PHARMO Institute for Drug Outcomes Research

Utrecht, Netherlands

PHARMO Institute for Drug Outcomes Research

Utrecht, Netherlands
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News Article | April 18, 2017

The commonly used antibiotic azithromycin is not linked to an increased risk of ventricular arrhythmia, an often life-threatening rapid, irregular heartbeat, according to a large study published in CMAJ (Canadian Medical Association Journal). Azithromycin is an antibiotic commonly used to treat bacterial infections -- mostly respiratory and urinary tract infections -- in people of all ages. It belongs to a class of drugs known as macrolides, of which at least one other drug, erythromycin, is known to disrupt the heart's normal rhythm, leading to a condition known as ventricular arrhythmia. Several recent studies have reported conflicting results over whether azithromycin is linked to an increased risk of death from ventricular arrhythmia in people taking the antibiotic. To provide clarity among these conflicting findings, a team of European researchers looked at data on nearly 29 million people in health care databases from Italy, the United Kingdom, Germany, the Netherlands and Denmark to determine if there is a link between azithromycin and ventricular arrhythmia. Of the more than 14 million new antibiotic users, 0.1% (12 874) people developed ventricular arrhythmia, of whom 30 were new users of azithromycin. When compared to amoxicillin, another commonly used antibiotic, from the penicillin class of drugs, there was no increased risk of this heart condition in people using azithromycin. However, there was an increased risk of ventricular arrhythmia in people taking azithromycin compared to people not using antibiotics at all. "This finding suggests that the risk of ventricular arrhythmia is more likely to be due to a person's poor health and caused by their infection, rather than to azithromycin itself," says Dr. Gianluca Trifirò, Department of Biomedical and Dental Sciences and Morpho-functional Imaging, University of Messina, Italy. "This finding was confirmed in several sensitivity analyses and replicated in single databases participating in the study." The authors note these findings may not be applied in hospital settings as the health of patients and use of antibiotics is quite different in community settings, from which the data were drawn. "Current azithromycin use was associated with an increased risk of ventricular arrhythmia when compared with nonuse of antibiotics, but not when compared with current amoxicillin use. The decreased risk with an active comparator suggests significant confounding by indication," the authors conclude. The study was conducted by researchers from Erasmus University, Rotterdam, Netherlands; University of Messina, Messina, Italy; Italian College of General Practitioners, Florence, Italy; PHARMO Institute for Drug Outcomes Research, Utrecht, Netherlands; Leibniz Institute for Prevention Research and Epidemiology - BIPS Gmbh, Bremen, Germany; University of Bologna, Italy; Aarhus University Hospital, Aarhus, Denmark; and King's College, London, United Kingdom.

Ruiter R.,Erasmus University Rotterdam | Ruiter R.,Drug Safety Unit | Visser L.E.,Erasmus University Rotterdam | Vn Herk-Sukel M.P.P.,PHARMO Institute for Drug Outcomes Research | And 9 more authors.
Diabetologia | Year: 2012

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. © 2011 The Author(s).

Ruiter R.,Erasmus University Rotterdam | Ruiter R.,Drug Safety Unit | Visser L.E.,Erasmus University Rotterdam | Van Herk-Sukel M.P.P.,PHARMO Institute for Drug Outcomes Research | And 9 more authors.
Diabetes Care | Year: 2012

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. © 2012 by the American Diabetes Association.

Zanders M.M.J.,Netherlands Comprehensive Cancer Organisation | Haak H.R.,Maxima Medical Center | Haak H.R.,Maastricht University | van Herk-Sukel M.P.P.,PHARMO Institute for Drug Outcomes Research | And 3 more authors.
Diabetologia | Year: 2015

Aims/hypothesis: Adherence to glucose-lowering drug (GLD) treatment regimens is crucial for metabolic control and improving prognosis. Because a diagnosis of cancer might have an impact on adherence to medication, this study explored changes in adherence to GLDs following a cancer diagnosis. Methods: All new users of GLDs between 1998 and 2011 who lived in the Eindhoven Cancer Registry–PHARMO Database Network catchment area were selected. Those with a primary cancer diagnosis during follow-up were considered cases and matched with eligible controls without cancer during follow-up. Medication possession ratio (MPR) was used as indicator for medication adherence. Segmented linear auto-regression analysis with interrupted time series was used to assess changes in MPR for cases compared with controls (i.e. overall trend) due to (any) cancer diagnosis and specific cancer types. Results: From the 52,228 GLD users selected, 3,281 cases with cancer and 12,891 controls without cancer during follow-up were included in the study. In our analyses, before cancer diagnosis the MPR increased by 0.10% per month (95% CI 0.10, 0.10). Besides a significant drop in MPR at the time of cancer diagnosis of −6.3% (95% CI −6.5, −6.0), there was an ongoing, yet lower, monthly decline in MPR (−0.20%; 95% CI −0.21, −0.20) after cancer diagnosis. The largest drops in MPR at the time of cancer diagnosis, in the range of 11–15%, were seen among patients with stage IV disease and gastrointestinal or pulmonary cancers. Conclusions/interpretation: Our findings indicate a clear decline in adherence to GLD treatment regimens following a cancer diagnosis. The reason for the decline in MPR needs to be further elucidated. © 2015, Springer-Verlag Berlin Heidelberg.

Reimers M.S.,Leiden University | Bastiaannet E.,Leiden University | Langley R.E.,University College London | Van Eijk R.,Leiden University | And 9 more authors.
JAMA Internal Medicine | Year: 2014

IMPORTANCE Use of aspirin (which inhibits platelet function) after a colon cancer diagnosis is associated with improved overall survival. Identifying predictive biomarkers of this effect could individualize therapy and decrease toxic effects. OBJECTIVE To demonstrate that survival benefit associated with low-dose aspirin use after a diagnosis of colorectal cancer might depend on HLA class I antigen expression. DESIGN, SETTING, AND PARTICIPANTS A cohort study with tumor blocks from 999 patients with colon cancer (surgically resected between 2002 and 2008), analyzed for HLA class I antigen and prostaglandin endoperoxide synthase 2 (PTGS2) expression using a tissue microarray. Mutation analysis of PIK3CA was also performed. Data on aspirin use after diagnosis were obtained from a prescription database. Parametric survival models with exponential (Poisson) distribution were used to model the survival. MAIN OUTCOMES AND MEASURES Overall survival. RESULTS The overall survival benefit associated with aspirin use after a diagnosis of colon cancer had an adjusted rate ratio (RR) of 0.53 (95%CI, 0.38-0.74; P < .001) when tumors expressed HLA class I antigen compared with an RR of 1.03 (0.66-1.61; P = .91) when HLA antigen expression was lost. The benefit of aspirin was similar for tumors with strong PTGS2 expression (0.68; 0.48-0.97; P = .03), weak PTGS2 expression (0.59; 0.38-0.97; P = .02), and wild-type PIK3CA tumors (0.55; 0.40-0.75; P < .001). No association was observed with mutated PIK3CA tumors (0.73; 0.33-1.63; P = .44). CONCLUSIONS AND RELEVANCE Contrary to the original hypothesis, aspirin use after colon cancer diagnosis was associated with improved survival if tumors expressed HLA class I antigen. Increased PTGS2 expression or the presence of mutated PIK3CA did not predict benefit from aspirin. HLA class I antigen might serve as a predictive biomarker for adjuvant aspirin therapy in colon cancer. © 2014 American Medical Association. All rights reserved.

Bastiaannet E.,Leiden University | Sampieri K.,Erasmus University Rotterdam | Dekkers O.M.,Leiden University | De Craen A.J.M.,Leiden University | And 9 more authors.
British Journal of Cancer | Year: 2012

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. © 2012 Cancer Research UK All rights reserved.

Houweling L.M.A.,PHARMO Institute for Drug Outcomes Research | Bezemer I.D.,PHARMO Institute for Drug Outcomes Research | Penning-Van Beest F.J.A.,PHARMO Institute for Drug Outcomes Research | Meijer W.M.,PHARMO Institute for Drug Outcomes Research | And 3 more authors.
Journal of Pediatrics | Year: 2013

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. © 2013 Mosby Inc. All rights reserved.

Binkhorst L.,Erasmus Medical Center | Binkhorst L.,Erasmus University Rotterdam | Mathijssen R.H.J.,Erasmus Medical Center | Van Herk-Sukel M.P.P.,PHARMO Institute for Drug Outcomes Research | And 5 more authors.
Breast Cancer Research and Treatment | Year: 2013

Tamoxifen is a largely inactive pro-drug, requiring metabolism into its most important metabolite endoxifen. Since the cytochrome P450 (CYP) 2D6 enzyme is primarily involved in this metabolism, genetic polymorphisms of this enzyme, but also drug-induced CYP2D6 inhibition can result in considerably reduced endoxifen formation and as a consequence may affect the efficacy of tamoxifen treatment. Selective serotonin reuptake inhibitors (SSRIs) and selective serotonin and norepinephrine reuptake inhibitors (SNRIs) have been effectively used for the treatment of depression and hot flashes, both of which occur frequently in tamoxifen-treated women. Due to the drug-drug interaction considerably reduced endoxifen concentrations by inhibition of CYP2D6 will be the result. Evidence of a significant influence of strong CYP2D6-inhibiting drugs on the pharmacokinetics of tamoxifen has resulted in recommendations to avoid potent CYP2D6-inhibiting antidepressants (e.g., paroxetine, fluoxetine) in patients treated with tamoxifen for breast cancer. Nevertheless, dispensing data for tamoxifen and seven regularly used SSRIs/SNRIs in the period between 2005 and 2010, obtained from a large community pharmacy database in the Netherlands (3,000,000 people), show that the potent CYP2D6-inhibiting drug paroxetine remains one of the most frequently used antidepressants in tamoxifen-treated patients. Moreover, trends in the use of SSRIs/SNRIs in the population of all women were similar with trends in women using tamoxifen. Apparently, the recommendations to avoid paroxetine in tamoxifen-treated women have not been implemented into clinical practice. Several reasons may underlie continued use of this drug-drug combination. Contrary to CYP2D6 polymorphisms, drug-induced CYP2D6 inhibition can easily be avoided, since alternative drugs are available. In clinical practice, one should strive to avoid potent CYP2D6 inhibitors as much as possible in tamoxifen-treated patients to reduce the risk of compromising the efficacy of the hormonal therapy. Co-medication should be reviewed by both physicians and pharmacists and potent CYP2D6 inhibitors ought to be switched to weaker alternatives. © 2013 Springer Science+Business Media New York.

Timmers L.,VU University Amsterdam | Beckeringh J.J.,Health Care Insurance Board CVZ | van Herk-Sukel M.P.P.,PHARMO Institute for Drug Outcomes Research | Boven E.,VU University Amsterdam | Hugtenburg J.G.,VU University Amsterdam
Pharmacoepidemiology and Drug Safety | Year: 2012

Purpose: In recent years, the number of oral anticancer agents has increased substantially. Although these agents have quickly been incorporated in the treatment of a variety of malignancies, data on their incidence, prevalence and costs are lacking. The objective of the present study was to obtain insight into the use and the costs of oral anticancer agents (with Anatomical Therapeutic Chemical classification system (World Health Organisation) code L01) in the Netherlands between 2000 and 2008. Methods: Incidence and prevalence were determined using community pharmacy dispensing records obtained from the PHARMO Record Linkage System database. The data of costs were provided by the Genees- en hulpmiddelen Informatie Project of the Dutch Health Care Insurance Board (CVZ, Diemen, The Netherlands). Results: In the years 2000-2008, the use of oral anticancer agents has more than doubled from 64 to 140 users per 100000 inhabitants. The increase is mainly caused by the prescription of capecitabine for various indications. There was a 50-fold rise in costs on oral anticancer agents from €2m in 2000 to approximately €100m in 2008. The share in the costs of tyrosine kinase inhibitors (TKIs) in 2008 was 67% (€70m) with the oldest TKI, imatinib, having a share of more than 50% within the group of TKIs. Conclusions: The increased use of oral anticancer agents is mainly due to the frequent prescription of capecitabine. The increased costs are caused by the registration of a variety of TKIs, in particular imatinib. The costs of new agents with an orphan drug status are very high as compared with those of capecitabine, a newer agent for which there are alternative treatment options. © 2011 John Wiley & Sons, Ltd.

Overbeek J.A.,PHARMO Institute for Drug Outcomes Research | Penning-Van Beest F.J.A.,PHARMO Institute for Drug Outcomes Research | Balp M.-M.,Novartis | Dekhuijzen P.N.R.,Radboud University Nijmegen | Herings R.M.C.,PHARMO Institute for Drug Outcomes Research
COPD: Journal of Chronic Obstructive Pulmonary Disease | Year: 2015

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. © 2015 Informa Healthcare USA, Inc.

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