http://repub.eur.nl/res/aut/5103/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png http://repub.eur.nl http://repub.eur.nl/res/pub/40263/ 2013-05-16T00:00:00Z 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. http://repub.eur.nl/res/pub/38999/ 2013-01-01T00:00:00Z The objective of this study was to assess the potential for cost-effectiveness of new technologies for chronic obstructive pulmonary disease (COPD) over the period from 2001 to 2010. Methods Lung function outcomes and drug prices were observed for a UK COPD population over the period from 2001 to 2010. Cost-effectiveness was assessed at regular intervals on the basis of an established cost-effectiveness model, and the maximum price a technology providing cure could achieve under the current cost-effectiveness rules was estimated. Results The results of this study show that although the scope for clinical improvement in COPD was still considerable, during the 10 years studied, the potential for cost-effectiveness at each point in time was dependent on momentary market characteristics, such as the changing price of comparators and improvements in clinical effectiveness. As a result, the analysis demonstrates that the future cost-effectiveness of a technology in development depends on the manner pricing and clinical effectiveness evolve throughout time. Conclusions Because any predictions will be short-lived and dependent on a number of uncertain factors, we conclude that producing accurate forecasts on the potential for cost-effectiveness of new therapies earlier during the development process is especially difficult under the current static cost-effectiveness framework. http://repub.eur.nl/res/pub/37403/ 2012-10-01T00:00:00Z 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. Copyright http://repub.eur.nl/res/pub/34926/ 2012-03-01T00:00:00Z Objective: When comparators' prices decrease due to market competition and loss of exclusivity, the incremental clinical effectiveness required for a new technology to be cost-effective is expected to increase; and/or the minimum price at which it will be funded will tend to decrease. This may be, however, either unattainable physiologically or financially unviable for drug development. The objective of this study is to provide an empirical basis for this discussion by estimating the potential for price decreases to impact on the cost-effectiveness of new therapies in hypertension. Methods: Cost-effectiveness at launch was estimated for all antihypertensive drugs launched between 1998 and 2008 in the United Kingdom using hypothetical degrees of incremental clinical effectiveness within the methodologic framework applied by the UK National Institute for Health and Clinical Excellence. Incremental cost-effectiveness ratios were computed and compared with funding thresholds. In addition, the levels of incremental clinical effectiveness required to achieve specific cost-effectiveness thresholds at given prices were estimated. Results: Significant price decreases were observed for existing drugs. This was shown to markedly affect cost-effectiveness of technologies entering the market. The required incremental clinical effectiveness was in many cases greater than physiologically possible so, as a consequence, a number of products might not be available today if current methods of economic appraisal had been applied. Conclusions: We conclude that the definition of cost-effectiveness thresholds is fundamental in promoting efficient innovation. Our findings demonstrate that comparator price attrition has the potential to put pressure in the pharmaceutical research model and presents a challenge to new therapies being accepted for funding. Copyright http://repub.eur.nl/res/pub/38000/ 2012-03-01T00:00:00Z The aim of present study was to investigate the risk of heart failure associated with dopamine agonist use in patients with Parkinson's disease. The data sources of this study were four different population-based, healthcare databases in United Kingdom, Italy and Netherlands. A case control study nested within a cohort of Parkinson's disease patients who were new users of either dopamine agonist or levodopa was conducted. Incident cases of heart failure were identified and validated, using Framingham criteria. Controls were matched to cases on age, gender and database. To estimate the risk of newly diagnosed heart failure with ergot and non-ergot derived dopamine agonists, as compared to levodopa, odds ratios and 95% confidence intervals were calculated through conditional logistic regression. In the cohort of 25,459 Parkinson's disease patients (11,151 new users of dopamine agonists, 14,308 new users of levodopa), 518 incident heart failure cases were identified during follow-up. Compared to levodopa, no increased risk of heart failure was found for ergot dopamine agonists (odds ratio: 1.03; 95% confidence interval: 0.69-1.55). Among non-ergot dopamine agonists, only pramipexole was associated with an increased risk of heart failure (odds ratio: 1.61; 95%confidence interval: 1.09-2.38), especially in the first three months of therapy (odds ratio: 3.06; 95% confidence interval: 1.74-5.39) and in patients aged 80 years and older (odds ratio: 3.30; 95% confidence interval: 1.62-7.13). The results of this study indicate that ergot dopamine agonist use in Parkinson's disease patients was not associated with an increased risk of newly diagnosed heart failure. Among non-ergot dopamine agonists, we observed a statistically significant association between pramipexole use and heart failure, especially during the first months of therapy and in very old patients. http://repub.eur.nl/res/pub/32893/ 2012-02-01T00:00:00Z 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. http://repub.eur.nl/res/pub/31935/ 2012-01-01T00:00:00Z 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. http://repub.eur.nl/res/pub/32890/ 2012-01-01T00:00:00Z 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. http://repub.eur.nl/res/pub/32900/ 2011-10-13T00:00:00Z 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. http://repub.eur.nl/res/pub/34173/ 2011-09-01T00:00:00Z 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 ≥18years hospitalized for TKR or THR between January 2003 and September 2008 were selected. Patients with pharmacy data up to 3months 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 19days. Median time between surgery and VTE was 24days for TKR and 60days 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. http://repub.eur.nl/res/pub/32945/ 2011-07-01T00:00:00Z 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. http://repub.eur.nl/res/pub/32947/ 2011-04-01T00:00:00Z Limited healthcare budgets result in payers adopting policies at national, regional or local level to achieve allocative efficiency in drug spending. Some of these aim at creating a link between pharmaceutical prices and the value they provide by setting a cost effectiveness (CE) threshold as the maximum acceptable ratio between incremental costs and effects of new drugs. The clinical effectiveness of the comparator used in those CE analyses tends to be greater over time, whilst, due to market competition and loss of exclusivity, their price is expected to be lower. At the same time, research and development (R&D) costs increase with inflation and with efforts to address regulation towards increased safety concerns. As effective patent times decrease, a minimum price constraint raises for the new entrant. These features occur at different rates across disease areas and are expected to result in differently shaped innovation curves. In this scenario, we demonstrate that a general arbitrary threshold may prevent further efficient R&D. Investment may be withdrawn before the optimum innovation point is reached and affordable clinical effectiveness may be lost. We conclude that disease-specific characteristics are an additional consideration in CE decision rules to accommodate the particularities of innovation across disease areas. http://repub.eur.nl/res/pub/32946/ 2011-03-01T00:00:00Z Background: Use of platelet aggregation inhibitors and vitamin K antagonists has been associated with an increased risk of intracranial hemorrhage (ICH). Whether the use of these antithrombotic drugs is associated with an increased risk of subarachnoid hemorrhage (SAH) remains unclear, especially as confounding by indication might play a role. Objective: The aim of the present study was to investigate whether use of platelet aggregation inhibitors or vitamin K antagonists increase the risk of SAH. Methods: We applied population-based case-control, case-crossover and case-time-control designs to estimate the risk of SAH while addressing issues both of confounding by indication and time varying exposure within the PHARMO Record Linkage System database. This system includes drug dispensing records from community pharmacies and hospital discharge records of more than 3million community-dwelling inhabitants in the Netherlands. Patients were considered a case if they were hospitalized for a first SAH (ICD-9-CM code 430) in the period between 1st January 1998 and 31st December 2006. Controls were selected from the source population, matched on age, gender and date of hospitalization. Conditional logistic regression was used to estimate multivariable adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for the risk of SAH during use of platelet aggregation inhibitors or vitamin K antagonists. In the case-crossover and case-time-control designs we selected 11 control periods preceding the index date in successive steps of 1month in the past. Results: In all, 1004 cases of SAH were identified. In the case-control analysis the adjusted OR for the risk of SAH in current use of platelet aggregation inhibitors was 1.32 (95% CI: 1.02-1.70) and in current use of vitamin K antagonists 1.29 (95% CI: 0.89-1.87) compared with no use. In the case-crossover analysis the ORs for the risk of SAH in current use of platelet aggregation inhibitors and vitamin K antagonists were 1.04 (95% CI: 0.56-1.94) and 2.46 (95% CI: 1.04-5.82), respectively. In the case-time-control analysis the OR for platelet aggregation inhibitors was 0.50 (95% CI: 0.26-0.98) and for vitamin K antagonists 1.98 (95% CI: 0.82-4.76). Conclusion: The use of platelet aggregation inhibitors was not associated with an increased SAH risk; the modest increase observed in the case-control analysis could be as a result of confounding. The use of vitamin K antagonists seemed to be associated with an increased risk of SAH. The increase was most pronounced in the case-crossover analysis and therefore cannot be explained by unmeasured confounding. http://repub.eur.nl/res/pub/31756/ 2011-02-01T00:00:00Z Background: Long-acting muscarinic antagonists (LAMA), long-acting β2-agonists (LABA) and fixed dose combinations (FDC) of inhaled corticosteroids (ICS) and LABA are used as inhaled maintenance therapies for COPD. Objective: To estimate persistence rates from dispensing patterns of long-acting inhaled drugs for COPD. Methods: From the PHARMO-database, COPD patients starting LAMA, LABA or LABA-ICS FDC between 2002 and 2006 were selected. Persistence with the initial as well as with any long-acting inhaled drug was determined, defined as time between start and stop of initial/any therapy, allowing ≤60-days gaps between refills. For patients who did not continue to receive dispensings of the initial therapy for at least one year, the first change in therapy was determined. Results: The study included 2201 LAMA, 1201 LABA and 4146 LABA-ICS FDC users. Persistence rates with initial therapy alone at 1, 2, and 3 years were 25%, 14%, 8% for LAMA, 21%, 10%, 6% for LABA and 27%, 14%, 8% for LABA-ICS FDC. Of patients who did not persist with LAMA alone for one year, 15% added and 13% switched therapy (both mostly LABA-ICS FDC). Of patients not persisting with LABA alone, 9% added therapy (mostly LAMA) and 31% switched therapy (mostly to LABA-ICS FDC). In patients not persisting with LABA-ICS FDC, add-on and switch occurred equally frequent (11%, mostly LAMA). Persistence rates with any long-acting drug at 1, 2 and 3 years were 36%, 23% and 17% respectively. Conclusion: Persistence with the initial as well as with any long-acting inhaled drug in COPD is low, with a substantial proportion of patients changing therapy. http://repub.eur.nl/res/pub/34257/ 2011-01-01T00:00:00Z Purpose: In this proof-of-concept paper we describe the framework, process, and preliminary results of combining data from European electronic healthcare record (EHR) databases for large-scale monitoring of drug safety. Methods: Aggregated demographic, clinical, and prescription data from eight databases in four countries (Denmark, Italy, Netherlands, the UK) were pooled using a distributed network approach by generation of common input data followed by local aggregation through custom-built software, Jerboa©. Comparison of incidence rates of upper gastrointestinal bleeding (UGIB) and nonsteroidal anti-inflammatory drug (NSAID) utilization patterns were used to evaluate data harmonization and quality across databases. The known association of NSAIDs and UGIB was employed to demonstrate sensitivity of the system by comparing incidence rate ratios (IRRs) of UGIB during NSAID use to UGIB during all other person-time. Results: The study population for this analysis comprised 19 647 445 individuals corresponding to 59 929 690 person-years of follow-up. 39 967 incident cases of UGIB were identified during the study period. Crude incidence rates varied between 38.8 and 109.5/100 000 person-years, depending on country and type of database, while age-standardized rates ranged from 25.1 to 65.4/100 000 person-years. NSAID use patterns were similar for databases within the same country but heterogeneous among different countries. A statistically significant age- and gender-adjusted association between use of any NSAID and increased risk for UGIB was confirmed in all databases, IRR from 2.0 (95%CI:1.7-2.2) to 4.3 (95%CI: 4.1-4.5). Conclusions: Combining data from EHR databases of different countries to identify drug-adverse event associations is feasible and can set the stage for changing and enlarging the scale for drug safety monitoring. http://repub.eur.nl/res/pub/21070/ 2010-08-01T00:00:00Z Observational studies on long-term endocrine treatment among breast cancer patients have presented discontinuation rates on tamoxifen, but lack information on the continuance of any endocrine treatment [both tamoxifen and aromatase inhibitors (AIs)] within the same cohort. In this study we determined switching rates from tamoxifen to AIs, discontinuation rates of tamoxifen only, discontinuation rates of any endocrine treatment and determinants of first treatment switch and treatment discontinuation. Patients with early stage breast cancer (stage I-IIIa) starting on tamoxifen were selected from the linked Eindhoven Cancer Registry-PHARMO RLS cohort in the period 1998-2006. Continuous use (allowing a 60 days gap between refills) of tamoxifen only and any endocrine treatment were determined after various follow-up periods: 1, 2, 3, 4, and 5 years. Time to first switch from tamoxifen to an AI was assessed. Cox regression was used to identify determinants of first treatment switch, discontinuation of tamoxifen, and discontinuation of any endocrine treatment. A total of 1,451 new early stage breast cancer patients started on tamoxifen. Of those, 380 had a treatment switch to an AI during follow-up. Of the patients followed for 5 years, 40% continuously used tamoxifen, which was 49% for any endocrine treatment. Older age (older than 70 versus 50-69 years) was independently associated with increased discontinuation of tamoxifen and any endocrine therapy. Patients with two or more concomitant diseases (versus no comorbidity) showed an increased likelihood to stop any endocrine treatment or switch treatment from tamoxifen to an AI. In conclusion, up to half of the breast cancer patients starting tamoxifen continued 5 years of endocrine treatment. Identification of patients at risk of discontinuation will assist in the development of interventions to improve treatment continuation comparable to that of patients included in clinical trials. http://repub.eur.nl/res/pub/19709/ 2010-04-01T00:00:00Z Introduction: The objective was to compare glycemic control, insulin utilization, and body weight in patients with type 2 diabetes (T2D) initiated on insulin detemir (IDet) or insulin glargine (IGlar) in a real-life setting in the Netherlands. Methods: Insulin-naïve patients with T2D, starting treatment with IDet or IGlar between January 1, 2004 and June 30, 2008, were selected from the PHARMO data network. Glycemic control (hemoglobin A1c [HbA1c]), target rates (HbA1c <7%), daily insulin dose, and weight gain were analyzed comparing IDet and IGlar for patients with available HbA1c levels both at baseline and at 1-year follow-up. Analysis of all eligible patients (AEP) and a subgroup of patients without treatment changes (WOTC) in the follow-up period were adjusted for patient characteristics, propensity scores, and baseline HbA1c. Results: A total of 127 IDet users and 292 IGlar users were included in the WOTC analyses. The mean HbA1c dropped from 8.4%-8.6% at baseline to 7.4% after 1 year. Patients at HbA1c goal increased from 9% at baseline to 32% for IDet and 11% to 35% for IGlar, which was not significantly different (OR 0.75, 95% CI 0.46, 1.24). Weight gain (n=90) was less among IDet users (+0.4kg) than among IGlar users (+1.1kg), albeit not significant. The AEP analysis (252 IDet + 468 IGlar users) showed similar results with 33%-36% at goal (OR 0.81, 95% CI 0.57, 1.16), and median daily insulin doses of 25 IU/day (P=0.70). Conclusion: There was no significant difference between users of IDet and IGlar with respect to glycemic control and insulin dose in a real-life setting. The low proportion of patients on target at baseline may indicate that insulin therapy is initiated too late. Moreover, the observation that one-third of the patients reached HbA1c target at follow-up may indicate that basal insulin analogs are not titrated intensively enough. http://repub.eur.nl/res/pub/18674/ 2010-03-01T00:00:00Z Objective: Opioid users often experience constipation. In this study the impact of constipation on QoL was assessed in patients using opioids either for non-advanced illness or advanced illness. Methods: Patients using opioids, recruited via public pharmacies, were asked to complete questionnaires on opioid use, constipation and the EuroQol five-dimension questionnaire (EQ-5D). Patients with a severe non-curable disease and relatively short life-expectancy were classified as having an advanced illness; a disabling yet not directly life-threatening condition was defined as non-advanced illness. Constipation was assessed based on questions on opioid side-effects and laxative use. EQ-5D index scores were compared between patients with and without constipation using Wilcoxon two-samples test. Results: Questionnaires were returned by 588 patients with non-advanced illness, of whom 326 (55%) were classified as having constipation and by 113 patients with advanced illness, of whom 76 (67%) were classified as having constipation. The median EQ-5D index, a weighted health state index score with 1 = full health, was lower in patients with constipation than in patients without constipation (0.31 vs. 0.65, p<0.01 for non-advanced illness and 0.41 vs. 0.61, p=0.12 for advanced illness). Conclusion: The results of this study suggest that, in patients using opioids either for non-advanced illness or advanced illness, constipation negatively influences QoL. By separately analysing patients with advanced illness and patients with non-advanced illness, possible selective non-response and confounding was accounted for, but not completely solved. http://repub.eur.nl/res/pub/27995/ 2010-02-01T00:00:00Z Objective: To determine in the Netherlands what proportions of high risk patients with established cardiovascular disease (CVD) or diabetes mellitus type 2 (DM2) who were not treated with statins on 1 January 2007 and which characteristics were associated with non-treatment. Methods: From the IPCI GP database patients were selected who were registered with a GP on 1 January 2007 who had a history of either CVD (CVD patients), DM2 (diabetics) or both (diabetics with CVD). The proportion of patients using statins around 1 January 2007 was determined. Associations of patient characteristics with non-treatment were quantified (CVD patients and diabetics only). Results: In all, 19 628 CVD patients, 5006 diabetics and 3767 diabetics with CVD were identified. Of these patients 71, 54 and 45, respectively did not use statins. These proportions were similar in the subgroups of patients with recent LDL-C measurements. Among these subgroups the vast majority of non-treated patients was eligible for statin treatment (LDL-C >2.5mmol/l). The proportion of statin-treated patients was larger among diabetics than among CVD patients. Among CVD patients, female gender, age below 40 years, living in a deprived area, a history of CVD of less than 1 year and arrhythmia were significantly associated with non-treatment. Among diabetics, significant associations were: living in a deprived area and specialist visits in the previous year. In 2003, treatment rates among diabetics were lower, but among CVD patients they were similar. This suggests that the higher treatment rates among diabetics compared to CVD patients in 2007 may be the result of disease-management programmes introduced for diabetics in 2004. Conclusion: The majority of patients with established CVD or DM2 were not treated with statins on 1 January 2007. Eligibility for statin treatment may have been overestimated due to unavailability of cholesterol levels among many non-treated patients. Implementation of care programmes for CVD patients may increase treatment rates among eligible CVD patients. http://repub.eur.nl/res/pub/28146/ 2010-01-01T00:00:00Z Background: Insight into co-morbidity and treatment effects is pivotal to improve quality of care for cancer patients. Objectives: To determine whether linkage of the Eindhoven Cancer Registry (ECR) and the PHARMO Record Linkage System (RLS) was technically feasible and to assess which patient-centric data would result from this linkage. Methods: The ECR records data on tumour stage and primary treatment of all newly diagnosed cancer patients in the southeastern Netherlands including co-morbidity at diagnosis, whereas the PHARMO RLS includes data from multiple linked observational databases such as data on drug utilisation (for both in- and out-patients, including chemotherapy), hospitalisations and clinical laboratory measurements. All patients who lived or had been living in the overlapping area served by the ECR and the PHARMO RLS during 1998-2006 were selected for linkage which was performed with probabilistic medical record linkage. Results: The linkage resulted in an ECR-PHARMO cohort of 40,004 cancer patients with a total of 42,767 primary tumours. The cancer patients in the linked ECR-PHARMO cohort were representatives for the cancer patients included in the total ECR during 1998-2006. Cancer patients included in the cohorts had a mean history of 5 years and a mean follow-up ranging from 2 to more than 4 years (dependent on the survival rate of the specific cancer type). Conclusions: Linkage of ECR and the PHARMO RLS creates the possibility to study patient-centric drug utilisation, health resources utilisation and their costs, in addition to the effectiveness and safety of pharmaceuticals in routine daily practice in cancer patients. http://repub.eur.nl/res/pub/19616/ 2009-12-01T00:00:00Z Objective To explore the 'real-life' therapy of type 2 diabetes mellitus with oral antidiabetic drugs (OADs). Methods From the PHARMO Record Linkage System comprising linked drug dispensing and clinical laboratory data from approximately 2.5 million individuals in the Netherlands, among others, new users of OADs were identified in the period 1999-2004. New users, aged 30 years and older, without insulin use before cohort entry date and with at least one year follow-up were included. We determined per initial therapy patient characteristics and first therapy change. Results Overall 35,514 patients were included. Metformin and sulfonylureas (SU) were the most frequent initial therapy. Patients on thiazolidinedione (TZD) monotherapy had lower percentages baseline HbA1c ≥ 7% compared to patients on metformin and SU. The proportion of patients still on initial therapy after one year ranged from 46% (TZDs) to around 60% (SU). Among patients starting on monotherapy, add-on (15-20%) and discontinuation (16-25%) of therapy occurred most frequently. In patients starting on combination therapy, a switch occurred in 30% of the patients. Conclusion In more than 40% of the patients a change in initial OAD-therapy is already observed in the first year of therapy. Maintaining patients on initial therapy remains a challenge. http://repub.eur.nl/res/pub/24117/ 2009-11-27T00:00:00Z Purpose: To compare hospitalization rates for serious upper and lower gastrointestinal (GI) events between chronic and acute users of a traditional non-steroidal anti-inflammatory drugs (tNSAID) + proton pump inhibitor (PPI) and users of a COX-2 selective inhibitor (Coxib). Methods: The PHARMO Record Linkage System, including linked drug-dispensing and hospital records of approximately 3 million individuals in the Netherlands was used. We selected new Coxib or tNSAID users (01/01/2000-31/12/2004) with ≥1 year history before the first NSAID dispensing and ≥1 year follow-up ending at thefirst hospitalization for GI event (the outcome), last dispensing, or end of the study period.Chronic users were patients who used any NSAIDs for ≥60 days during the first year (n = 58 770); others were acute users (n = 538 420). Multivariate analysis was performed by Poisson regression adjusted for gender, age, and duration of follow-up, tNSAID and Coxib dose, NSAID/PPI adherence, use of other gastroprotective agents, anticoagulants, acetaminophen, corticosteroids, and cardiovascular disease. Results: The cohort included 23 999 new tNSAIDs + PPI users and 25 977 new Coxib users, with main characteristics: mean ± SD age 58.1 ± 15.5 vs. 56.7 ± 17.5; female 55.3% vs. 62.2%; duration of treatment (days): 137 ± 217 vs. 138 ± 179, respectively. Among acute users, adjusted hazard ratios (95% Confidence Interval) were 0.21 (0.14-0.32) for upper and 0.26 (0.16-0.42) for lower GI events, for Coxib versus tNSAIDs + PPI users. Among chronic users, these were 0.35 (0.22-0.55) for upper GI and 0.43 (0.25-0.75) for lower GI events. Conclusions: Coxib users had significantly lower rates of GI events. Further research should elucidate the possible impact of selection bias. Copyright http://repub.eur.nl/res/pub/24299/ 2009-11-01T00:00:00Z A reduced incidence of nonmelanoma skin cancer among users of angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARb) has been reported. A similar effect is suggested for cutaneous melanoma. We aimed to investigate the possible association between use of ACEi and ARb and the risk of cutaneous melanoma. A general population-based case control study with the PHARMO database, containing drug-dispensing records from community pharmacies and the national pathology database (PALGA) was conducted. Cases were patients with a primary cutaneous melanoma between January 1st 1991 and December 14th 2004, aged ≥18 years and having ≥3 years of follow-up prior to diagnosis. Finally, 1272 cases and 6520 matched controls were included. Multivariable conditional logistic regression showed no statistically significant associations between the incidence of melanoma and the use of ACEi (adjusted OR = 1.0, 95%CI: 0.8-1.3) or ARb (adjusted OR = 1.0, 95%CI: 0.7-1.5). Thus, in this study, the use of ACEi or ARb does not seem to protect against the development of cutaneous melanoma. However, we cannot exclude an association between ACEi and ARb exposure and an increased or decreased incidence of cutaneous melanoma. http://repub.eur.nl/res/pub/24560/ 2009-11-01T00:00:00Z This case-control study investigates the potential chemoprophylactic properties of non-steroidal anti-inflammatory drugs (NSAIDs) on the incidence of cutaneous melanoma (CM). Data were extracted from the Dutch PHARMO pharmacy database and the PALGA pathology database. Cases had a primary CM between 1991 and 2004, were 18 years, and were observed for 3 years in PHARMO before diagnosis. Controls were matched for date of birth, gender, and geographical region. NSAIDs and acetylsalicylic acids (ASAs) were analyzed separately. Adjusted odds ratio (OR) and 95% confidence interval (CI) were calculated using multivariable logistic regression, and the results were stratified across gender. A total of 1,318 CM cases and 6,786 controls were eligible to enter the study. CM incidence was not significantly associated with ever ASA use (adjusted OR: 0.92, 95% CI: 0.76-1.12) or ever non-ASA NSAID use (adjusted OR: 1.10, 95% CI: 0.97-1.24). However, continuous use of low-dose ASAs was associated with a significant reduction of CM risk in women (adjusted OR: 0.54, 95% CI: 0.30-0.99) but not in men (OR: 1.01, 95% CI: 0.69-1.47). A significant trend (P0.04) from no use, non-continuous use to continuous use was observed in women. Continuous use of low-dose ASAs may be associated with a reduced incidence of CM in women, but not in men. http://repub.eur.nl/res/pub/24936/ 2009-11-01T00:00:00Z Objective: To compare incidences of cardiovascular disease (CVD) in general and myocardial infarction (MI) specifically between new users of different statins in daily practice. Design and methodology: Retrospective observational cohort study. Data were obtained from the PHARMO Record Linkage System; the PHARMO database contains pharmacy dispensing records of 3 million patients in the Netherlands registered with community pharmacies, linked to hospitalisation records. The participants were new statin users in the period 2000-2005, excluding patients hospitalised for CVD events in the year prior to start of statin use. Main outcome measures: Adjusted hazard ratios of hospitalisations for CVD (including any type of ischemic heart disease, stroke, or revascularisation procedure) in general, or MI in particular, occurring during use of the initial statin within two years of start of therapy, comparing users of different statins. Results: The mean follow-up duration of 76,147 new statin users (14,530 pravastatin, 27,752 simvastatin, 25,777 atorvastatin, 8088 rosuvastatin) was 55 weeks. Incidence rates of CVD and MI per 100 person years ranged from 0.75 and 0.15 for rosuvastatin to 1.72 and 0.29 for pravastatin. Rosuvastatin users had a lower incidence rate of CVD compared to other statin users in general (28% lower), and simvastatin (29% lower) and pravastatin users (40% lower) in particular. The difference with atorvastatin was not statistically significant. Since this was not a prospective randomised study, there is the potential for unobserved risk factors to be responsible for some of the differences observed. Conclusion: Compared to other statin users without recent prior cardiovascular events, the incidence of fatal and nonfatal CVD in this retrospective observational cohort study was 28% lower among rosuvastatin users. http://repub.eur.nl/res/pub/25427/ 2009-10-26T00:00:00Z Most studies investigating the association between psoriasis and cardiovascular disease have shown a significant relationship. This comparison study investigated the association between psoriasis and prevalent use of cardiovascular drugs. Drug exposure data for 1998 to 2006 were extracted from the Dutch PHARMO-Record Linkage System database. Psoriasis patients were selected using an algorithm of hospitalization and drug dispensing records specific for psoriasis and matched with controls for gender, age and time-period. From the records of 2.5 million Dutch residents, 9,804 (0.4%) psoriasis patients and 15,288 (0.6%) controls were selected. Psoriasis patients used significantly more anti-hypertensives, anti-coagulant and anti-platelet agents, digoxin, nitrates, lipid-lowering and anti-diabetic drugs than the reference population during a 5-year period observation. In a multiple linear regression model adjusting for the number of unique drugs used, psoriasis was no longer significantly associated with any of these drug classes. Psoriasis patients used more cardiovascular-related drugs, but surveillance bias appears to affect this association considerably. http://repub.eur.nl/res/pub/24710/ 2009-10-01T00:00:00Z Recently, we showed there was a cumulative dose-dependent association between the use of estrogens and the incidence of cutaneous melanoma (CM). This association was shown for both oral contraceptives (OC) and hormonal replacement therapy (HRT). Some in-vitrostudies, however, have suggested a direct inhibitory effect on melanoma tumor growth. Therefore, the use of different types of estrogens, OC and HRT, may be associated with a decreased Breslow thickness. Consequently, the clinical impact of our earlier findings may be limited. In this study, we investigated whether estrogen use (0.5 year), OC or HRT, is associated with a decreased Breslow thickness. For this study, we linked the national Dutch pathology database (PALGA) to a pharmacy database (PHARMO). Cases were women with a primary CM between 1 January 1991 and 14 December 2004, aged Z18 years and having Z3 years of follow-up before diagnosis of CM. In total, 687 women with melanoma were included. Univariable linear regression analysis suggested a decreased Breslow thickness with the use of OC and HRT. Statistically significant interaction was observed between age and estrogen use (P < 0.01) suggesting effect modification by age. However, in stratified multivariable analyses for different age groups (< 45, 45-55, ≥ 55 years), no statistically significant associations between the use of OC or HRT and Breslow thickness were observed. In conclusion, an association between use of OC and HRT and Breslow thickness could not be confirmed. Melanoma Res 19:327-332 http://repub.eur.nl/res/pub/24834/ 2009-09-01T00:00:00Z Objective: To estimate the burden of diabetes mellitus (DM) and its complications in The Netherlands. Methods: The PHARMO Record Linkage System comprised among others linked drug dispensing, hospital and clinical laboratory data from approximately 2.5 million individuals in The Netherlands. Patients with DM (type 1 and type 2) were included in the study cohort from 2000 to 2004 if they used antidiabetic drugs or had HbA1c ≥ 6.5 mmol/L or had a hospitalization for DM or a diabetic complication in the measurement year or in the preceding year. Controls, defined as subjects without a diagnosis of DM and/or subjects not prescribed glucose-lowering medication, were 1:1 matched to patients with diabetes, on birth year, zip code, and gender. Complications (hospitalizations and dispensings for cardiovascular disease/eye problems/amputations) were classified into stages. Complications attributed to DM were estimated as complication stages 1 and 2 among patients minus those among controls. Drug costs were extrapolated to The Netherlands by direct standardization. Results: Among the total population in The Netherlands, the prevalence of DM increased from 2.8% in 2000 to 4.0% in 2004. Severe cardiovascular complications attributed to DM increased from 18,000 to 39,000 patients. Per DM patient the cost of direct treatment attributed to DM increased from 974 in 2000 to 1283 in 2004. Per 100 members of the total population, this increase was from 2764 in 2000 to 5140 in 2004. Most of these costs (65% in 2004) were because of hospitalizations. Conclusion: Drug treatment, hospitalizations, and cost attributed to diabetes mellitus have almost doubled between 2000 and 2004, but so did the "background" costs in the general population, perhaps because of preventive efforts. http://repub.eur.nl/res/pub/25293/ 2009-08-01T00:00:00Z BACKGROUND AND PURPOSE-: Vascular endothelium, which can be affected by statins, is believed to play a substantial role in subarachnoid hemorrhage (SAH). Our objective was to estimate the association between use and withdrawal of statins and the risk of SAH. METHODS-: We conducted a population-based case-control study within the PHARMO database. A case was defined as a person hospitalized for SAH (ICD-9-CM code 430) in the period January 1, 1998 to December 31, 2006. Ten randomly chosen controls were matched to each case on age, gender, and calendar date. RESULTS-: During the study period 1004 incident cases of SAH were identified. Current use of statins did not significantly decrease the risk of SAH (OR=0.77, 95% CI 0.55 to 1.07). The odds ratio for recent withdrawal compared to nonusers was 1.62 (95% CI 0.96 to 2.73). Compared to current use, recent withdrawal was associated with an increased risk of SAH (OR=2.34, 95% CI 1.35 to 4.05). Interaction analysis showed that the effect of statin withdrawal was highest in patients who had also recently stopped antihypertensive drugs (OR=6.77, 95% CI 2.10 to 21.8). CONCLUSIONS-: Current use of statins seems to lower the risk of SAH, although the reduction was not significant in new users. Statin withdrawal increased the risk of SAH by a factor 2, even more in patients who had also recently stopped their antihypertensive treatment. http://repub.eur.nl/res/pub/25375/ 2009-08-01T00:00:00Z Context: Few data exist on sex- and age-specific incidence and prevalence of idiopathic hyperprolactinemia and prolactinomas. Objectives: Our objective was to assess incidence and prevalence of dopamine agonist-treated hyperprolactinemia by age and sex. Design: From the PHARMO network, we identified an open cohort of patients who were ever dispensed dopamine agonists for hyperprolactinemia. The network includes complete medication histories for more than 2 million community-dwelling residents. Prolonged use of low-dose dopamine agonist is a reliable marker for hyperprolactinemia, provided that use for Parkinson's disease and lactation withdrawal is excluded. Diagnoses were verified by prolactin values in a random subsample using the same network. Results: We identified 11,314 subjects with at least one dispensing of dopamine agonist in the period 1996-2006, of whom 1607 subjects were considered to have dopamine agonist-treated hyperprolactinemia based on the prescribing pattern. The majority of patients were women (n = 1342, 84%). The diagnosis proved to be incorrect in only 1.5% of a random subsample. The estimated incidence rate of dopamine agonist-treated hyperprolactinemia for women was 8.7/100,000 person-years and for men 1.4/100,000 person-years. The highest incidence rate was found in women 25-34 yr of age: 23.9/100,000 person-years. The mean prevalence of ever treated female patients was almost five times higher (93.9/100,000) compared with male patients (19.6/100,000). Conclusion: The incidence rates and the prevalence of dopamine agonist-treated hyperprolactinemia showed an overall preponderance in women, with a strong peak for women aged 25-34 yr. In men, no peak was found. Copyright http://repub.eur.nl/res/pub/24876/ 2009-05-01T00:00:00Z Objective: To simultaneously assess cardiovascular (CV) and gastrointestinal (GI) risk with traditional non-steroidal anti-inflammatory drugs (tNSAIDs) and cyclo-oxygenase 2 (COX-2) inhibitors. Methods: Using the PHARMO Record Linkage System, including drug-dispensing and hospitalisation data of >2 million residents of The Netherlands, subjects with first hospitalisation for acute myocardial infarction (AMI), CV and GI events were identified. Use of COX-2 inhibitors and traditional non-selective NSAIDs was classified into remote, recent and current. Cases were matched to controls in a 1:4 ratio on age and event date. Multivariate analyses adjusted for gender, history of hospitalisations and medications. Results: Compared to remote use, AMI risk was increased among current users of COX-2 inhibitors combined (adjusted odds ratio (OR) 1.73, 95% CI 1.37 to 2.19) and tNSAIDs combined (OR 1.41, 95% CI 1.23 to 1.61). AMI risk with celecoxib (OR 2.53, 95% CI 1.53 to 4.18), rofecoxib (OR 1.60, 95% CI 1.22 to 2.10), ibuprofen (OR 1.56, 95% CI 1.19 to 2.05) and diclofenac (OR 1.51, 95% CI 1.22 to 1.87) was significantly increased. CV risk with current use of individual COX-2 inhibitors and tNSAIDs was significantly increased (OR from 1.17 to 1.64), as was GI risk with current use of rofecoxib (OR 1.99, 95% CI 1.51 to 2.63), naproxen (OR 4.44, 95% CI 3.36 to 5.86), ibuprofen (OR 1.90, 95% CI 1.40 to 2.58), diclofenac (OR 4.77, 95% CI 3.94 to 5.76), other tNSAIDs (OR 2.59, 95% CI 2.08 to 3.21), but not celecoxib (OR 1.36, 95% CI 0.70 to 2.66). Compared to current use of celecoxib and AMI risk was significantly decreased with current use of naproxen (OR 0.48, 95% CI 0.26 to 0.87) only. GI risk was increased with current naproxen (OR 3.26, 95% CI 1.59 to 6.70) and diclofenac (OR 3.50, 95% CI 1.76 to 6.98). Conclusions: AMI and CV risk increased similarly with individual COX-2 inhibitors and tNSAIDs, whereas GI risk was found to be greater with naproxen and diclofenac. Residual confounding and "channelling" cannot be excluded. http://repub.eur.nl/res/pub/24630/ 2009-02-25T00:00:00Z Background: Multiple studies showed conflicting results on the association between oral contraceptive (OC) use and the development of cutaneous melanoma (CM). We investigated the association between estrogen use and CM incidence. Patients and methods: Data from PHARMO Pharmacy database and PALGA, the pathology database in The Netherlands, were linked. Women, ≥18 years, with a pathology report of a primary CM from 1 January 1991 to 14 December 2004 and ≥3 years of follow-up before CM diagnosis were eligible cases. Controls were matched for age and geographic region. Multivariate logistic regression was used to calculate adjusted odds ratio (OR) and 95% confidence interval (CI) for the association between CM incidence and estrogen use, OCs and hormonal replacement therapy (HRT), separately. Results: In total, 778 cases and 4072 controls were included. CM risk was significantly associated with estrogen use (≥0.5 year; adjusted OR = 1.42, 95% CI 1.19-1.69). This effect was cumulative dose dependent (P trend < 0.001). CM risk was also significantly associated with the use of HRT (≥0.5 year: OR = 2.08; 95% CI 1.37-3.14) and OC (≥0.5 year: OR = 1.28; 95% CI 1.06-1.54). Conclusion: Our study suggests a cumulative dose-dependent increased risk of CM with the use of estrogens. http://repub.eur.nl/res/pub/17943/ 2009-01-01T00:00:00Z Although psoriasis has been associated with components of the metabolic syndrome, its association with myocardial infarction is less clear. A cohort study was conducted using hospital and pharmacy records of 2.5 million Dutch residents between 1997 and 2008. The risk of ischemic heart disease (IHD) hospitalizations was compared between psoriasis patients and a matched reference cohort. Additional adjustments were made for healthcare consumption and use of cardiovascular drugs. A total of 15,820 psoriasis patients and 27,577 reference subjects were included, showing an incidence rate of 611 and 559 IHD per 100,000 person-years, respectively (P=0.066). The age- and gender-adjusted risk of IHD was comparable between both cohorts (hazard ratio (HR)=1.10, 95% confidence interval 0.99-1.23). Before cohort entry, psoriasis patients used more antihypertensive, antidiabetic, and lipid-lowering drugs and were more often hospitalized. Adjusting for these confounders decreased the HR for IHD, but it remained comparable between both populations. There was no different risk of IHD between the subgroup of patients who only used topicals versus those who received systemic therapies or inpatient care for their psoriasis. This study, therefore, suggests that psoriasis is not a clinically relevant risk factor for IHD hospitalizations on the population level.Journal of Investigative Dermatology advance online publication, 8 October 2009; doi:10.1038/jid.2009.321. http://repub.eur.nl/res/pub/25119/ 2009-01-01T00:00:00Z Methods: Data for this retrospective follow-up study were extracted from the PHARMO database. We selected new chronic users of COX-2 inhibitors (coxibs) or traditional NSAIDs (tNSAIDs) between 1st January 2000 and 31st December 2004. GP strategies were defined as: use of proton pump inhibitors (PPI), coxibs or both. GI RF score at index date was based on: history of GI drug use, high dose of NSAIDs, age >60 years, use of corticosteroids/anticoagulants/SSRIs, rheumatoid arthritis, heart failure or diabetes, with each condition accounting for one factor. Switching was assessed among those with ≥ 1 GI RF during the first year of follow-up. Results: Among 58 770 new chronic NSAID users at index date, 80% used tNSAIDs alone, 8% used tNSAID+PPI, 10% used a coxib alone and 2% used coxib+PPI. Mean (SD) number of GI RF among these groups was 1.6 (2.1), 3.1 (1.3), 1.5 (1.5) and 2.8 (1.3), respectively. Among 48 390 patients (82.3%) with a GI RF score of ≥ 1, 20.9% used a GP strategy, this increased with number of GI RFs. Within the first year, 5.3% (n=2067) and 4.8%(n=1 843) of tNSAID users with ≥ 1 GI RF switched to tNSAID+PPI and coxib alone, respectively. Conclusions: Gastroprotection in users of tNSAIDs was inadequate. Over 80% of NSAID users with ≥ 1 GI RF did not receive any gastroprotection, and even when prescribed, a PPI is used only half the time. More research should show if gastroprotection was used for prevention. http://repub.eur.nl/res/pub/29629/ 2008-12-01T00:00:00Z Objectives: To investigate the relationship between duration of compliant bisphosphonate use and the risk of osteoporotic fractures. Methods: The PHARMO database was used to identify new female bisphosphonate users, aged ≥45 years or with diagnosed post-menopausal osteoporosis in the period of January 1996 - June 2004. Within this cohort a matched case-control study was performed. Cases were defined as patients who were hospitalized for an osteoporotic fracture and were matched to ten controls without a fracture by duration of follow-up. The duration of compliant bisphosphonate use (i.e., medication possession ratio ≥80%) preceding the outcome date was determined. Results: Of 14 760 new female bisphosphonate users, 387 fracture patients fulfilled the inclusion criteria. These cases were matched to 3950 controls. Increasing duration of compliant bisphosphonate use was associated with a decreased risk of fracture (trend p < 0.01). Adjusted for several cofactors, 1-2 years of compliant bisphosphonate use and 3-4 years of compliant bisphosphonate use decreased fracture risk by 12% and 46%, respectively, compared to < 1 year of compliant bisphosphonate use (OR 0.88; 95% CI 0.66-1.18 and OR 0.54; 95% CI 0.35-0.84, respectively). Unexpectedly, 5-6 years of compliant bisphosphonate use was no longer associated with a decreased risk of fractures compared to < 1 year of compliant bisphosphonate use (OR 1.12, 95% CI 0.66-1.88). Conclusions: These results show a direct link between duration of compliant bisphosphonate use and fracture risk, and confirm the importance of continuing the use of bisphosphonates to maintain optimal bone protection. However, this link is inconclusive for bisphosphonate use for more than 4 years. http://repub.eur.nl/res/pub/15254/ 2008-09-01T00:00:00Z Background: This study evaluated trends in adjuvant systemic treatment among breast cancer patients and analyzed the factors on which treatment choice was based. Patients and methods: Patients diagnosed with early stage breast cancer in 1990-2006 were selected from the registry of the Comprehensive Cancer Centre South (n = 8261). The probability of receiving therapy was determined per characteristic for the periods 1990-1997, 1998-2001 and 2002-2006, separately. Results: The use of any adjuvant systemic treatment increased from 37% in 1990-1997 to 51% in 1998-2001 and 53% in 2002-2006 (p for trend < 0.0001). In the period 1990-1997, lymph node status (positive vs. negative: probability ratio (PR = 25.8; 95% CI, 16.5-40.4) and age (≥ 60 vs. ≤ 35 years: PR = 0.01; 95% CI, 0.00-0.02) were the main determinants of the likelihood of receiving chemotherapy. From 1998 onwards, age remained the most important factor in decreasing the likelihood of receiving chemotherapy. During 1990-1997 the use of hormonal therapy was mainly determined by positive lymph node status (PR = 35; 95% CI, 25-49) and age (≥ 70 vs. ≤ 35 years: PR = 9.3; 95% CI, 4.4-20), whereas positive hormone receptor status mainly affected hormonal therapy use (PR = 17; 95% CI, 10-28) in the period 2002-2006. Marked differences were observed between hospitals in the adoption of adjuvant systemic treatment for node-negative patients. Conclusions: The impact of patient and tumour characteristics on treatment choice varied over time, reflecting major changes in the Dutch treatment guidelines. Patients older than 70 years received almost no chemotherapy. http://repub.eur.nl/res/pub/29642/ 2008-09-01T00:00:00Z Objectives: The aim of this study was to quantify the effect of non-persistence with oral glucose-lowering drugs (OGLD) on HbA1cgoal attainment (<7%) in daily practice. Methods: From the PHARMO Record Linkage System comprising among others linked drug dispensing and clinical laboratory data from approximately 2.5 million individuals in the Netherlands, new users of OGLD in the period 1999-2004 were identified. Patients with a baseline HbA1c≥7% and at least one HbA1cmeasurement in the period of 6-12 months after treatment onset were included in the study cohort. Persistence with OGLD in the first year of treatment was determined using the method of Catalan. In case the first treatment episode overlapped the first HbA1cmeasurement within 6-12 months after treatment onset, a patient was considered persistent at that measurement. Patients with a HbA1c<7% were defined as having attained goal. Results: The study cohort included 2023 patients with a mean baseline HbA1cof 8.9 ± 1.8%. Three-quarters (1512 patients) were persistent with any OGLD at the first HbA1cmeasurement within 6-12 months after treatment onset; of these, 861 (57%) were at goal. Of the 511 non-persistent patients, 239 (47%) were at goal. Non-persistent patients were about 20% less likely to attain goal (RRadj 0.82; 95%Cl 0.74-0.91), compared to persistent OGLD users. Conclusion: Non-persistent use of OGLD leads to a 20% decreased probability of HbA1cgoal attainment in daily practice. This effect of non-persistence seems modest, but represents around 12 000 new and 10 000 prevalent OGLD users a year in the Netherlands in whom OGLD use could be better controlled. http://repub.eur.nl/res/pub/29641/ 2008-08-01T00:00:00Z Objective: The effectiveness of statin therapy in a real life setting may differ from that in clinical trials, as physicians make non-randomised treatment decisions for patients with less uniform and possibly different characteristics. We therefore performed a study to compare the effectiveness of different statins and doses in routine clinical practice with respect to total serum cholesterol and LDL-cholesterol (LDL-C) reduction and goal attainment according to European guidelines on the prevention of cardiovascular disease (CVD). Research design and methods. Naive statin users starting treatment in 2003 and 2004 with LDL-C measurements at baseline and between 30 and 365 days after start of treatment were extracted from the PHARMO database. During treatment with their initial statin dose LDL-C reduction and attainment of cholesterol goals were compared between different statins and doses. Results: Of 2303 identified naive patients, approximately 30% were allocated to the high CVD-risk group. Average LDL-C reductions were 48%, 42%, 39%, and 32% at mean doses of 11 mg rosuvastatin, 17 mg atorvastatin, 22 mg simvastatin and 35 mg pravastatin, respectively. The proportion of patients attaining cholesterol goals was 75% for rosuvastatin, 68% for atorvastatin, 56% for simvastatin, and 42% for pravastatin. Dose comparisons showed greater LDL-C reduction and increased goal attainment for rosuvastatin 10 mg compared to other statins at most doses (adjusted p < 0.05). Conclusions. In a real life setting, both LDL-C reduction and the proportion of patients attaining cholesterol goals appear to be significantly increased among users of rosuvastatin compared to other statins. These results confirm and extend reported clinical trial results to a real world setting. http://repub.eur.nl/res/pub/29404/ 2008-07-01T00:00:00Z OBJECTIVE - Women with diabetes have a high incidence and complication rate of urinary tract infections (UTIs). Our aims were to compare current treatment strategies with respect to recurrence rates in women with diabetes with those without diabetes. RESEARCH DESIGN AND METHODS - We used a Dutch registration database containing pharmacy dispensing data. A total of 10,366 women with diabetes (17.5% premenopausal) (aged ≤55 years) and 200,258 women without diabetes (68% premenopausal) who received a first course of trimethoprim, nitrofurantoin, fosfomycin, or norfloxacin between January 1999 and January 2006 were included. We compared short (≤5 days) with long (>5 days) prescriptions and norfloxacin with trimethoprim, nitrofurantoin, and fosfomycin. A recurrence was defined as a second prescription for one of the above-mentioned agents or a first with amoxicillin (clavulanic acid), fluoroquinolones, or trimethoprim/sulfamethoxazole between 6 and 30 days after inclusion. RESULTS - Premenopausal women with diabetes more often received a long (26.5 vs. 19.2%; P < 0.001) treatment with norfloxacin (10.7 vs. 6.2%; P < 0.001) but still had a higher recurrence rate (16.1 vs. 12.2%; P = 0.003) compared with those without diabetes. Similarly, postmenopausal women with diabetes more often received a longer (32.8 vs. 28.8%; P < 0.001) treatment with norfloxacin (15.2 vs. 12.7%; P < 0.001) but had a higher recurrence rate (19.1 vs. 16.4%; P < 0.001) compared with those without diabetes. CONCLUSIONS - Despite the fact that patients with diabetes more often received longer and more potent initial treatment than patients without diabetes, pre- and postmenopausal women with diabetes more often had recurrences of their UTIs. http://repub.eur.nl/res/pub/29684/ 2008-05-01T00:00:00Z Objective: To identify determinants of non-compliance with bisphosphonates in women with postmenopausal osteoporosis. By considering the year of the introduction of weekly bisphosphonates important additional information is obtained. Methods: New female users of daily or weekly alendronate or risedronate between 1999 and 2004, aged ≥ 45 years were identified from PHARMO RLS, including drug-dispensing and hospitalisation data of > 2 million residents of the Netherlands. One-year compliance with bisphosphonates was measured using the Medication Possession Ratio (MPR). To identify determinants of non-compliance, non-compliant women (MPR < 50%) were compared to compliant women (MPR ≥ 80%). The effect of patient age, prescriber, initial dosing regimen, gastrointestinal adverse events, co-medication and fractures on non-compliance was investigated. Results: The study cohort included 8822 new users of bisphosphonates, of whom 5079 (58%) were compliant and 2720 (31%) were non-compliant after 1 year. Only 1023 women (11%) had a MPR between ≥ 50% and < 80%. Daily dosing at start, increased number of co-medications and new use of intestinal agents in the year after starting bisphosphonates were independently associated with an increased odds of non-compliance. In contrast, higher age, first prescription from a specialist, osteoporosis related hospitalisation and use of NSAIDs in the year preceding bisphosphonate therapy decreased the odds of non-compliance. Conclusion: This study revealed several determinants of non-compliance with bisphosphonates, the best controllable being the type of initial bisphosphonate, with daily dosing leading to more non-compliance than weekly dosing. However, compliance for both regimens is suboptimal, pointing to an unmet medical need. http://repub.eur.nl/res/pub/29604/ 2008-04-01T00:00:00Z Objective: Discontinuation rates with antihypertensive drugs in real life are high. The present study investigates the relationship between persistence with antihypertensive drugs (AHT) and blood pressure (BP) goal attainment in daily clinical practice. Methods: In the PHARMO Record Linkage System, which includes drug dispensing and hospital records for >2 million inhabitants in the Netherlands, new users of AHT ≥ 18 years were identified for the period 1999-2004. Patients with elevated blood pressure (systolic BP ≥ 140 and/or diastolic BP ≥ 90 mmHg) within 6 months prior to onset of AHT treatment and a BP measurement within 6-12 months of treatment onset were included in the study cohort. Persistent AHT use was determined by summing the number of days of continuous treatment (gap between dispensings < 30 days) from start of treatment onwards. Patients with a BP below 140/90 mmHg at the first BP measurement within 6-12 months of treatment onset were defined as having attained goal. Results. The study included 1271 patients with a mean systolic BP of 174 ± 22 mmHg and a mean diastolic BP of 100 ± 12 mmHg. Persistent AHT use was associated with a 40% increased chance of BP goal attainment (RRadj= 1.41; 95% CI: 1.08-1.85) after adjustment for gender, age, systolic blood pressure at start, and time to the BP measurement. Conclusion: Persistent use of AHT leads to increased blood pressure goal attainment in daily clinical practice. http://repub.eur.nl/res/pub/29664/ 2008-04-01T00:00:00Z Objective: Asthma is a major public health problem with considerable economic impact. The highest costs being observed in patients with severe asthma. Furthermore, despite the use of recommended therapies, asthma control can still be poor. Therefore, the objective of this study was to assess the extent of uncontrolled disease and associated medical costs in severe asthma. Methods: The PHARMO Record Linkage System includes among others drug dispensing and hospitalizations for ≥ 2 million subjects in The Netherlands. Severe asthma patients used long-acting beta-agonists and inhaled corticosteroids for over 200 days and short-acting beta-agonists for at least 100 days in 2004. Severe uncontrolled asthma was defined as a hospitalization for asthma or use of multiple short courses of oral corticosteroids assessed in 2004. Reimbursed costs of asthma drugs and hospitalizations were calculated during this year. A matched nested-case control study was performed to identify treatment-related risk factors for uncontrolled disease. Information on clinical diagnosis of (severity of) asthma was not available. Results: About 17% of patients with severe asthma aged 12-49 years (N = 1158) showed lack of control. Excess drug costs for severe uncontrolled asthma with hospitalization mounted up to 700 Euro per patient per year and 300 Euro per patient per year for patients without hospitalization. Including hospital admission costs, excess costs mounted up to over 10 000 Euro per patient per year. Lack of control did not seem to be caused by under-treatment. Conclusion: Poor control of severe asthma leads to disproportionately increased direct costs compared to severe controlled asthma, especially when hospital admission is required. http://repub.eur.nl/res/pub/29894/ 2008-04-01T00:00:00Z Among 8,822 new female bisphosphonate users, non-compliant bisphosphonate use was associated with a 45% increased risk of osteoporotic fracture compared to compliant use (MPR ≥80%). Classifying compliance into five categories, fracture risk gradually increased with poorer compliance. These results emphasize the importance of treatment compliance in obtaining maximal treatment benefit. Introduction: Bisphosphonates are widely used to treat osteoporosis and reduce fracture risk. Low compliance is frequent and will limit treatment benefit. Methods: New female users of alendronate or risedronate between 1999-2004, aged ≥45 years were identified from PHARMO-RLS, including drug-dispensing and hospitalization data of ≥2 million residents of the Netherlands. Patients were followed until first hospitalisation for an osteoporotic fracture, death, or end of study period. Compliance with bisphosphonates during follow-up was measured over 90-day intervals using Medication Possession Ratio (MPR). The association between compliance and fracture risk was analyzed using time-dependent Cox-regression. Results: The study cohort included 8,822 new female bisphosphonate users, contributing in total 22,484 person-years of follow-up. During follow-up, 176 osteoporotic fractures occurred (excluding the first six months). Non-compliant bisphosphonate use was associated with a 45% increased fracture risk compared to compliant use (MPR ≥80%). Classifying compliance into five categories, fracture risk gradually increased with poorer compliance (p-value <0.05 for trend). A MPR <20% was associated with an 80% increased fracture risk compared to a MPR ≥90%. Conclusions: These results show a statistically significant association between level of compliance with bisphosphonates and level of fracture risk, emphasizing the importance of treatment compliance in obtaining maximal treatment benefit. http://repub.eur.nl/res/pub/30195/ 2008-04-01T00:00:00Z Purpose: To study persistence with inhaled corticosteroids (ICS) and its determinants in asthma-patients. Methods: From the PHARMO database, asthma-patients (age<35 years) with a first dispensing for ICS in 1999-2002 and≥2 dispensings in the first year were included. Persistence during the first year was defined as the number of days from start to time of first failure to continue renewal of the initial ICS. Potential determinants of persistence were assessed at ICS-start and 1 year before. Results: The study-cohort included 5563 new users of single ICS and 297 of fixed-combined ICS. Less than 10% of patients using single ICS and 15% of patients using fixed-combined ICS were persistent at 1 year. Similar persistence-rates were observed when stratified for age (children/adolescents: 0-18 years and adults: 19-34 years). Increased persistence with single ICS was observed with the type of ICS (budesonide), prescriber (specialist), prior use of long-acting beta-agonists, previous hospitalization for asthma, metered-dose inhaler, low starting-dose and once-daily dosing regimen at start. Persistence with fixed combined ICS-treatment increased with younger age and was decreased in patients having high starting-dose of ICS and prior use of antibiotics. Conclusion: New users of both single and fixed combined ICS have alarming low persistence rates with ICS-treatment in the first year of follow-up. Persistence was mainly related to patient factors, such as severity of disease, and to treatment-related factors, such as once-daily dosing frequency. Copyright http://repub.eur.nl/res/pub/30085/ 2008-02-01T00:00:00Z Purpose: To assess the incidence of cardiovascular events among breast cancer patients after chemotherapy. Methods: Women ≥18 years with a breast tumour who received chemotherapy in 1992-2003 were selected from the PHARMO RLS. Chemotherapy with anthracyclines, a combination of anthracyclines and taxanes or second line treatment with trastuzumab was classified as cardiotoxic. Cardiovascular events were determined based on drug use and hospital admissions. Incidence rates of cardiovascular events and hazard ratios (HR) for the cardiotoxic versus non-cardiotoxic chemotherapy group were assessed during the first year and total follow-up. Results: Of 648 patients with breast cancer included in the study cohort, 353 (54%) received cardiotoxic chemotherapy. At baseline, patients who received cardiotoxic chemotherapy compared with patients receiving non-cardiotoxic chemotherapy, received less anticoagulants/ baemostatics (5 vs. 11%; p = 0.012) and had been less often hospitalised for cardiovascular disease (1 vs. 5%;p = 0.007)2 years before the cohort entry date. After 1-year follow-up, the incidence rate of cardiovascular events was 69/1000 person years (py) for patients with cardiotoxic chemotherapy and 98/1000py for patients with non-cardiotoxic chemotherapy, which did not differ significantly (HR 0.74 95% confidence interval (CI): 0.39, 1.41). After total follow-up, this was 81/1000py for patients with cardiotoxic and 92/1000 py for patients with non-cardiotoxic chemotherapy (HR 0.81, 95%CI: 0.54, 1.20). Conclusions: This study showed similar cardiovascular incidence rates during follow-up for breast cancer patients treated with cardiotoxic and non-cardiotoxic chemotherapy. Specialists seemed to take pre-existing cardiovascular diseases into account when treating the breast cancer patient. Copyright http://repub.eur.nl/res/pub/30135/ 2008-01-01T00:00:00Z Purpose: To compare treatment changes after the rofecoxib withdrawal with changes occurring normally and to re-assess 12 months afterwards. Methods: The PHARMO database comprised medication and hospital discharge records of over 3 million inhabitants in the Netherlands. The Study cohort included chronic coxib users with a coxib prescription on 30th September 2004; the Reference cohort others with a coxib prescription on 1st June 2004. Initial treatment changes were based on first new prescription since cohort entry. Twelve-month changes were studied within the Study cohort only. Results: The Study cohort (n = 6974) and Reference cohort (n = 5393) had similar demographics, stratified on type of coxib. In the Study cohort, 3341 (48%) initially stopped coxibs, of whom 1121 (16%) stopped all analgesic, versus 13 and 5% in the Reference cohort (p < 0.001). Among 'other coxib' users 32% stopped coxibs, and 15% stopped all analgesics, versus 14% and 4%, p < 0.001 in the Reference cohort. Among those who stopped coxibs, 34% switched to non-selective non-steroidal anti-inflammatory drug (nsNSAID) without PPI, 21% to nsNSAID with PPI, and 45% stopped NSAID treatment (Reference cohort: 35, 20, and 44%, respectively). These rates for 'other coxib users' were: switching to nsNSAID without PPI 23% (Study Cohort) versus 35% (Reference Cohort), 13 versus 28%, and 64 versus 37% respectively (p < 0.001). Twelve months later, stopping NSAID increased to 43%, stopping all analgesics to 32%. Rheumatologists continued coxibs more frequently than other caregivers (87, 65, 54%, respectively). Conclusions: The rofecoxib withdrawal resulted in a large proportion of patients who discontinued analgesic treatment altogether regardless of original coxib therapy. Copyright http://repub.eur.nl/res/pub/36350/ 2007-12-01T00:00:00Z In The Netherlands, since September 2003, a legal medicinal cannabis product, constituting the whole range of cannabinoids, is available for clinical research, drug development strategies, and on prescription for patients. To date, this policy, initiated by the Dutch Government, has not yet led to the desired outcome; the amount of initiated clinical research is less than expected and only a minority of patients resorts to the legal product. This review aims to discuss the background for the introduction of legal medicinal cannabis in The Netherlands, the past years of Dutch clinical experience in oncology practice, possible reasons underlying the current outcome, and future perspectives. http://repub.eur.nl/res/pub/36377/ 2007-11-01T00:00:00Z Background: Statins show anticancer activity in melanoma cells. We investigated the association between statins and incidence and Breslow thickness of cutaneous melanoma (CM). Methods: Data were used from PHARMO, a pharmacy database, and PALGA, a pathological database, in the Netherlands. Cases had a primary CM diagnosis between January 1st 1991 and December 14th 2004, were ≥18 years and had ≥3 years of follow up in PHARMO before CM diagnosis. Controls were matched for gender, date of birth and geographic region. Analyses were adjusted for age, gender, year of diagnosis, number of medical diagnoses and the use of NSAIDs and oestrogens. Findings: Finally, 1318 cases and 6786 controls were selected. CM risk was not associated with statin use (≥0.5 years) (adjusted odds ratio (OR) = 0.98, 95% confidence interval (CI) = 0.78-1.2). However, statin use was associated with a reduced Breslow thickness (-19%, 95% CI = -33, -2.3, p = 0.03). Conclusion: Our study suggests protective effects of statins on melanoma progression. http://repub.eur.nl/res/pub/10223/ 2003-01-01T00:00:00Z BACKGROUND: Since most hip fractures are related to osteoporosis, treating accelerated bone loss can be an important strategy to prevent hip fractures. Thiazides have been associated with reduced age-related bone loss by decreasing urinary calcium excretion. OBJECTIVE: To examine the association between dose and duration of thiazide diuretic use and the risk for hip fracture and to study the consequences of discontinuing use. DESIGN: Prospective population-based cohort study. SETTING: The Rotterdam Study. PARTICIPANTS: 7891 individuals 55 years of age and older. MEASUREMENTS: Hip fractures were reported by the general practitioners and verified by trained research assistants. Details of all dispensed drugs were available on a day-to-day basis. Exposure to thiazides was divided into 7 mutually exclusive categories: never use, current use for 1 to 42 days, current use for 43 to 365 days, current use for more than 365 days, discontinuation of use since 1 to 60 days, discontinuation of use since 61 to 120 days, and discontinuation of use since more than 120 days. RESULTS: 281 hip fractures occurred. Relative to nonuse, current use of thiazides for more than 365 days was statistically significantly associated with a lower risk for hip fracture (hazard ratio, 0.46 [95% CI, 0.21 to 0.96]). There was no clear dose dependency. This lower risk disappeared approximately 4 months after thiazide use was discontinued. CONCLUSIONS: Thiazide diuretics protect against hip fracture, but this protective effect disappears within 4 months after use is discontinued. http://repub.eur.nl/res/pub/8261/ 2002-01-01T00:00:00Z