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Background: Routinely collected clinical data based on electronic medical records could be used to define frailty., Aim: To estimate the ability of four potential frailty measures that use electronic medical record data to identify older patients who were frail according to their GP., Design and Setting: This retrospective cohort study used data from 36 GP practices in the Dutch PHARMO Data Network., Method: The measures were the Dutch Polypharmacy Index, Charlson Comorbidity Index (CCI), Chronic Disease Score (CDS), and Frailty Index. GPs' clinical judgement of patients' frailty status was considered the reference standard. Performance of the measures was assessed with the area under the receiver operating characteristic curve (AUC). Analyses were done in the total population and stratified by age and sex., Results: Of 31 511 patients aged ≥65 years, 3735 (11.9%) patients were classified as frail by their GP. The CCI showed the highest AUC (0.79, 95% confidence interval [CI] = 0.78 to 0.80), followed by the CDS (0.69, 95% CI = 0.68 to 0.70). Overall, the measures showed poorer performance in males and females aged ≥85 years than younger age groups (AUC 0.55-0.58 in females and 0.57-0.60 in males)., Conclusion: This study showed that of four frailty measures based on electronic medical records in primary care only the CCI had an acceptable performance to assess frailty compared with frailty assessments done by professionals. In the youngest age groups diagnostic performance was acceptable for all measures. However, performance declined with older age and was least accurate in the oldest age group, thereby limiting the use in patients of most interest., (© The Authors.)

Background: GPs have been shown to be important providers of medical care during pregnancy, however, little evidence exists on their awareness of pregnancy when prescribing medication to women., Aim: To assess GPs' awareness of pregnancy and its association with prescribing medication with potential safety risks., Design and Setting: Population-based study using confirmed pregnancy records linked to GP records from the PHARMO Perinatal Research Network., Method: GPs' awareness of pregnancy, defined as the presence of a pregnancy confirmation in the GP information system during pregnancy, was assessed from 2004 to 2020. GP prescriptions of medication with potential safety risks were selected during pregnancy and its association with GPs' awareness of pregnancy was assessed using multivariable logistic regression., Results: A pregnancy confirmation was present in the GP records for 48% ( n = 67 496/140 976) of selected pregnancies, increasing from 28% ( n = 34/121) in 2004 to 63% in 2020 ( n = 5763/9124). During 3% ( n = 4489/140 976) of all pregnancies, the GP prescribed highly hazardous medication with teratogenic effects that should have been (temporarily) avoided. Pregnancy was GP confirmed for only 13% ( n = 585/4489) at the first occurrence of such a prescription. Comparative analyses showed that women without a pregnancy confirmation were 59% more likely to be prescribed this highly hazardous medication (odds ratio [OR] 1.59, 95% confidence interval [CI] = 1.49 to 1.70) compared with those with a confirmed pregnancy., Conclusion: Results of this study indicate a potential issue with GP awareness about pregnancy status at the time medication with potential safety risks is prescribed. Although pregnancy registration by GPs improved over the years, inadequate use still seems to be made of the available information systems for appropriate drug surveillance., (© The Authors.)

Background: Long-term use of statins is associated with a small reduced risk of colorectal cancer but their mechanism of action is not well understood. While they are generally believed to act on KRAS, we have previously proposed that they act via influencing the BMP pathway. The objective of this study was to look for associations between statin use and the risk of developing colorectal cancer of a particular molecular subtype., Methods: By linking two registries unique to the Netherlands, 69,272 statin users and 94,753 controls were identified and, if they developed colorectal cancer, their specimens traced. Colorectal cancers were molecularly subtyped according to the expression of SMAD4 and the mutation status of KRAS and BRAF., Results: Statin use was associated with a reduction in the risk of developing colorectal cancer regardless of molecular subtype (HR 0.77; 95% CI 0.66-0.89) and a larger reduction in the risk of developing SMAD4-positive colorectal cancer (OR 0.64; 95% CI 0.42-0.82). There was no relationship between statin use and the risk of developing colorectal cancer with a mutation in KRAS and/or BRAF., Conclusions: Statin use is associated with a reduced risk of developing colorectal cancer with intact SMAD4 expression., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Objectives: Pharmacological treatment of peripheral arterial disease (PAD) comprises of antiplatelet therapy (APT), blood pressure control and cholesterol optimisation. Guidelines provide class-I recommendations on the prescription, but there are little data on the actual prescription practices. Our study provides insight into the prescription of medication among patients with PAD in the Netherlands and reports a 'real-world' patient journey through primary and secondary care., Design: We conducted a cohort study among patients newly diagnosed with PAD between 2010 and 2014., Setting: Data were obtained from the PHARMO Database Network, a population-based network of electronic pharmacy, primary and secondary healthcare setting records in the Netherlands. The source population for this study comprised almost 1 million individuals., Participants: 'Newly diagnosed' was defined as a recorded International Classification of Primary Care code for PAD, a PAD-specific WCIA examination code or a diagnosis recorded as free text episode in the general practitioner records with no previous PAD diagnosis record and no prescription of P2Y12 inhibitors or aspirin the preceding year. The patient journey was defined by at least 1 year of database history and follow-up relative to the index date., Results: Between 2010 and 2014, we identified 3677 newly diagnosed patients with PAD. Most patients (91%) were diagnosed in primary care. Almost half of all patients (49%) had no APT dispensing record. Within this group, 33% received other anticoagulant therapy (vitamin K antagonist or direct oral anticoagulant). Mono-APT was dispensed as aspirin (40% of patients) or P2Y12 inhibitors (2.5% of patients). Dual APT combining aspirin with a P2Y12 inhibitor was dispensed to 8.5% of the study population., Conclusion: Half of all patients with newly diagnosed PAD are not treated conforming to (international) guideline recommendations on thromboembolism prevention through APT. At least 33% of all patients with newly diagnosed PAD do not receive any antithrombotic therapy. Evaluation and improvement of APT prescription and thereby improved prevention of (secondary) cardiovascular events is warranted., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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., (© 2020 The Authors. Pharmacoepidemiology and Drug Safety published by John Wiley & Sons Ltd.)

Objectives: Laboratory monitoring of patients using lithium is important to prevent harm and to increase effectiveness. The aim of this study is to determine compliance with the guidelines for laboratory monitoring of patients treated with lithium overall and within subgroups., Methods: Patients having at least one lithium dispensing for 6 months or longer between January 2010 and December 2015 were identified retrospectively using data from the Dutch PHARMO Database Network. Laboratory monitoring was defined as being compliant with the Dutch Multidisciplinary Clinical Guideline Bipolar Disorders when lithium serum levels, creatinine and thyroid-stimulating hormone (TSH) had been measured at least every 6 months during lithium use., Results: Data were analyzed from 1583 patients with a median duration of 7- to 6-months period of lithium use. Results indicated that patients had been monitored over 6-month period for lithium serum levels 65% of the time, for creatinine 73% of the time and for TSH 54% of the time. Just over one seventh (16%) of patients had been monitored in compliance with the guidelines for all three parameters during total follow-up. Especially males, patients aged below 65 years, patients receiving prescriptions solely from general practitioners, prevalent users of lithium, patients without interacting co-medication, and patients without other days with laboratory measurements had been monitored less frequently in compliance with the guidelines., Conclusions: A considerable proportion of patients had not been monitored in accordance with the guidelines. Further research is needed to understand the reasons for noncompliance and to implement strategies with the ultimate goal of optimizing safety and effectiveness for patients treated with lithium., (© 2018 The Authors. Bipolar Disorders Published by John Wiley & Sons Ltd.)

Background: Cohort matching and regression modeling are used in observational studies to control for confounding factors when estimating treatment effects. Our objective was to evaluate exact matching and propensity score methods by applying them in a 1-year pre-post historical database study to investigate asthma-related outcomes by treatment., Methods: We drew on longitudinal medical record data in the PHARMO database for asthma patients prescribed the treatments to be compared (ciclesonide and fine-particle inhaled corticosteroid [ICS]). Propensity score methods that we evaluated were propensity score matching (PSM) using two different algorithms, the inverse probability of treatment weighting (IPTW), covariate adjustment using the propensity score, and propensity score stratification. We defined balance, using standardized differences, as differences of <10% between cohorts., Results: Of 4064 eligible patients, 1382 (34%) were prescribed ciclesonide and 2682 (66%) fine-particle ICS. The IPTW and propensity score-based methods retained more patients (96%-100%) than exact matching (90%); exact matching selected less severe patients. Standardized differences were >10% for four variables in the exact-matched dataset and <10% for both PSM algorithms and the weighted pseudo-dataset used in the IPTW method. With all methods, ciclesonide was associated with better 1-year asthma-related outcomes, at one-third the prescribed dose, than fine-particle ICS; results varied slightly by method, but direction and statistical significance remained the same., Conclusion: We found that each method has its particular strengths, and we recommend at least two methods be applied for each matched cohort study to evaluate the robustness of the findings. Balance diagnostics should be applied with all methods to check the balance of confounders between treatment cohorts. If exact matching is used, the calculation of a propensity score could be useful to identify variables that require balancing, thereby informing the choice of matching criteria together with clinical considerations., Competing Interests: Disclosure AB and CM were employees of Research in Real-Life (RiRL), Cambridge, UK. Research in Real-Life was subcontracted by Observational and Pragmatic Research Institute Pte Ltd, Singapore, to conduct this study and has conducted paid research in respiratory disease on behalf of the following other organizations in the past 5 years: Aerocrine, AKL Ltd, Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Meda, Mundipharma, Napp, Novartis, Orion, Takeda, Teva, and Zentiva, a Sanofi company. NR has received over the past 3 years: 1) fees for speaking, organizing education, participation in advisory boards or consulting from 3M, Aerocrine, Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, GlaxoSmithKline, MSD-Chibret, Mundipharma, Novartis, Pfizer, Sanofi, Sandoz, Teva; 2) research grants from Novartis, Boehringer Ingelheim and Pfizer. EVH is a consultant to RiRL and has received payment for writing and editorial support to Merck. The University of Groningen has received money for DSP regarding an unrestricted educational grant for research from AstraZeneca, Chiesi. Travel to conferences for the European Respiratory Society (ERS) and/or the American Thoracic Society (ATS) has been partially funded by AstraZeneca, Chiesi, GSK, Takeda. Fees for consultancies were given to the University of Groningen by AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Takeda, and TEVA. Travel and lectures in China were paid by Chiesi. RMCH and JAO are employees of the PHARMO Institute. This independent research institute performs financially supported studies for government and related health care authorities and several pharmaceutical companies. DvE and JMK are employees of Takeda. DBP has Board Membership with Aerocrine, Almirall, Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, Meda, Mundipharma, Napp, Novartis, and Teva. Consultancy: Almirall, Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Meda, Mundipharma, Napp, Novartis, Pfizer, Teva, and Zentiva; Grants/Grants Pending with UK National Health Service, British Lung Foundation, Aerocrine, AstraZeneca, Boehringer Ingelheim, Chiesi, Eli Lilly, GlaxoSmithKline, Meda, Merck, Mundipharma, Novartis, Orion, Pfizer, Respiratory Effectiveness Group, Takeda, Teva, and Zentiva; Payments for lectures/speaking: Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, GlaxoS-mithKline, Kyorin, Meda, Merck, Mundipharma, Novartis, Pfizer, SkyePharma, Takeda, and Teva; Payment for manuscript preparation: Mundipharma and Teva; Patents (planned, pending or issued): AKL Ltd.; payment for the development of educational materials: GlaxoSmithKline, Novartis; Stock/Stock options: Shares in AKL Ltd which produces phyto-pharmaceuticals and owns 80% of Research in Real-Life Ltd, 75% of the social enterprise Optimum Patient Care Ltd and 75% of Observational and Pragmatic Research Institute Pte Ltd; received payment for travel/accommodations/meeting expenses from Aerocrine, Boehringer Ingelheim, Mundipharma, Napp, Novartis, and Teva; funding for patient enrolment or completion of research: Almirral, Chiesi, Teva, and Zentiva; peer reviewer for grant committees: Medical Research Council (2014), Efficacy and Mechanism Evaluation programme (2012), HTA (2014); and received unrestricted funding for investigator-initiated studies from Aerocrine, AKL Ltd, Almirall, Boehringer Ingelheim, Chiesi, Meda, Mundi-pharma, Napp, Novartis, Orion, Takeda, Teva, and Zentiva. The authors report no other conflicts of interest in this work.

Purpose: Extrafine-particle inhaled corticosteroids (ICS) have greater small airway deposition than standard fine-particle ICS. We sought to compare asthma-related outcomes after patients initiated extrafine-particle ciclesonide or fine-particle ICS (fluticasone propionate or non-extrafine beclomethasone)., Methods: This historical, matched cohort study included patients aged 12-60 years prescribed their first ICS as ciclesonide or fine-particle ICS. The 2 cohorts were matched 1:1 for key demographic and clinical characteristics over the baseline year. Co-primary endpoints were 1-year severe exacerbation rates, risk-domain asthma control, and overall asthma control; secondary endpoints included therapy change., Results: Each cohort included 1,244 patients (median age 45 years; 65% women). Patients in the ciclesonide cohort were comparable to those in the fine-particle ICS cohort apart from higher baseline prevalence of hospitalization, gastroesophageal reflux disease, and rhinitis. Median (interquartile range) prescribed doses of ciclesonide and fine-particle ICS were 160 (160-160) μg/day and 500 (250-500) μg/day, respectively (P<0.001). During the outcome year, patients prescribed ciclesonide experienced lower severe exacerbation rates (adjusted rate ratio [95% CI], 0.69 [0.53-0.89]), and higher odds of risk-domain asthma control (adjusted odds ratio [95% CI], 1.62 [1.27-2.06]) and of overall asthma control (2.08 [1.68-2.57]) than those prescribed fine-particle ICS. The odds of therapy change were 0.70 (0.59-0.83) with ciclesonide., Conclusions: In this matched cohort analysis, we observed that initiation of ICS with ciclesonide was associated with better 1-year asthma outcomes and fewer changes to therapy, despite data suggesting more difficult-to-control asthma. The median prescribed dose of ciclesonide was one-third that of fine-particle ICS., Competing Interests: There are no financial or other issues that might lead to conflict of interest.

Background: Medication use in patients with psoriasis has been studied mostly in the context of psoriasis comorbidities., Objectives: To investigate detailed drug utilization in patients with psoriasis compared with controls in a population-based sample., Methods: This was a case-control study based on drug prescriptions derived from a Dutch general practitioner database where patients with psoriasis and controls without psoriasis were matched 1 : 1 for age, sex, general practitioner and duration of follow-up, between 2002 and 2012. We calculated Mantel-Haenszel odds ratios (ORs) and 95% confidence intervals (CIs) for all therapeutic groups and chemical substances., Results: In total 17 627 patients with psoriasis and 17 627 controls were followed for > 4 years. Overall 20% of patients with psoriasis received no psoriasis treatment and 8% had moderate-to-severe disease. During the entire follow-up a mean of nine unique drugs were prescribed in patients with psoriasis; this was significantly higher than in controls (mean of seven). Drug use did not peak around the date of diagnosis for psoriasis, but remained constant over time. All of the most commonly prescribed therapeutic groups were significantly more often prescribed in patients with psoriasis than in controls. These included drugs associated with psoriasis symptoms and treatment (OR 2·17, 95% CI 2·07-2·28 and OR 22, 95% CI 21-25, respectively), drugs related to psoriasis comorbidities (1·46, 95% CI 1·39-1·53) and a proportion of drugs that were a priori not expected to be increased in patients with psoriasis, such as nasal preparations and laxatives., Conclusions: Patients with psoriasis received more prescriptions for all drugs, regardless of associated comorbidities. This overall increased use of drugs suggests an increased healthcare utilization in patients with psoriasis identified in routine databases., (© 2016 British Association of Dermatologists.)

Objective: To study the trend in the prevalence of diabetes in the Netherlands during the period 1999-2014., Design: Descriptive study of prevalence., Methods: The prevalence of diabetes during the period 1999-2014 was calculated on the basis of data from the PHARMO Database Network, a network of electronic databases that includes data from public pharmacies for 3.8 million residents of the Netherlands. A person with diabetes was defined as someone with at least two dispensings for a glucose lowering-drug within six months. Prevalence was adjusted for variation in age demographics per sex to investigate the influence of these variations on population demographics., Results: The prevalence of diabetes in the Netherlands increased from 1.8% in 1999 to 4.9% in 2014. The increase was more pronounced among men as age increased. Only half of the increase was explained by changes in age demographics per sex., Conclusion: The study showed that the prevalence of diabetes more than doubled during the period 1999-2014. This trend can only be partly explained by changes in age demographics per sex.

Aims: This study aims to evaluate the impact of cancer and its treatment on HbA1c values among individuals with colorectal cancer (CRC) using glucose-lowering drugs (GLDs)., Methods: Patients with primary CRC (1998-2011) were selected from the Eindhoven Cancer Registry and linked to the PHARMO Database Network including outpatient pharmacy and clinical laboratory data. Patients with more than 2 years of GLDs use prior to cancer diagnosis were included. Linear mixed-effects models were conducted to evaluate changes in HbA1c for colon cancer (CC) and rectal cancer (RC) patients in the 4 years around CRC diagnosis., Results: Of all CRC patients (n = 4714), 294 (6 %) GLDs users with CC and 144 (3 %) with RC were selected. In the crude model, mean HbA1c at cancer diagnosis was 6.9 % (51.6 mmol/mol) among CC patients and 7.1 % (53.5 mmol/mol) among RC patients. Among CC patients, HbA1c decreased with 0.12 % per year (p = 0.0002) before cancer diagnosis in the adjusted model, and after diagnosis, it increased with 0.12 % per year (p = 0.02). In subgroup analyses, effects on HbA1c were more pronounced in users of anti-anaemic preparations. Among RC patients, HbA1c decreased before diagnosis with 0.18 % per year (p = 0.0006), whereas after diagnosis it changed non-significantly., Conclusions: Among users of GLDs, HbA1c decreased with 0.12-0.18 % (1-2 mmol/mol) per year before CRC diagnosis. Only among CC patients, HbA1c increased after diagnosis (0.12 % per year; 1.3 mmol/mol). Modest changes in HbA1c before CRC diagnosis may reflect the effects of an undiagnosed cancer, such as weight loss, anaemia, or the use of anti-anaemic preparations.

Background: Previous studies have suggested a greater benefit for various outcomes in men diagnosed with benign prostatic hyperplasia (BPH) who are treated with dutasteride than for men treated with finasteride. This study investigates whether the rates of BPH-related prostate surgery and acute urinary retention (AUR) differ between dutasteride and finasteride users in the Netherlands., Methods: From the PHARMO Database Network, men aged ≥50 years with a dispensing of dutasteride or finasteride with or without concomitant alpha-blocker treatment between March 1, 2003 and December 31, 2011 were selected. The incidence of BPH-related prostate surgery and AUR was determined during dutasteride or finasteride treatment and stratified by type of initial BPH-treatment (5-ARI monotherapy or combination with alpha-blocker) and prescriber (general practitioner (GP) or urologist). Comparison of the incidence of BPH-related prostate surgery and AUR between the treatment groups was done by Cox proportional hazard regression., Results: 11,822 dutasteride users and 5,781 finasteride users were identified. Most users started treatment in combination with an alpha-blocker. Overall, dutasteride users had a lower risk of BPH-related prostate surgery was lower among dutasteride users than finasteride users (HR: 0.75; 95 % CI: 0.56-0.99). This lower risk among dutasteride users was also seen when stratifying by monotherapy or combination therapy (HR: 0.73; 95 % CI: 0.54-0.98 for monotherapy and HR: 0.85; 95 % CI: 0.74-0.97 for combination therapy). However, the association was only present among men treated by urologists. For AUR the rates were low and no statistical significant difference was observed between dutasteride and finasteride users., Conclusions: The risk of undergoing BPH-related prostate surgery was lower among men using dutasteride compared to men using finasteride. The association was observed for monotherapy as well as combination therapy, however, only among men who received their prescription from a urologist.

Objectives: To compare rates of specific adverse outcomes between patients starting quetiapine, olanzapine, or risperidone use in the Netherlands., Methods: Observational study using the PHARMO Database Network, including patients starting quetiapine (4658), olanzapine (5856), or risperidone (7229) in 2000-2009, comparing rates of all-cause mortality, failed suicide attempts, extrapyrimidal symptoms (EPS), diabetes mellitus (DM), hypothyroidism, and acute myocardial infarction (AMI)., Key Findings: Median follow-up until discontinuation/end of follow-up was 0.6 years. Prescribed doses were generally lower than the approved defined daily doses, especially for quetiapine. Quetiapine was significantly associated with lower EPS rates (HR 0.18; 95% CI 0.13-0.24), but higher failed suicide attempt rates (HR 2.07; 95% CI 1.35-3.16) compared to risperidone. Quetiapine was significantly associated with lower EPS rates (HR 0.59; 95% CI 0.42-0.84) and DM rates (HR 0.66; 95% CI 0.44-0.97) compared to olanzapine. Rates for all-cause mortality, hypothyroidism, and stroke were similar between groups. AMI events were too infrequent to draw conclusions., Conclusions: Quetiapine was associated with lower EPS, but higher failed suicide attempt rates compared to risperidone. Quetiapine was associated with lower EPS and DM rates compared to olanzapine. The results should be interpreted with caution because of possible channelling and residual confounding. Copyright © 2016 John Wiley & Sons, Ltd., (Copyright © 2016 John Wiley & Sons, Ltd.)

Background: Most randomised clinical trials typically exclude a significant proportion of asthma patients, including those at higher risk of adverse events, with comorbidities, obesity, poor inhaler technique and adherence, or smokers. However, these patients might differentially benefit from extrafine-particle inhaled corticosteroids (ICS). This matched cohort, database study, compared the effectiveness of extrafine-particle with fine-particle ICS in a real-life population initiating ICS therapy in the Netherlands., Methods: Data were from the Pharmo Database Network, comprising pharmacy and hospital discharge records, representative of 20 % of the Dutch population. The study population included patients aged 12 - 60, with a General Practice-recorded diagnosis for asthma (International Classification of Primary Care code R96), when available, ≥2 prescriptions for asthma therapy at any time in their recorded history, and receiving first prescription of ICS therapy as either extrafine-particle (ciclesonide or hydrofluoroalkane beclomethasone dipropionate [BDP]) or fine-particle ICS (fluticasone propionate or non-extrafine-particle-BDP). Patients were matched (1:1) on relevant demographic and clinical characteristics over 1-year baseline. Primary outcomes were severe exacerbation rates, risk domain asthma control and overall asthma control during the year following first ICS prescription. Secondary outcomes, treatment stability and being prescribed higher versus lower category of short-acting β2 agonists (SABA) dose, were compared over a 1-year outcome period using conditional logistic regression models., Results: Following matching, 1399 patients were selected in each treatment cohort (median age: 43 years; males: 34 %). Median (interquartile range) initial ICS doses (fluticasone-equivalents in μg) were 160 (160 - 320) for extrafine-particle versus 500 (250 - 500) for fine-particle ICS (p < 0.001). Following adjustment for residual confounders, matched patients prescribed extrafine-particle ICS had significantly lower rates of exacerbations (adjusted rate ratio [95 % CI], 0.59 [0.47-0.73]), and significantly higher odds of achieving asthma control and treatment stability in the year following initiation than those prescribed fine-particle ICS, and this occurred at lower prescribed doses. Patients prescribed extrafine-particle ICS had lower odds of being prescribed higher doses of SABA (0.50 [0.44-0.57])., Conclusion: In this historical, matched study, extrafine-particle ICS was associated with better odds of asthma control than fine-particle ICS in patients prescribed their first ICS therapy in the Netherlands. Of importance, this was reached at significantly lower prescribed dose.

Unlabelled: Analyses of healthcare data from 30 million individuals in three countries showed that current use of bisphosphonates may be associated with a small increased risk of cardiac valvulopathy (vs. those not exposed within the previous year), although confounding cannot be entirely ruled out. The observed tendency for decreased valvulopathy risk with cumulative duration of bisphosphonate use >6 months may even indicate a protective effect with prolonged use. Further studies are still needed to evaluate whether bisphosphonates increase or decrease the risk of valvulopathy., Introduction: A signal of cardiac valve disorders with use of bisphosphonates was identified in the literature and EudraVigilance database, which contains reports of suspected adverse drug reactions from worldwide sources. The aim of this study was to evaluate the association using population-based healthcare data., Methods: This was a case-control study among users of bisphosphonates and other drugs for osteoporosis in six healthcare databases covering over 30 million individuals in Italy, Netherlands and the UK from 1996 to 2012. Prescriptions/dispensations were used to assess drug exposure. Newly diagnosed cases of cardiac valvulopathy were identified via disease codes/free-text search. Controls were matched to each case by age, sex, database and index date. Adjusted odds ratios (ORs) were estimated using conditional logistic regression for the pooled data and meta-analysis of individual database risk estimates., Results: A small but statistically significant association was found between exposure to bisphosphonates as a class and risk of valvulopathy. Overall risk was 18 % higher (95 % CI 12-23 %) in those currently exposed to any bisphosphonate (mainly alendronate and risedronate) vs. those not exposed within the previous year. Risk of valve regurgitation was 14 % higher (95 % CI 7-22 %). Decreased valvulopathy risk was observed with longer cumulative duration of bisphosphonate use, compared to use of less than 6 months. Meta-analyses of database-specific estimates confirmed results from pooled analyses., Conclusions: The observed increased risks of cardiac valvulopathy with bisphosphonate use, although statistically significant, were quite small and unlikely to be clinically significant. Further studies are still needed to evaluate whether bisphosphonates increase or decrease the risk of valvulopathy and to investigate possible mechanisms for the association.

Objective: To assess the trends in the incidence and prevalence rates of type 1 diabetes (T1D) among children and adolescents in the Netherlands., Methods: A population-based cohort study was conducted in the Dutch PHARMO record linkage system (1998-2011). All children and adolescents aged ≤19 yr with at least one insulin dispensing (as a proxy for T1D) were identified and the numbers of incident and prevalent cases (numerators) were calculated. Overall age-adjusted (0-19 yr) incidence and prevalence rates together with age- and sex-specific rates of T1D and their 95% confidence intervals (CI) were calculated using data from the Dutch Central Bureau of Statistics as denominator. Trends over time were assessed using Joinpoint regression software (National Cancer Institute, Bethesda, MD, USA)., Results: In 2011, the overall age-adjusted incidence and prevalence rates of T1D were 25.2/100 000 (95% CI, 23.7-26.8) person-years (PY) and 174.4/100 000 (95% CI, 170.2-178.5) children, respectively. The average annual percentage change (AAPC) in the overall age-adjusted incidence and prevalence rate was 3.7% (95% CI, 1.8-5.7) and 3.8% (95% CI, 2.4-5.2), respectively. While during the study period the largest increases in the incidence and prevalence rates of T1D were observed for the oldest age groups (10-14 and 15-19 yr), a decreasing trend was detected for the 0- to 4-yr-old category (with AAPCs of -1.8 (95% CI, -9.9 to 7.1) and -6.9% (95% CI, -11.5 to -2.1) for incidence and prevalence, respectively)., Conclusion: Age-adjusted incidence (1999-2011) and prevalence rates (1998-2011) of T1D in Dutch children (aged 0-19 yr) continued to increase and a shift was observed to a later onset of the disease., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objectives: The aim of the study was to assess the prevalence of oral contraceptive (OC) use, user characteristics and prescribing patterns by accessing health care databases of three European countries., Methods: A retrospective study was performed from 2009 to 2010 in three general practice (GP) databases from the Netherlands, UK and Italy and in one database of linked pharmacy and hospitalisation data in the Netherlands. The presence of selected chronic conditions and diagnoses of diseases associated with OC use were assessed, as were switches, discontinuations and types of OC used during the study period., Results: Among 2.16 million women aged 15 to 49 years, 16.0% were using an OC on 1 January 2010. The prevalence ranged from 19.7% in a Dutch database to 2.6% in the Italian database. During 2009 and 2010, mainly second-generation progestogens were prescribed in the Netherlands (79.4% and 78.3% of users), both second- (57.9%) and third-generation progestogens (43.6%) were prescribed in the UK, and mainly third-generation progestogens in Italy (61.8%). Most switches were to third- or fourth-generation pills. The prevalence of chronic diseases tended to be higher among OC users, and the proportions of women with a history of disease associated with OC use tended to be lower than among non-users., Conclusions: Second-generation OCs were most frequently prescribed in the Netherlands. In the UK, and even more so in Italy, many women used third- or fourth-generation OCs. Preparation switches were mainly to third- or fourth-generation OCs. Among OC users, a somewhat higher prevalence of chronic diseases was observed; however, information bias cannot be ruled out.

Aim: Palivizumab is reported to be effective in reducing respiratory syncytial virus hospitalisation. Its licensed uses include infants younger than six months of age, born before 35 weeks of gestation or under two years old with congenital heart disease or bronchopulmonary dysplasia. We redressed lack of research in the Netherlands by studying whether infants who met the licensed indications received the drug., Methods: Data were obtained from the PHARMO Database Network and The Netherlands Perinatal Registry for all linked infants born between 1 April 1999 and 31 March 2007. Determinants for receiving palivizumab were examined using logistic regression analyses., Results: Only 15% of the 3321 infants who met the licensed indications received palivizumab and the strongest predictor was being born before 32 weeks of gestation, with an odds ratio of 49.1 (95% confidence interval 31.5-76.4). However, 50% of infants born before 32 weeks did not receive palivizumab and the subanalyses showed that the probability increased for infants born in later years, those who had respiratory distress syndrome and those hospitalised during the respiratory syncytial virus season., Conclusion: Only 15% of eligible infants in the Netherlands received palivizumab and they were mostly born before 32 weeks, in line with Dutch guidelines., (©2015 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Aim: The aim of the study was to document long term trends in oral antidiabetic drug (OAD) use among children and adolescents in the Netherlands., Methods: A population-based cohort study was conducted using the Dutch PHARMO Database Network. All patients younger than 20 years old with at least one OAD dispensing were identified. Age-adjusted and age-specific incidence (1999-2011) and prevalence (1998-2011) rates of OAD use were calculated. Trends over time were assessed using joinpoint regression software. A subset of PHARMO Database Network (including community pharmacy dispensing records linked to general practitioner data (OPD-GP database)) was used to assess indications for OADs., Results: In 2011, the overall age-adjusted incidence and prevalence rates of OAD use were 20.7/100 000 (95% CI 19.2, 22.1) person-years (PY) and 53.8/100 000 (95% CI 51.5, 56.1) persons, respectively. The average annual percentage change (AAPC) in the overall age-adjusted incidence rates from 1999 to 2011 was 18.9% (95% CI 4.5, 35.2). The incidence and prevalence rates of OAD use were higher among females and older age categories. The increases in rates of OAD use were mainly driven by metformin. For only 50% of the 98 patients in the OPD-GP database, indications for OAD prescriptions were reported with type 1 diabetes (n = 20), type 2 diabetes (n = 16), and overweight/obesity (n = 10)., Conclusions: Incidence and prevalence rates of OAD use in children and adolescents substantially increased in the Netherlands, especially among older age categories (10-14 and 15-19 years) and females. The main indications for use of OADs were type 1 and 2 diabetes and overweight/obesity., (© 2015 The British Pharmacological Society.)

Background: Metformin, statin and aspirin use seem associated with decreased mortality in cancer patients, though, without adjusting for one another. Independent associations of these drugs with overall mortality after colorectal cancer (CRC) diagnosis within glucose-lowering drugs (GLDs) users were assessed., Methods: Patients starting GLDs before CRC diagnosis (1998-2011) were selected from the Eindhoven Cancer Registry linked with the PHARMO Database Network. The Cox regression model, with time since CRC diagnosis, included time-dependent variables of cumulative exposure to metformin, statins and aspirin after cancer diagnosis and time-dependent ever-never terms for drug exposure., Results: A total of 1043 patients used GLDs before CRC diagnosis; 666 (64%) used metformin, 639 (61%) used statins and 490 (47%) used aspirin after CRC diagnosis. Multivariable analyses revealed that longer cumulative exposure to metformin was not associated with overall mortality (HRCumulative exposure/6 months 1.02; 95% CI 0.97-1.07), whereas the favourable effect of statins increased with cumulative exposure (HRCumulative exposure/6 months 0.93; 95% CI 0.89-0.98). No association between aspirin use and overall mortality was seen (HRCumulative exposure/6 months 0.98; 95% CI 0.93-1.03)., Conclusions: No independent association between cumulative exposure to metformin, aspirin and overall mortality was found. Cumulative exposure to statins after CRC diagnosis was associated with lower overall mortality, supporting a drug effect of statins among GLDs users.

Objective: To study the dispensing of potentially teratogenic drugs in the 12-month period before as well as during pregnancy in the Netherlands., Design: Population-based study., Setting: A cohort was constructed using a linkage between the PHARMO Database Network and the Netherlands Perinatal Registry (PRN)., Population: A total of 203 962 Dutch pregnancies reported between 1999 and 2007 METHODS: Drug-dispensing information was identified from the PHARMO Database Network for the 12-month period before conception and during pregnancy. Drugs with either a Swedish FASS 'D' classification, an Australian ADEC or American FDA 'D' or 'X' classification were considered potentially teratogenic (n = 202)., Mean Outcome Measures: Proportion of pregnancies that received potentially teratogenic drugs in the 12-month period before and during pregnancy and specific for the risk category X drugs and newly initiated drugs., Results: Sixteen percent of the pregnancies received a potentially teratogenic drug in the 12-month period before and 5.07% during pregnancy. Doxycycline and paroxetine were most frequently received during pregnancy by 1.01% and 0.85% of women, respectively; 0.66% of the women received a risk category X drug during pregnancy which most frequently consisted of triptorelin (0.25%), norethisterone (0.22%) and simvastatin (0.03%). Fifty-three percent of the women who received a potentially teratogenic drug during pregnancy received this for the first time during the study period. These percentages were heterogeneous between therapeutic drug classes., Conclusions: Five percent of the pregnancies received a potentially teratogenic drug during pregnancy and 0.66% received a drug from the risk category X. It may be possible to reduce these proportions when reasons for prescription have been explored., (© 2014 Royal College of Obstetricians and Gynaecologists.)

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., (Copyright © 2015 John Wiley & Sons, Ltd.)

Objective: The objective of this study was to compare rates of different types of acute exacerbations of COPD (AECOPDs) and healthcare utilization among patients with different severities of COPD., Methods: Data for this study was obtained from the PHARMO Database Network, which includes drug dispensing records from pharmacies, hospitalization records and information from general practitioners. Patients with moderate to very severe COPD (GOLD II-III-IV) and a moderate or severe AECOPD between 2000 and 2010 were included in the study. Moderate and severe AECOPDs were defined by drug use and hospitalizations respectively. Study patients were followed from the first AECOPD to end of registration in PHARMO, death or end of study period, whichever occurred first. During follow-up, all recurrent AECOPDs were characterized and healthcare utilization was assessed., Results: Of 886 patients in the study, 52% had GOLD-II, 34% GOLD-III and 14% had GOLD-IV. The overall AECOPD recurrence rate per person year (PY) increased from 0.63 for patients with GOLD-II to 1.09 for patients with GOLD-III and 1.33 for patients with GOLD-IV. The rate of severe AECOPD was 0.06, 0.14 and 0.17 per PY, respectively., Conclusion: AECOPD recurrence rates and healthcare utilization are significantly higher among patients with more severe COPD.

Objective: To estimate isotretinoin exposure in Dutch pregnant women despite the implemented pregnancy prevention programme (PPP) and second, to analyse the occurrence of adverse fetal or neonatal outcomes in these isotretinoin exposed pregnancies., Design: Population-based study., Setting: The Netherlands., Participants: A cohort of 203,962 pregnancies with onset between 1 January 1999 and 1 September 2007 consisting of 208,161 fetuses or neonates., Main Outcome Measures: Isotretinoin exposure in the 30 days before or during pregnancy. Proportions of adverse fetal or neonatal outcomes, defined as intrauterine deaths ≥16 week of gestation and neonates with major congenital anomalies. ORs with 95% CIs adjusted for maternal age were calculated to estimate the risk of adverse fetal or neonatal outcome after maternal isotretinoin exposure., Results: 51 pregnancies, 2.5 (95% CI 1.9 to 3.3) per 10,000 pregnancies, were exposed to isotretinoin despite the pregnancy prevention programme. Forty-five of these pregnancies, 2.2 (95% CI 1.6 to 2.9) per 10,000 pregnancies, were exposed to isotretinoin during pregnancy and six additional women became pregnant within 30 days after isotretinoin discontinuation. In 60% of isotretinoin exposed pregnancies, women started isotretinoin while already pregnant. In five out of the 51 isotretinoin exposed pregnancies (53 fetuses), 9.4% (95% CI 1.3% to 17.6%), had an adverse fetal or neonatal outcome. The OR for adverse fetal or neonatal outcomes after isotretinoin exposure in 30 days before or during pregnancy was 2.3 (95% CI 0.9 to 5.7) after adjustment for maternal age., Conclusions: Although a PPP was already implemented in 1988, we showed that isotretinoin exposed pregnancies and adverse fetal and neonatal events potentially related to the exposure still occur. These findings from the Netherlands add to the evidence that there is no full compliance to the isotretinoin PPP in many Western countries. Given the limited success of iPLEDGE, the question is which further measures are able to improve compliance., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Observational and intervention studies suggest that low dose aspirin use may prevent cancer. The objective of this study was to investigate the protective effect of long term low dose aspirin use (≤100 mg daily) on cancer in general and site-specific cancer among low dose aspirin users in the Dutch general population. We conducted a population-based cohort study with detailed information on aspirin exposure and cancer incidence. Only incident (new) low dose aspirin users, who were included in the linkage between PHARMO and the Eindhoven Cancer Registry (1998-2010) and free of cancer before the start of follow up were included. A Cox proportional hazard model with cumulative aspirin use as a time-varying determinant was used to obtain hazard ratios (HR). Duration of aspirin use amongst 109,276 incident low dose aspirin users was not associated with a decreased risk of any of the site-specific cancers or cancer in general (adjusted HR per year of aspirin use for all cancers: 1.02, 95% confidence interval [CI] 1.00-1.04, HR of >6 years aspirin use compared to <2 years: 1.17, 95% CI 1.02-1.34). After adjusting for current and past aspirin use, 2-6 years of low dose aspirin use was associated with a reduced colorectal cancer risk compared to <2 years of aspirin use (adjusted HR 0.75, 95% CI 0.59-0.96). However, a clear dose-response relationship was not observed (adjusted HR >6 years aspirin use 0.95, 95% CI 0.60-1.49). Our results do not support the primary prevention of cancer among long term aspirin users., (© 2013 UICC.)

Background: Evidence on recent time trends in age-gender differences in cardiovascular drug use is scarce. We studied time trends in age-gender-specific cardiovascular drug use for primary prevention, secondary prevention, and in-hospital treatment of coronary heart disease., Methods and Results: The PHARMO database was used for record linkage of drug dispensing, hospitalization, and population data to identify drug use between 1998 and 2010 in 1 203 290 persons ≥25 years eligible for primary prevention, 84 621 persons hospitalized for an acute coronary syndrome (ACS), and 15 651 persons eligible for secondary prevention. The use of cardiovascular drugs increased over time in all three settings. In primary prevention, the proportion of women that used lipid-lowering drugs was lower than men between 2003 and 2010 (5.7 vs. 7.3% in 2010). The higher proportion of women that used blood pressure-lowering drugs for primary prevention, compared with men, attenuated over time (15.1 vs. 13.8% in 2010). During hospital admission for an ACS, the proportion of women that used cardiovascular drugs was lower than men. In secondary prevention (36 months after hospital discharge), drug use was lowest in young women. The proportion receiving lipid-lowering drugs declined after the age of 75 in all three settings. This age difference attenuated over time., Conclusion: Age differences in drug use tended to attenuate over time, whereas gender differences persisted. Areas potentially for improvement are in the hospital treatment of ACS in young women, in secondary prevention among young women and the elderly, and in the continuity of drug use in secondary prevention.

Background: The Observational Medical Outcomes Partnership (OMOP) has just completed a large scale empirical evaluation of statistical methods and analysis choices for risks identification in longitudinal observational healthcare data. This experiment drew data from four large US health insurance claims databases and one US electronic health record (EHR) database, but it is unclear to what extend the findings of this study apply to other data sources., Objective: To replicate the OMOP experiment in six European EHR databases., Research Design: Six databases of the EU-ADR (Exploring and Understanding Adverse Drug Reactions) database network participated in this study: Aarhus (Denmark), ARS (Italy), HealthSearch (Italy), IPCI (the Netherlands), Pedianet (Italy), and Pharmo (the Netherlands). All methods in the OMOP experiment were applied to a collection of 165 positive and 234 negative control drug-outcome pairs across four outcomes: acute liver injury, acute myocardial infarction, acute kidney injury, and upper gastrointestinal bleeding. Area under the receiver operator characteristics curve (AUC) was computed per database and for a combination of all six databases using meta-analysis for random effects. We provide expected values of estimation error as well, based on negative controls., Results: Similarly to the US experiment, high predictive accuracy was found (AUC >0.8) for some analyses. Self-controlled designs, such as self-controlled case series, IC temporal pattern discovery and self-controlled cohort achieved higher performance than other methods, both in terms of predictive accuracy and observed bias., Conclusions: The major findings of the recent OMOP experiment were also observed in the European databases.

Purpose: In this cohort study, the rates of pulmonary embolism (PE), myocardial infarction (MI), and ischemic stroke (IS) before and after lung cancer (LC) diagnosis were compared to cancer-free controls., Methods: Patients with LC during 2000-2007 were selected from PALGA, the Dutch Pathology Registry, and linked to the PHARMO medical record linkage system, including drug use and hospitalizations of 3 million inhabitants in the Netherlands. Included LC patients were matched 1:10 by age and gender to cancer-free controls. Hospitalizations for PE, MI, and IS were assessed in the 12 months before and after LC diagnosis., Results: LC patients (N = 3,717) were six times more likely than cancer-free controls to have had a PE in the 12 months before diagnosis. After LC diagnosis, patients experienced an extremely increased risk of PE in the first 6 months (hazard ratio [HR] 16.8; 95 % confidence interval [CI] 7.6-36.8) compared with controls), which decreased to a five times increased risk (HR 5.1; 95 % CI 2.7-9.4) thereafter. However, there were less than two events per 100 person years during both time periods. LC patients receiving chemotherapy were eight times more likely to develop PE, whereas surgery increased the risk on PE three times. For MI and IS, no significant difference was observed compared with cancer-free controls before or after LC diagnosis., Conclusions: LC patients have a higher risk of developing PE compared with cancer-free controls, although the frequency of PE hospitalizations was low. Surgery and chemotherapy were associated with an increased risk of PE.

Psoriasis has a major impact on health-related quality of life. The present cohort study investigated the use of antidepressant drugs in psoriasis patients and a reference cohort, using pharmacy and hospitalization data from 1998 to 2008 for more than 2.5 million Dutch residents. Multivariate Cox regression was used to compare the risk of first antidepressant use, and Poisson regression to compare the number of episodes of antidepressant use. A total of 25,691 psoriasis cases and 128,573 reference subjects were followed for more than 9 years. The incidence of first antidepressant use was 21 and 9 per 1,000 person years, respectively, and the adjusted hazard ratio (HR) was 1.55 (95% confidence interval (CI) 1.50-1.61). Within the psoriasis cohort, the HR of receiving an antidepressant was significantly higher after the first antipsoriatic treatment (HR 1.07, 95% CI 1.02-1.12). Psoriasis patients have a two-fold increase in antidepressant use, the period after antipsoriatic treatment being characterized by a further increase in antidepressant drug dispenses.

There is little information available on the patterns of chemotherapy regimens administered in daily practice to patients with early stage and metastatic or recurrent breast cancer. To determine the trends in type of chemotherapy regimens used in breast cancer patients, newly diagnosed breast cancer patients in the period 2000-2008 who received chemotherapy were identified from the Eindhoven Cancer Registry (ECR) and linked to the PHARMO RLS, including data on, e.g., in- and outpatient drug use. Chemotherapy regimens were classified based on the received combinations and sequences. Trends in the distribution of adjuvant chemotherapy regimens (for early-stage breast cancer) and palliative chemotherapy regimens (for metastatic or recurrent breast cancer) were determined and stratified by Her2/neu status when possible. In this study, 422 patients diagnosed with early-stage breast cancer received adjuvant chemotherapy. The use of CMF (cyclophosphamide, methotrexate, and 5-fluorouracil) decreased from 90% in 2000 to almost none since 2005. Administration of regimens that included anthracyclines increased from 4% in 2000 to 96% in 2005, but decreased to 68% in 2008. The use of trastuzumab- and taxane-containing regimens (with or without anthracyclines) increased from 2005 onwards to 24% and 34%, respectively, in 2008. Among the 82 breast cancer patients who received palliative chemotherapy at diagnosis or after breast cancer recurrence, the use of CMF and anthracyclines (without taxanes) decreased, while the use of taxanes (with or without anthracyclines) increased (26% in 2008). Trastuzumab was used as palliative chemotherapy from 2003 onwards, with 22% of the metastatic breast cancer patients receiving trastuzumab-containing regimens in 2008, and bevacizumab was administered since 2007 with 19% of the patients receiving bevacizumab-containing regimens in 2008. In conclusion, major changes have taken place in the chemotherapeutic treatment of patients with early and recurrent breast cancer. These changes reflect the key findings from large clinical trials, as incorporated in the Dutch guidelines., (© 2013 Wiley Periodicals, Inc.)

Purpose: Ultraviolet radiation exposure is the most important exogenous risk factor for cutaneous malignancies. It is possible that phototoxic drugs promote the development of cutaneous melanoma (CM) by intensifying the effect of ultraviolet light on the skin. We investigated the association between the use of common systemic phototoxic drugs and development of CM., Methods: This study was a case-control study in a Dutch population-based cohort. The drug dispensing data was obtained from PHARMO, a Dutch drug dispensing and hospital admissions registry, and linked to PALGA, the nationwide pathology network of the Netherlands. The cases were patients diagnosed with pathologically confirmed primary CM between 1991 and 2004. Controls were sampled from the PHARMO population. Exposure to systemic phototoxic drugs was measured and included antimicrobial agents, diuretics, antipsychotic drugs, antidiabetic drugs, cardiac drugs, antimalarials and nonsteroidal anti-inflammatory drugs (NSAIDs). A multivariate conditional logistic regression analysis was performed to study the association between exposure to phototoxic drugs and CM., Results: The study population included 1,318 cases and 6,786 controls. Any phototoxic drug during the study period was dispensed for 46 % of the cases and 43 % of the controls (p = 0.012). The use of quinolones [odds ratio (OR) 1.33, 95 % confidence interval (CI) 1.01-1.76] and propionic acid derivative NSAIDs (OR 1.33, 95 % CI 1.14-1.54) had a positive association with CM., Conclusions: Our study shows that the use of phototoxic drugs is associated with an increased risk of developing CM. Even a short-term use of phototoxic quinolones and propionic acid derivative NSAIDs may increase the risk for CM. Patient education to promote sun-protective behaviour is essential to avoid immediate adverse effects and possible long-term effects of phototoxic drugs.

Objective: To compare hospitalization and medication use during the first year of life in preterm-born and term-born infants., Study Design: Data for this retrospective cohort study were obtained from the linked PHARMO-Netherlands Perinatal Registry cohort. From this linked birth cohort, preterm infants (<37 weeks) born between 2004 and 2007 were randomly matched to 4 full-term infants. During follow-up, hospitalization and medication use were assessed. Cox proportional hazard regression models were used to estimate and compare the relative risk (RR) of hospitalization and medication use in preterm and full-term infants. Population-attributable risk percentages were calculated to estimate the proportion of hospitalizations and medication use attributable to preterm birth., Results: Among the 71,607 singletons born between 2004-2007, 4277 (6%) were born preterm. Of these, 90% were hospitalized at birth, compared with 55% of full-term infants. Preterm infants were twice as likely to be rehospitalized (RR, 2.0; 95% CI, 1.9-2.2), specifically for respiratory-related diseases. Prematurity accounted for 6% of the respiratory disease readmissions. The most frequently used outpatient drugs in the second half year of life were antibacterials for systemic use and drugs for obstructive airway diseases. Preterm infants were 50% more likely to receive a respiratory medication (RR, 1.5; 95% CI, 1.4-1.7)., Conclusion: In the first year of life, preterm born infants are up to 2 times more likely than full-term infants to be hospitalized or use medication, especially related to respiratory disease., (Copyright © 2013 Mosby, Inc. All rights reserved.)

Background: The use of thiazolidinediones (TZDs) has been associated with increased fracture risks. Our aim was to estimate the risk of fracture with TZDs in three different healthcare registries, using exactly the same study design, and to perform an individual patient data meta-analysis of these three studies., Methods: Population-based cohort studies were performed utilizing the British General Practice Research Database (GPRD), the Dutch PHARMO Record Linkage System (RLS), and the Danish National Health Registers. In all three databases, the exposed cohort consisted of all patients (aged 18+) with at least one prescription of antidiabetic (AD) medication. Cox proportional hazards models were used to estimate hazard ratios (HRs) of fracture. The total period of follow-up for each patient was divided into periods of current exposure and past exposure, with patients moving between current and past use., Results: In all three registries, the risk of fracture was increased for women who were exposed to TZDs: HR 1.48 (1.37-1.60) in GPRD, HR 1.35 (1.15-1.58) in PHARMO, and HR 1.22 (1.03-1.44) in Denmark. Combining the data in an individual patient data meta-analysis resulted, for women, in a 1.4-fold increased risk of any fracture for current TZD users versus other AD drug users [adj. HR 1.44 (1.35-1.53)]. For men, there was no increased fracture risk [adj. HR 1.05 (0.96-1.14)]. Risks were increased for fractures of the radius/ulna, humerus, tibia/fibula, ankle, and foot, but not for hip/femur or vertebral fractures. Current TZD users with more than 25 TZD prescriptions ever before had a 1.6-fold increased risk of fracture compared with other AD drug users [HR 1.59 (1.46-1.74)]., Conclusion: In this study, we consistently found a 1.2- to 1.5-fold increased risk of fractures for women using TZDs, but not for men, across three different healthcare registries. TZD users had an increased risk for fractures of the extremities, and risks further increased for prolonged users of TZDs.

Background: Drug safety monitoring relies primarily on spontaneous reporting, but electronic health care record databases offer a possible alternative for the detection of adverse drug reactions (ADRs)., Objectives: To evaluate the relative performance of different statistical methods for detecting drug-adverse event associations in electronic health care record data representing potential ADRs., Research Design: Data from 7 databases across 3 countries in Europe comprising over 20 million subjects were used to compute the relative risk estimates for drug-event pairs using 10 different methods, including those developed for spontaneous reporting systems, cohort methods such as the longitudinal gamma poisson shrinker, and case-based methods such as case-control. The newly developed method "longitudinal evaluation of observational profiles of adverse events related to drugs" (LEOPARD) was used to remove associations likely caused by protopathic bias. Data from the different databases were combined by pooling of data, and by meta-analysis for random effects. A reference standard of known ADRs and negative controls was created to evaluate the performance of the method., Measures: The area under the curve of the receiver operator characteristic curve was calculated for each method, both with and without LEOPARD filtering., Results: The highest area under the curve (0.83) was achieved by the combination of either longitudinal gamma poisson shrinker or case-control with LEOPARD filtering, but the performance between methods differed little. LEOPARD increased the overall performance, but flagged several known ADRs as caused by protopathic bias., Conclusions: Combinations of methods demonstrate good performance in distinguishing known ADRs from negative controls, and we assume that these could also be used to detect new drug safety signals.

Study Objectives: To compare the cholesterol level goal attainment rates in patients receiving simvastatin doses recommended in clinical practice guidelines and simvastatin doses most frequently prescribed in clinical practice versus other statins at various dose levels, and to assess statin adherence rates in patients receiving all statins., Design: Retrospective cohort study., Data Source: PHARMO database, which contains linked prescription drug information, hospitalization records, and laboratory test results of over 1 million patients in the Netherlands., Patients: A total of 7355 new statin users with available cholesterol level measurements before and 12 months after starting statin treatment between 1999 and 2006., Measurements and Main Results: Simvastatin was chosen as the reference drug because policy makers in the Netherlands have promoted the use of generically available statins to reduce costs. Cholesterol level goal attainment rates were compared in patients receiving simvastatin 40 mg/day, which was the statin dose promoted in the 2006 Dutch cardiovascular risk management guidelines, or simvastatin 20 mg/day, which was the most frequently prescribed dose up to 2006, versus other statins at various dose levels. Relative risks (RRs) were adjusted for age, sex, year of therapy initiation, cardiovascular disease, type 2 diabetes mellitus, hypertension, baseline low-density lipoprotein cholesterol level, and adherence during the 3 months before the 12-month follow-up cholesterol measurement. Compared with simvastatin 40 mg/day, cholesterol goal attainment rates were significantly higher with atorvastatin 40 mg/day (RR 1.15, 95% confidence interval [CI] 1.04-1.28) and rosuvastatin 10 mg/day (RR 1.13, 95% CI 1.04-1.23), were similar with atorvastatin 20 mg/day (RR 1.06, 95% CI 0.97-1.16) and rosuvastatin 20 mg/day (RR 1.14, 95% CI 0.93-1.39), and were significantly lower with all other frequently used statin dose levels. Compared with simvastatin 20 mg/day, cholesterol goal attainment was significantly higher with any dose of atorvastatin and rosuvastatin, but were lower with any dose of pravastatin. Goal attainment rates were similar among patients with lower and higher cardiovascular risk. Among the 13-18% of patients who had follow-up cholesterol level measurements at 12 months in all statin groups, the proportion of adherent patients was approximately 75%; this was higher than the proportion of adherent patients in the total population (48-55%), which included patients without follow-up cholesterol levels., Conclusion: A larger proportion of patients reached cholesterol lipid goals with simvastatin 40 mg/day. Cholesterol level goals were achieved by many patients using the recommended simvastatin 40 mg/day, but by fewer patients among those using the more commonly prescribed simvastatin 20 mg/day. Therefore, especially in high-risk patients, the choice of statin should be based on baseline cholesterol levels and expected reductions in these levels, and treatment should be adapted if targets are not met. Improved cholesterol level monitoring may increase adherence and cholesterol management., (© 2012 Pharmacotherapy Publications, Inc. All rights reserved.)

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.

Background: Relevant safety signals in the EU are regularly communicated in so-called 'Direct Healthcare Professional Communications' (DHPCs) or European Medicines Agency (EMA) press releases. Trends of a decrease in the use of rosiglitazone following regulatory safety warnings have been described in the US. In the EU, however, relatively little is known about dispensing patterns following DHPCs or other safety signals such as EMA press releases., Objective: The objective of this study was to analyse trends in dispensing patterns of rosiglitazone and pioglitazone following DHPCs and EMA press releases in the EU member state, the Netherlands., Methods: Data for this study were obtained from the PHARMO Record Linking System, which includes drug dispensing records from community pharmacies of approximately 2.5 million individuals in the Netherlands. Over the period 1998-2008 an auto-regressive, integrated, moving average model (ARIMA) was fitted. The DHPC letters or EMA press releases were used as determinants. Adjustments were made for publication of certain literature. Stratification was performed for dispensings prescribed by general practitioners (GPs) and those prescribed by specialists., Results: For rosiglitazone, four EMA press releases and two DHPCs were issued; for pioglitazone, one DHPC was issued. The number of rosiglitazone dispensings prescribed by GPs decreased significantly after publication of DHPCs and EMA press releases concerning the risk of macular oedema and risk of fractures (both p-values 0.001). The number of rosiglitazone dispensings decreased statistically significantly after publication of EMA press releases 2 and 3 concerning cardiovascular risks but not for EMA press release 4. Adjustment for certain publications in the literature reduced the effect of communicated safety issues on the proportion of dispensings., Conclusions: Although it is difficult to disentangle the effect of DHPCs and EMA press releases from the effect of reports published in the literature, our results suggest that prescribers may react to such safety communications.

Background: The preventive role of non-steroid anti-inflammatory drugs (NSAIDs) and aspirin, in particular, on colorectal cancer is well established. More recently, it has been suggested that aspirin may also have a therapeutic role. Aim of the present observational population-based study was to assess the therapeutic effect on overall survival of aspirin/NSAIDs as adjuvant treatment used after the diagnosis of colorectal cancer patients., Methods: Data concerning prescriptions were obtained from PHARMO record linkage systems and all patients diagnosed with colorectal cancer (1998-2007) were selected from the Eindhoven Cancer Registry (population-based cancer registry). Aspirin/NSAID use was classified as none, prediagnosis and postdiagnosis and only postdiagnosis. Patients were defined as non-user of aspirin/NSAIDs from the date of diagnosis of the colorectal cancer to the date of first use of aspirin or NSAIDs and user from first use to the end of follow-up. Poisson regression was performed with user status as time-varying exposure., Results: In total, 1176 (26%) patients were non-users, 2086 (47%) were prediagnosis and postdiagnosis users and 1219 (27%) were only postdiagnosis users (total n=4481). Compared with non-users, a survival gain was observed for aspirin users; the adjusted rate ratio (RR) was 0.77 (95% confidence interval (CI) 0.63-0.95; P=0.015). Stratified for colon and rectal, the survival gain was only present in colon cancer (adjusted RR 0.65 (95%CI 0.50-0.84; P=0.001)). For frequent users survival gain was larger (adjusted RR 0.61 (95%CI 0.46-0.81; P=0.001). In rectal cancer, aspirin use was not associated with survival (adjusted RR 1.10 (95%CI 0.79-1.54; P=0.6). The NSAIDs use was associated with decreased survival (adjusted RR 1.93 (95%CI 1.70-2.20; P<0.001)., Conclusion: Aspirin use initiated or continued after diagnosis of colon cancer is associated with a lower risk of overall mortality. These findings strongly support initiation of a placebo-controlled trial that investigates the role of aspirin as adjuvant treatment in colon cancer patients.

Background: Limited data exist on the burden of comorbidity among patients with squamous cell head and neck cancer (SCCHN) before and during cancer treatment., Methods: The precancer prevalence and incidence rates of 8 comorbid conditions were estimated among a population-based cohort of 1499 patients with SCCHN in the Netherlands. Patients with cancer, treatments, and comorbidities were identified in the PHARMO Record Linkage System (RLS) using hospital admissions and/or dispensing codes. Prevalence proportions and incidence rates were also compared against a matched cancer-free population., Results: Cardiovascular (41%) and respiratory diseases (12%) were the most prevalent comorbidities. Incidence rates of most comorbidities were highest the first 6 months after cancer diagnosis and decreased over time. Patients receiving chemotherapy-based treatment had significantly higher incidence rates of anemia and other malignant diseases., Conclusions: High rates of acute and chronic comorbidity were observed; knowledge of comorbidity burden aids in establishing a benefit-risk profile for investigational SCCHN therapies., (Copyright © 2011 Wiley Periodicals, Inc.)

Background. Data is limited on the burden of common comorbidities, such as cardiovascular disease (CVD), respiratory disease and diabetes, or comorbidities related to cancer and its treatment, such as anemia and depression, in patients with soft tissue sarcoma (STS). Patients and Methods. From the Dutch Pathology Registry linked to the PHARMO database (including data on drug use and hospitalizations), 533 patients with STS were selected during 2000-2007 and matched 1 : 10 to cancer-free controls. The occurrences of comorbidities were assessed in the 12 months before and after STS diagnosis. Results. STS patients were 2-4 times more likely to have comorbidities at diagnosis compared with cancer-free controls. The incidence of CVD, anemia, and depression after STS diagnosis differed significantly from cancer-free controls and decreased during followup from 40-124 per 1,000 person-years (py) during the first six months to 11-38 per 1,000 py more than 12 months after diagnosis. The incidence of respiratory disease and diabetes among STS patients remained stable during followup (5-21 per 1,000 py) and did not differ significantly from cancer-free controls. Conclusions. STS patients were more likely to have comorbidities before cancer diagnosis and to develop CVD, anemia, and depression after diagnosis compared to cancer-free controls.

Objective: Numerous studies have suggested a decreased risk of cancer in patients with diabetes on metformin. Because different comparison groups were used, the effect magnitude is difficult to estimate. Therefore, the objective of this study was to further analyze whether, and to what extent, use of metformin is associated with a decreased risk of cancer in a cohort of incident users of metformin compared with users of sulfonylurea derivatives., Research Design and Methods: Data for this study were obtained from dispensing records from community pharmacies individually linked to hospital discharge records from 2.5 million individuals in the Netherlands. The association between the risk of cancer in those using metformin compared with those using sulfonylurea derivatives was analyzed using Cox proportional hazard models with cumulative duration of drug use as a time-varying determinant., Results: Use of metformin was associated with a lower risk of cancer in general (hazard ratio 0.90 [95% CI 0.88-0.91]) compared with use of sulfonylurea derivatives. When specific cancers were used as end points, similar estimates were found. Dosage-response relations were identified for users of metformin but not for users of sulfonylurea derivatives., Conclusions: In our study, cumulative exposure to metformin was associated with a lower risk of specific cancers and cancer in general, compared with cumulative exposure to sulfonylurea derivatives. However, whether this should indeed be seen as a decreased risk of cancer for the use of metformin or as an increased risk of cancer for the use sulfonylurea derivatives remains to be elucidated.

Background: An increasing need has developed for the post-approval surveillance of (new) anti-cancer drugs by means of pharmacoepidemiology and outcomes research in the area of oncology., Objectives: To create an overview that makes researchers aware of the available database linkages in Northern America and Europe which facilitate pharmacoepidemiology and outcomes research in cancer patients., Methods: In addition to our own database, i.e. the Eindhoven Cancer Registry (ECR) linked to the PHARMO Record Linkage System, we considered database linkages between a population-based cancer registry and an administrative healthcare database that at least contains information on drug use and offers a longitudinal perspective on healthcare utilization. Eligible database linkages were limited to those that had been used in multiple published articles in English language included in Pubmed. The HMO Cancer Research Network (CRN) in the US was excluded from this review, as an overview of the linked databases participating in the CRN is already provided elsewhere. Researchers who had worked with the data resources included in our review were contacted for additional information and verification of the data presented in the overview., Results: The following database linkages were included: the Surveillance, Epidemiology, and End-Results-Medicare; cancer registry data linked to Medicaid; Canadian cancer registries linked to population-based drug databases; the Scottish cancer registry linked to the Tayside drug dispensing data; linked databases in the Nordic Countries of Europe: Norway, Sweden, Finland and Denmark; and the ECR-PHARMO linkage in the Netherlands. Descriptives of the included database linkages comprise population size, generalizability of the population, year of first data availability, contents of the cancer registry, contents of the administrative healthcare database, the possibility to select a cancer-free control cohort, and linkage to other healthcare databases., Conclusions: The linked databases offer a longitudinal perspective, allowing for observations of health care utilization before, during, and after cancer diagnosis. They create new powerful data resources for the monitoring of post-approval drug utilization, as well as a framework to explore the (cost-)effectiveness of new, often expensive, anti-cancer drugs as used in everyday practice., (Copyright © 2011 John Wiley & Sons, Ltd.)

Aims/hypothesis: Several publications suggest an association between certain types of insulin and cancer, but with conflicting results. We investigated whether insulin glargine (A21Gly,B31Arg,B32Arg human insulin) is associated with an increased risk of cancer in a large population-based cohort study., Methods: Data for this study were obtained from dispensing records from community pharmacies individually linked to hospital discharge records from 2.5 million individuals in the Netherlands. In a cohort of incident users of insulin, the association between insulin glargine and other insulin analogues, respectively, and cancer was analysed in comparison with human insulin using Cox proportional hazard models with cumulative duration of drug use as a time-varying determinant. The first hospital admission with a primary diagnosis of cancer was considered as the main outcome; secondary analyses were performed with specific cancers as outcomes., Results: Of the 19,337 incident insulin users enrolled, 878 developed cancer. Use of insulin glargine was associated with a lower risk of malignancies in general in comparison with human insulin (HR 0.75, 95% CI 0.71, 0.80). In contrast, an increased risk was found for breast cancer (HR 1.58, 95% CI 1.22, 2.05). Dose-response relationships could not be identified., Conclusion/interpretation: Users of insulin glargine and users of other insulin analogues had a lower risk of cancer in general than those using human insulin. Both associations might be a consequence of residual confounding, lack of adherence or competing risk. However, as in previous studies, we demonstrated an increased risk of breast cancer in users of insulin glargine in comparison with users of human insulin.

Background: Dupuytren's contracture is a condition of the palmar fascia involving contractures of the fascia and skin in the hand. Current treatment for Dupuytren's contracture is mainly limited to surgery. In the Netherlands, little is known about the prevalence of Dupuytren's contracture. In this study we determined the prevalence of patients with a hospitalization for Dupuytren's contracture in the Netherlands and characterized their (re)hospitalizations., Methods: From the PHARMO database, which consists of multiple observational databases linked on a patient level, all patients hospitalized for Dupuytren's contracture between 2004 and 2007 were included in the source population (ICD-9-CM code 728.6). Numbers from this source population were used to provide estimates of hospitalizations for Dupuytren's contracture in the Netherlands. Patients with a medical history in the PHARMO database of at least 12 months before their hospitalization were included in the study cohort and followed until end of data collection, death, or end of study period, whichever occurred first. Type of admission, length of stay, recorded procedures, treating specialty, number of rehospitalizations for Dupuytren's contracture, and time to first rehospitalization were assessed., Results: Of 3, 126 patients included in the source population, 3, 040 were included in the study population. The overall prevalence of patients with a hospitalization for Dupuytren's contracture was 0.04%, with the highest prevalence (0.25%) among 60-79 year old males. The majority (85%) of all hospitalizations were day-case admissions. Of the admitted inpatients (15%) the majority (81%) had one overnight stay in the hospital. The most common recorded procedure was fasciectomy (87%) and 78% of patients was treated by a plastic surgeon. During a median (IQR) follow-up of 2.9 (1.8-4.0) years, 523 patients were rehospitalized for Dupuytren's contracture. The median (IQR) time to first rehospitalization was 0.8 (0.4-1.9) years., Conclusions: This study is a first exploration of Dupuytren's contracture in the Netherlands based on hospitalizations, showing a prevalence of 0.25% among 60-79 year old males. Future studies should also address outpatient procedures to get a complete picture of the treatment of Dupuytren's contracture. In addition, patients not yet treated should be included to be able to estimate the prevalence of Dupuytren's contracture.

Purpose: To determine the thromboprophylactic treatment pattern and occurrence of venous thromboembolism (VTE), major bleeding, and wound infections in patients undergoing total knee replacement (TKR) or total hip replacement (THR)., Methods: From the PHARMO database, all patients ≥ 18 years hospitalized for TKR or THR between January 2003 and September 2008 were selected. Patients with pharmacy data up to 3 months after hospitalization were included in the study cohort. Duration and type of thromboprophylaxis were assessed. VTE, major bleeding, and wound infections were identified by hospitalizations. Regarding VTE, timing of event in relation to thromboprophylaxis was determined., Results: The study population included 2930 patients with TKR, 5332 patients with THR without hip fracture, and 289 patients with THR and hip fracture. Mean duration of thromboprophylaxis was about 30 (± 20) days for all procedures, with low-molecular-weight heparin being the most frequently used drug. During 3 months of follow-up, 1% to 2% of patients were hospitalized for an event. The most observed event was wound infection (58%), followed by major bleeding (29%), and VTE (13%). For wound infection and major bleeding, median time after surgery was about 19 days. Median time between surgery and VTE was 24 days for TKR and 60 days for THR. Eighteen of 23 VTE occurred during thromboprophylaxis., Conclusions: Although patients are often treated for fewer days than recommended, thromboprophylaxis after TKR and THR in the Netherlands is adequate. Only 5 of 23 VTE hospitalizations occurred off-treatment and might have been prevented. Furthermore, fewer than 1% of patients were hospitalized for bleeding., (Copyright © 2011 John Wiley & Sons, Ltd.)

We studied the occurrence of myocardial infarction (MI), ischaemic stroke (IS) and pulmonary embolism (PE) before and after breast cancer hospitalisation compared with cancer-free controls. For this, women with a first breast cancer hospitalisation during 2000-2007 were selected from the PHARMO Record Linkage System, including drug use and hospitalisations of three million inhabitants in the Netherlands, and matched 1:10 by age to cancer-free women. The occurrence of MI, IS and PE were assessed in the 12 months before and after breast cancer hospitalisation. The study included 11,473 breast cancer patients, with a mean (± SD) age of 59 (± 14) years. Breast cancer patients were two to three times as likely as their cancer-free controls to have had a hospitalisation for PE, MI or IS in the 12 months before diagnosis, though prevalence was <1% in all groups. Breast cancer patients experienced an extreme high risk of PE in the first six months after diagnosis (hazard ratio [HR] 23.5, 95% confidence interval [CI] 11.1-49.7 compared to controls), which declined gradually to a four times increased risk (HR 3.6, 95%CI 2.4-5.5) more than 12 months after breast cancer hospitalisation. However, incidence was low: less than five events per 1,000 person years during all time periods. For MI and IS we did not observe significant increased HRs after breast cancer hospitalisation compared to controls. Breast cancer patients seem to have a higher risk profile to develop MI and IS, and receive treatment that increases the risk of PE compared to cancer-free controls, although the frequency of hospitalisations was low.