conducted a cross-sectional study among adults registered with four Dutch general practitioners (GPs). In the Netherlands, all citizens are registered with a GP. Two samples of different patient populations were selected: (i) a random sample of adults (general population), and (ii) a sample of adult patients with a high risk of developing a serious ADE in case of NSAID use (high-risk population). The patients’ risk profiles were determined using their electronic medical records. Based on Dutch clinical prescription guidelines1, patients were considered at high risk if they had a history of a peptic ulcer or ulcer complication, myocardial infarction, stroke or heart failure, were aged over 70 years, had a glomerular filtration rate < 30ml/L, or had a combination of two or more of the following: use of an anticoagulant, aspirin, corticosteroid or selective serotonin reuptake inhibitor; age 60-70 years; history of severe rheumatoid arthritis or diabetes mellitus. All included patients were sent a questionnaire regarding their use of OTC NSAIDs in the four weeks prior to participation. Results In the general population, 120 of 456 included patients chose to participate. Of these, 35 (29%) had used an OTC NSAID in the four weeks prior to participation. In the high-risk population, 265 of 713 included patients chose to participate and 33 (13%) had used an OTC NSAID. Musculoskeletal complaints formed the most common reason for OTC NSAID use in the high-risk population, with 67% of OTC NSAID users giving this as a reason for use. In the general population, 46% of OTC NSAID users reported using these drugs because of musculoskeletal complaints. Over 20% of OTC NSAID users had used the OTC NSAID for more than seven days in the general population and over 30% in the high risk-population. OTC NSAIDs were used in a dosage exceeding the recommended daily maximum by 9% and 3% of OTC NSAID users in respectively the general and the high-risk population. Conclusions OTC NSAIDs are used by around one third of the general population and by one in eight patients with a high risk of developing a serious ADE. In this high-risk group, musculoskeletal complaints form the most common reason for OTC NSAID use. Continued efforts by healthcare professionals to inform patients of the risks of these drugs is warranted, particularly when a new diagnosis is made or medication prescribed which alters the patient’s risk profile. References Warlé-Van Herwaarden MF, Kramers C, Sturkenboom MC, et al. Targeting outpatient drug safety: Recommendations of the Dutch Harm-Wrestling Task Force. Drug Saf 2012;35(3):245-59 Disclosure of Interest None Declared

I. Lisanne Holster, Vera E. Valkhoff, Ernst J. Kuipers, Eric T.T.L. Tjwa 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.

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.

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.