Pharmo Institute

Utrecht, Netherlands

Pharmo Institute

Utrecht, Netherlands
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Van Den Ban E.,Institute for Mental Health | Van Den Ban E.,University Utrecht | Souverein P.,University Utrecht | Meijer W.,PHARMO Institute | And 4 more authors.
European Child and Adolescent Psychiatry | Year: 2014

To study the association between attention deficit hyperactivity disorder (ADHD) drug use and the incidence of hospitalization due to injuries. A random sample of 150,000 persons (0-18 years) was obtained from the Dutch PHARMO record linkage system. An ADHD medication cohort as well as an up to six age/sex/index date sampled control cohort with no history of ADHD drug use was formed. Differences in incidence of hospitalization due to injuries were stratified for age and sex and compared prior, during and after exposure on ADHD drugs. The overall incidence of hospital admissions for injuries was two times higher in the ADHD medication cohort [incidence rate ratios (IRR) 2.2 (95 % CI 1.6-2.9)]. The incidence rate for injuries during exposure to ADHD drugs was lower in the exposed period compared to the period prior to ADHD drug use, although the difference was not statistically significant [IRR 0.68 (95 % CI 0.29-1.60)]. The relative risk for injuries was almost five times higher in the ADHD medication cohort among those who concomitantly used other psychotropics [IRR 4.8 (95 % CI 1.4-16.9)]. Risk for injuries was highest in 12-18 years olds. Children and adolescents using ADHD medication showed a twofold risk for hospital admissions for injuries. ADHD drug use might diminish the increased injury risk, but still overall risk is higher than in age/sex sampled children and adolescents without treatment with ADHD drugs. Use of ADHD and concomitant psychotropics increases the risk for injuries compared to only ADHD drug use. © 2013 Springer-Verlag Berlin Heidelberg.


Masclee G.M.C.,Erasmus Medical Center | Valkhoff V.E.,Erasmus Medical Center | Coloma P.M.,Erasmus Medical Center | De Ridder M.,Erasmus Medical Center | And 12 more authors.
Gastroenterology | Year: 2014

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. © 2014 AGA Institute.


Coloma P.M.,Erasmus Medical Center | Schuemie M.J.,Erasmus Medical Center | Trifiro G.,Erasmus Medical Center | Gini R.,Agenzia Regionale di Sanita | And 8 more authors.
Pharmacoepidemiology and Drug Safety | Year: 2011

Purpose: In this proof-of-concept paper we describe the framework, process, and preliminary results of combining data from European electronic healthcare record (EHR) databases for large-scale monitoring of drug safety. Methods: Aggregated demographic, clinical, and prescription data from eight databases in four countries (Denmark, Italy, Netherlands, the UK) were pooled using a distributed network approach by generation of common input data followed by local aggregation through custom-built software, Jerboa©. Comparison of incidence rates of upper gastrointestinal bleeding (UGIB) and nonsteroidal anti-inflammatory drug (NSAID) utilization patterns were used to evaluate data harmonization and quality across databases. The known association of NSAIDs and UGIB was employed to demonstrate sensitivity of the system by comparing incidence rate ratios (IRRs) of UGIB during NSAID use to UGIB during all other person-time. Results: The study population for this analysis comprised 19 647 445 individuals corresponding to 59 929 690 person-years of follow-up. 39 967 incident cases of UGIB were identified during the study period. Crude incidence rates varied between 38.8 and 109.5/100 000 person-years, depending on country and type of database, while age-standardized rates ranged from 25.1 to 65.4/100 000 person-years. NSAID use patterns were similar for databases within the same country but heterogeneous among different countries. A statistically significant age- and gender-adjusted association between use of any NSAID and increased risk for UGIB was confirmed in all databases, IRR from 2.0 (95%CI:1.7-2.2) to 4.3 (95%CI: 4.1-4.5). Conclusions: Combining data from EHR databases of different countries to identify drug-adverse event associations is feasible and can set the stage for changing and enlarging the scale for drug safety monitoring. © 2010 John Wiley & Sons, Ltd..


Coloma P.M.,Erasmus Medical Center | Trifiro G.,Erasmus Medical Center | Trifiro G.,Messina University | Schuemie M.J.,Erasmus Medical Center | And 9 more authors.
Pharmacoepidemiology and Drug Safety | Year: 2012

Purpose: To provide estimates of the number and types of drugs that can be monitored for safety surveillance using electronic healthcare databases. Methods: Using data from eight European databases (administrative claims, medical records) and in the context of a cohort study, we determined the amount of drug exposure required for signal detection across varying magnitudes of relative risk (RR). We provide estimates of the number and types of drugs that can be monitored as a function of actual use, minimal detectable RR, and empirically derived incidence rates for the following adverse events: (i) acute myocardial infarction; (ii) acute renal failure; (iii) anaphylactic shock; (iv) bullous eruptions; (v) rhabdomyolysis; and (vi) upper gastrointestinal bleeding. We performed data simulation to see how expansion of database size would influence the capabilities of such system. Results: Data from 19647452 individuals (59594132person-years follow-up) who used 2289 drugs in the EU-ADR network show that for a frequent event such as acute myocardial infarction, there are 531 drugs (23% of total) for which an association with RR=2, if present, can be investigated. For a rare event such as rhabdomyolysis, there are 19 drugs (1%) for which an association of same magnitude can be investigated. Conclusion: Active surveillance using healthcare data-based networks for signal detection is feasible, although the leverage to do so may be low for infrequently used drugs and for rare outcomes. Extending database network size to include data from heterogeneous populations and increasing follow-up time are warranted to maximize leverage of these surveillance systems. © 2012 John Wiley & Sons, Ltd.


Bazelier M.T.,University Utrecht | Van Staa T.-P.,University Utrecht | Van Staa T.-P.,Medicines and Healthcare Products Regulatory Agency | Van Staa T.-P.,University of Southampton | And 8 more authors.
Neurology | Year: 2012

Objective: To examine the risk of fracture in patients with multiple sclerosis (MS) compared with population-based controls. Methods: A population-based cohort study was performed in the Dutch PHARMO Record Linkage System (1998-2008). Patients with MS (n = 2,415) were matched by year of birth, sex, and practice to up to 6 patients without MS (controls). We used Cox proportional hazards models to estimate the hazard ratio (HR) of fracture in MS. Time-dependent adjustments were made for age, history of disease, and drug use. Results: During follow-up, there were 59 fractures among patients with MS (2.4%) and 227 fractures among controls (1.8%). Patients with MS had a 1.7-fold increased risk of osteoporotic fracture (HR 1.73 [95% confidence interval (CI) 1.18-2.53]) and a 4-fold increased risk of hip fracture (HR 4.08 [95% CI 2.21-7.56]). The risk of osteoporotic fracture was significantly greater for patients with MS who had been prescribed antidepressants (HR 3.25 [95% CI 1.77-5.97]) or hypnotics/anxiolytics (HR 3.40 [95% CI 2.06-5.63]) in the previous 6 months, compared with controls. Conclusions: Increased awareness of the risk of hip fracture is warranted in patients with MS, especially in those who have recently been prescribed antidepressants or hypnotics/anxiolytics. Copyright © 2012 by AAN Enterprises, Inc.


Garcia Rodriguez L.A.,Spanish Center for Pharmacoepidemiologic Research | Herings R.,PHARMO Institute | Herings R.,Erasmus University Rotterdam | Johansson S.,Astrazeneca | Johansson S.,Gothenburg University
Pharmacoepidemiology and Drug Safety | Year: 2010

Background: Statins (inhibitors of 3-hydroxy-3-methyl-glutaryl-CoA reductase) are associated with rare but serious adverse events involving the muscle, kidney and liver. To compare the safety profile of rosuvastatin with other marketed statins, four pharmacoepidemiological studies were conducted using different national healthcare databases. These studies used a coordinated methodology to facilitate future meta-analysis. Objective: To achieve enhanced estimates of rosuvastatin safety relative to other statins, by performing a meta-analysis of four rosuvastatin safety studies. Methods: Outcomes were identified using computerised codes, and validated using hospital records or questionnaires. Incidence estimates were based on current statin exposure. Incidence estimates for hospitalised myopathy, rhabdomyolysis, acute renal failure and acute liver injury among users of rosuvastatin and users of other statins were pooled across studies using a weighted average corresponding to the Mantel-Haenszel estimate of the common relative risk. Results: More than 29 900 person-years were accrued for rosuvastatin use and more than 166 900 person-years were accrued for other statin use. Relative to other statins, rosuvastatin was not associated with significant differences in the incidence of hospitalised myopathy (+0.5 cases per 10 000 person-years; 95%CI: -0.6 to 1.6), rhabdomyolysis (+0.7 cases per 10 000 person-years; 95%CI: -0.3 to 1.6), acute renal failure (-0.2 cases per 10 000 person-years; 95%CI: -2.9 to 2.5) or acute liver injury (-0.8 cases per 10 000 person-years; 95%CI: -1.8 to 0.2). Conclusion: In this large sample (~200 000 person-years), no significant difference in the risk of myopathy, rhabdomyolysis, acute liver injury or acute renal failure was seen between rosuvastatin and other statins. Copyright © 2010 John Wiley & Sons, Ltd.


Hodgkins P.,Shire Inc | Sasane R.,Shire Inc | Meijer W.M.,PHARMO Institute
Clinical Therapeutics | Year: 2011

Background: The prevalence of attention-deficit/hyperactivity disorder (ADHD) and the associated use of stimulant medications may have increased in the Netherlands in recent years, but there is a lack of data to confirm this trend. This retrospective analysis examined the incidence, prevalence, and treatment pattern of ADHD among children from a large sample representation of the general population of the Netherlands and represents the first such analysis in a large cohort of European children. Objective: The aim of this study was to estimate the incidence and prevalence of children receiving initial pharmacotherapy for ADHD between 2000 and 2007 in the Netherlands and to describe treatment patterns (including persistence and adherence to ADHD medications) in this pediatric population. Methods: Prescription and hospitalization data from the PHARMO medical record linkage system database in the Netherlands (2003 to 2006) were analyzed for patients with newly prescribed ADHD medication who were aged 6 to 17 years and received follow-up for at least 12 months after treatment initiation with methylphenidate, dexamphetamine, atomoxetine, or combination therapy. The yearly incidence and prevalence of children receiving ADHD pharmacotherapy were estimated for the period 2000 to 2007. Demographic characteristics and baseline medication data at treatment initiation were collected along with data on hospitalizations and psychotropic treatments in the year before initiation of ADHD treatment. Results: Of the 4909 patients in the study cohort, 82% were male and 46% were between 6 and 9 years of age. The yearly incidence of children receiving ADHD medication-extrapolated from the PHARMO database to the Netherlands population-increased from 30 per 10,000 in the year 2000 to 75 per 10,000 in the year 2007. Prevalence rates showed a similar trend, increasing from 110 per 10,000 in 2000 to 210 per 10,000 in 2007. Prevalence and incidence rates both were consistently higher among boys than girls, although the greatest increases over time were observed in female patients. Analysis of treatment patterns revealed that most children (98%) initiated treatment with methylphenidate. Of those, 89% received an immediate-release formulation, although increased use of long-acting amphetamine and atomoxetine was apparent over the study period. Persistence and adherence rates varied according to the medications used and the prescribing physician. Antipsychotic agents and melatonin were the most commonly used therapeutics in the year before ADHD treatment initiation (6% and 4% of patients, respectively). Conclusions: The incidence and prevalence of children treated for ADHD increased from 2000 to 2007. Most children (98%) initiated treatment with immediate-release methylphenidate. © 2011 Elsevier HS Journals, Inc.


Beest F.P.-V.,PHARMO Institute | Herk-Sukel M.V.,PHARMO Institute | Gale R.,Novartis | Lammers J.-W.,University Utrecht | And 2 more authors.
Respiratory Medicine | Year: 2011

Background: Long-acting muscarinic antagonists (LAMA), long-acting β2-agonists (LABA) and fixed dose combinations (FDC) of inhaled corticosteroids (ICS) and LABA are used as inhaled maintenance therapies for COPD. Objective: To estimate persistence rates from dispensing patterns of long-acting inhaled drugs for COPD. Methods: From the PHARMO-database, COPD patients starting LAMA, LABA or LABA-ICS FDC between 2002 and 2006 were selected. Persistence with the initial as well as with any long-acting inhaled drug was determined, defined as time between start and stop of initial/any therapy, allowing ≤60-days gaps between refills. For patients who did not continue to receive dispensings of the initial therapy for at least one year, the first change in therapy was determined. Results: The study included 2201 LAMA, 1201 LABA and 4146 LABA-ICS FDC users. Persistence rates with initial therapy alone at 1, 2, and 3 years were 25%, 14%, 8% for LAMA, 21%, 10%, 6% for LABA and 27%, 14%, 8% for LABA-ICS FDC. Of patients who did not persist with LAMA alone for one year, 15% added and 13% switched therapy (both mostly LABA-ICS FDC). Of patients not persisting with LABA alone, 9% added therapy (mostly LAMA) and 31% switched therapy (mostly to LABA-ICS FDC). In patients not persisting with LABA-ICS FDC, add-on and switch occurred equally frequent (11%, mostly LAMA). Persistence rates with any long-acting drug at 1, 2 and 3 years were 36%, 23% and 17% respectively. Conclusion: Persistence with the initial as well as with any long-acting inhaled drug in COPD is low, with a substantial proportion of patients changing therapy. © 2010 Elsevier Ltd. All rights reserved.


Sasane R.,Global Health Economics and Outcomes Research | Hodgkins P.,Global Health Economics and Outcomes Research | Meijer W.,PHARMO Institute | Meijer W.,Erasmus Medical Center
Current Medical Research and Opinion | Year: 2010

Objective: To evaluate the number of patients reaching stable treatment with a stimulant (methylphenidate or dexamphetamine) or non-stimulant (atomoxetine) attention-deficit/hyperactivity disorder (ADHD) medication approved for use in the Netherlands, and the time to treatment stabilization among children and adolescents aged 617 years. Research design and methods: Prescription data from the PHARMO medical record linkage system from 48 geo-demographic areas in the Netherlands (20032006) were analyzed from newly treated patients with ADHD aged 617 years. Only patients with 5 dispensings for any ADHD drug during follow-up (at least 12 months) and no missing information on type of drug, strength, and number of pills per day were included. Main outcome measures: Attainment of a stable dosing regimen was defined as no change in type of drug (including a switch from an immediate release (IR) to a long-acting (LA) formulation), strength, and number of pills per day for five consecutive dispensings. Time to stable dosing regimen was defined as the number of days between the first dispensing for an ADHD drug and the first of five unchanged dispensings. Results: Of 4909 children or adolescents initiating treatment, 3099 met selection criteria. More patients starting therapy with LA methylphenidate (82.4) achieved treatment stabilization during follow-up than with IR methylphenidate (74.8; p<0.01) or atomoxetine (69.8; p<0.05). More patients initiated on LA methylphenidate patients (43.9) achieved treatment stabilization without changing their index medication or dose compared to those initiated on IR methylphenidate (25.3) or atomoxetine (8.1; p<0.0001 for both comparisons). Among patients achieving treatment stabilization, those initiating treatment with LA methylphenidate had a significantly shorter time to treatment stabilization (14 days) than patients initially treated with IR methylphenidate (56 days; p<0.001) or atomoxetine (31 days; p<0.05). Mean number of pills per day varied between 1.0 and 1.8 at initial treatment and 1.1 and 1.9 at treatment stabilization. Potential limitations of the study include the use of ADHD-medication dispensing as a proxy for an ADHD diagnosis and the impact of different titration schedules for the various ADHD medications. Conclusion: Overall, 2316 of the 3066 eligible patients (75.5) achieved treatment stabilization during follow-up. Among children and adolescents with ADHD in the Netherlands, the time to treatment stabilization varied according to choice of initial treatment and was shortest for LA methylphenidate. © 2010 Informa UK Ltd All rights reserved.


Penning-van Beest F.J.,PHARMO Institute
Journal of medical economics | Year: 2011

Several pharmacological therapies are available to help smokers quit. The aim was to investigate the utilisation and effectiveness of smoking cessation drugs in daily practice in the Netherlands. Subjects aged ≥18 years with a pharmacy prescription of varenicline, bupropion, nicotine replacement therapy (NRT) or nortriptyline between March 2007 and September 2008 were identified from the PHARMO data warehouse, which includes drug dispensing, hospitalisation and other data from approximately 2.5 million residents in the Netherlands. Using an encrypted methodology, corresponding non-person-identifiable dispensing IDs were linked to a web-based system for patient-reported data collection. Corresponding pharmacists asked the subjects to participate in the study and complete a web-based questionnaire on smoking history and cessation, including utilisation of (pharmaco) therapies. Of 2,684 invited subjects, 698 responded (26%), of whom 612 were included in the analyses. Bupropion was the most frequently used smoking cessation drug (35% of patients), followed by varenicline (28%), bupropion+NRT (12%) and varenicline+NRT (9%). Overall, 51% of patients also reported behavioural therapy. A total of 53% of bupropion users, 51% of varenicline users, 42% of NRT users and 20-40% of patients using multiple drugs reported to not smoke at the time of questionnaire. Median (interquartile range) number of days between time of questionnaire and start date of last quit attempt ranged from 271 (104-432) for varenicline+bupropion to 356 (205-518) for bupropion. Mean duration of drug use ranged from 42 to 53 days among quitters and from 19 to 42 days among relapsers. In this study up to 50% of patients who obtained smoking cessation drugs at the pharmacy stopped smoking. Better access to smoking cessation drugs as recommended in guidelines will help to further decrease smoking prevalence.

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