Search

Edith M Heintjes,1 Irene D Bezemer,1 Daniel Prieto-Alhambra,2,3 Elisabeth Smits,1 Helen P Booth,4 Daniel Dedman,4 Ying He,3 Fabian Hoti,5 Minna Vehkala,5 Stefan de Vogel,6 Noah Jamie Robinson,6 Kwame Appenteng,7 Fernie JA Penning-van Beest1 1PHARMO Institute for Drug Outcomes Research, Utrecht, the Netherlands; 2Idiap Jordi Gol Primary Care Research Institute and CIBERFes, Universitat Autonoma de Barcelona and Instituto de Salud Carlos III, Barcelona, Catalonia, Spain; 3Centre for Statistics in Medicine, NDORMS, University of Oxford, Oxford, England, UK; 4Clinical Practice Research Datalink (CPRD), London, UK; 5Statfinn - EPID Research, Espoo, Finland; 6Astellas Pharma Europe B.V., Leiden, Netherlands; 7Astellas Pharma Global Development, Inc., Northbrook, IL, USACorrespondence: Edith M HeintjesPHARMO Institute for Drug Outcomes Research, Van Deventerlaan 30-40, Utrecht, AE 3528, the NetherlandsTel +31 30 7440 800Email pharmo@pharmo.nlBackground: Mirabegron, indicated for the treatment of overactive bladder, is contraindicated in patients with severe uncontrolled hypertension (systolic blood pressure ≥ 180 mm Hg and/or diastolic blood pressure ≥ 110 mm Hg). In September 2015, a Direct Healthcare Professional Communication (DHPC) letter was disseminated as an additional risk minimisation measure.Purpose: To assess the effectiveness of the DHPC in reducing the proportions of patients with severe or non-severe uncontrolled hypertension at mirabegron initiation.Methods: An observational multi-database cohort study was undertaken using routinely collected healthcare data (December 2012–December 2016) from the PHARMO Database Network (Netherlands), SIDIAP database (Spain), CPRD (United Kingdom, UK) and national healthcare registers and electronic medical records from Finland. DHPC effectiveness was evaluated using interrupted time series analyses comparing trends and changes in monthly proportions of severe or non-severe uncontrolled hypertensive mirabegron initiations relative to the timing of the DHPC dissemination.Results: The study population comprised 52,078 patients. Prior to DHPC dissemination, across the four databases, 0.3– 1.3% had severe uncontrolled hypertension. Estimated absolute changes (EAC) in proportions of severe uncontrolled hypertension post-DHPC indicated a tendency towards a lower proportion in the Netherlands (EAC − 0.36%, p=0.053), unchanged proportions in Spain and the UK and a higher proportion in Finland (EAC +0.73%, p=0.016). For non-severe uncontrolled hypertension (13– 16% pre-DHPC), post-DHPC proportions tended to be lower in the Netherlands (EAC − 2.02%, p=0.038) and Spain (EAC − 1.04%, p=0.071), and unchanged in the UK and Finland.Conclusion: Severe uncontrolled hypertension prior to mirabegron initiation was uncommon in these four European countries even before DHPC dissemination. This suggests that other risk minimisation communications (prior to the DHPC dissemination) had worked adequately with respect to minimising mirabegron use among patients with severe uncontrolled hypertension. No strong and consistent evidence of further risk minimisation after the DHPC dissemination was observed in this study.Keywords: drug utilisation study, direct healthcare professional communication, risk minimization, interrupted time series analysis

Purpose: We examined safety outcomes of interest (SOI) and overall survival (OS) among lung cancer patients initiating crizotinib and erlotinib in routine clinical practice., Methods: This descriptive cohort study used routinely collected health data in Denmark, Finland, Sweden, the Netherlands, and the United States (US) during 2011-2017, following crizotinib commercial availability in each country. Among crizotinib or erlotinib initiators, we reported baseline characteristics and incidence rates and cumulative incidences of the SOI - hepatotoxicity, pneumonitis/interstitial lung disease, QT interval prolongation-related events, bradycardia, vision disorders, renal cysts, edema, leukopenia, neuropathy, photosensitivity, malignant melanoma, gastrointestinal perforation, cardiac failure and OS. Results from the European Union (EU) countries were combined using meta-analysis; results from the US were reported separately., Results: There were 456 patients in the crizotinib cohort and 2957 patients in the erlotinib cohort. Rates of the SOI per 1000 person-years in the crizotinib cohort ranged from 0 to 65 in the EU and from 0 to 374 in the US. Rates of the SOI per 1000 person-years in the erlotinib cohort ranged from 0 to 91 in the EU and from 3 to 394 in the US. In the crizotinib cohort, 2-year OS was ~50% in both EU and US. In the erlotinib cohort, 2-year OS was 21% in the EU and 35% in the US., Conclusions: This study describes clinical outcomes among lung cancer patients initiating crizotinib or erlotinib in routine clinical practice. Differences between SOI rates in EU and US may be partially attributable to differences in the underlying databases., (© 2021 John Wiley & Sons Ltd.)

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

Objectives: To study the effect of risk minimization measures taken in 2013 for cyproterone acetate/ethinylestradiol (CPA/EE) on initiation, concomitant use of other hormonal contraceptives (HC) and potential indications., Study Design: This retrospective study included data on CPA/EE use in 2011-2017 from the Netherlands, UK, and Italy., Results: The initiation rate of CPA/EE decreased by 44%-91% between 2011 and 2017. Proportions with concomitant use of other HC (<3%) and approved indications did not change over time., Conclusion: Apart from a strong reduction in CPA/EE use following risk minimization measures, no major changes were observed regarding concomitant use of other HC or potential reasons for use., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Aim: Recent evidence is emerging indicating long-term effects in infants born after an episode of preterm labour (PTL), even if birth is at term. This population-based study compared long-term rates of outcomes and health-care utilisation (HCU) in children born following spontaneous preterm labour, irrespective of gestational age at delivery or of an uncomplicated pregnancy (SPTLu), with children born following full-term labour (FTL), overall stratified by comorbidity status and assessed using a composite morbidity measure (CM)., Methods: Retrospective data on mother-neonate pairs were collected from a patient-linked dataset from the Netherlands Perinatal Registry and the PHARMO Database Network. Children born between 2000 and 2010 were followed until 2012., Results: Of pregnancies in 134 006 mother-neonate pairs, 122 894 (92%) pregnancies resulted in FTL, and 11 112 (8%) resulted in PTL. Of the PTL pregnancies, 6599 (59%) were SPTLu. Mean follow-up after birth was 6.6-6.7 years. Children from SPTLu pregnancies were at increased risk of neurodevelopmental and respiratory conditions compared with those from FTL pregnancies. In children from SPTLu pregnancies, the presence of the CM was associated with an increased risk of respiratory conditions and failure to thrive. Post-natal hospitalisations (incidence rate (IR) per 100 patient-years: 18.1 vs. 11.7) and specialist referrals (IR per 1000 patient-years: 290.6 vs. 184.5) occurred significantly more frequently in children from SPTLu versus FTL pregnancies., Conclusion: The increased risk of morbidities and HCU in children born following SPTLu pregnancy in this population-based setting reinforces the need for safe interventions that can effectively halt labour and lead to an improvement in childhood outcomes., (© 2018 Paediatrics and Child Health Division (The Royal Australasian College of Physicians).)

Purpose: The aim of this analysis was to identify factors associated with the choice of type 2 diabetes mellitus (T2DM) therapy at the time of intensification of antidiabetic treatment across 4 European countries., Methods: Antidiabetic drug prescription/dispensing records and patients' characteristics were obtained from the electronic health care records of patients with T2DM from the Netherlands (NL), Italy, and Spain (ES) (all, 2007-2011); and the United Kingdom (UK; 2008-2012). Oral monotherapy was defined as first-line; oral dual therapy, as second-line; >2 oral treatments or oral combined with an injectable, as third-line; and injectables only, as fourth-line treatment. Treatment intensification was defined as the start of a higher line of treatment. Comedication, comorbidities, clinical parameters, and other factors associated with treatment choice were identified using multivariate relative risk estimation by Poisson regression with robust error variance., Findings: In the 5-year study period, 485,120 patients (79% of the treated T2DM population) underwent treatment intensification. Changes in treatment choice were clearly visible over the study period, such as a decline in the use of thiazolidinediones (NL, ES, UK) and increases in the use of dipeptidyl peptidase-4 inhibitors (DPP4i) (NL, ES, UK) and glucagon-like peptide-1 receptor agonists (UK). With first-line treatment, advanced age and renal comorbidity were associated with the use of sulfonylureas (SUs; all countries), whereas high body mass index (BMI) was inversely associated with SU use in the United Kingdom and Spain. With second-line treatment, advanced age was associated with metformin + SU use (all countries); and renal comorbidity with SU + DPP4i use in the United Kingdom and the Netherlands. High BMI was associated with metformin + thiazolidinedione (TZD) use in the United Kingdom and Spain, and with metformin + DPP4i in the United Kingdom. With third-line treatment, advanced age and renal comorbidity were associated with the use of SU + insulin (NL, ES, UK). Hemoglobin A 1c >8.5% was positively associated, and high BMI was inversely associated, with the use of any third-line combination containing insulin. Across treatment lines TZD and metformin were negatively associated with renal and cardiac morbidity. Second and third line treatment choices strongly depended on prior treatments. With fourth-line treatment, women were more likely to receive glucagon-like peptide-1 receptor agonists than were men in the United Kingdom and Spain., Implications: The results suggest that the main factors driving treatment choice at any stage of intensification were age, hemoglobin A 1c , BMI, renal and cardiac morbidity, and treatment history. These drivers were consistent with guidelines on, and contraindications of, specific medications. Differences between countries were generally consistent with, but not solely attributable to, differences in local guidelines and reimbursement policies., (Copyright © 2017 Elsevier HS Journals, Inc. All rights reserved.)

Background: This study aimed to evaluate the effect of risk minimization measures on cyproterone acetate/ethinylestradiol (CPA/EE) use in the Netherlands. Potential indications of use and concomitant pharmacy dispensing of other hormonal contraceptives (HC) were assessed among new users in 2011, 2012, and 2014., Methods: In this retrospective drug utilization study, new CPA/EE users were identified by pharmacy dispensings in the PHARMO Database Network in 2011, 2012, and 2014. Recent dispensing of drugs to treat acne and concomitant dispensing of other HC were also assessed. General practitioner records were linked to identify diagnoses of acne, other hyperandrogenic conditions, menstrual problems, or consultations for contraceptive management in the preceding year., Results: The number of new CPA/EE users identified per year was 7876 in 2011 and 7562 in 2012 (3.7 new users per 1000 women in both years) and 1401 in 2014 (0.7 per 1000 women). The proportions of users with acne diagnosis or treatment were 55% in 2011, 52% in 2012, and 47% in 2014. Concomitant use of other HC was observed for 3% of new CPA/EE users in 2011, and 2% in 2012 and 2014 (median duration 78 days). Another 25% were potential concomitant users (median duration 60 days)., Conclusion: This descriptive analysis showed similar proportions of CPA/EE users examined with acne or other hyperandrogenic conditions, or with recent acne treatment, or concomitant dispensing of other HC in the Netherlands before and after the referral procedure. The key observation was a strong overall reduction of CPA/EE use in the Netherlands., (Copyright © 2017 John Wiley & Sons, Ltd.)

Purpose: The aim of this study was to determine the similarities and differences of type 2 diabetes mellitus (T2DM) treatment patterns in daily practice in 5 European countries and whether these reflect differences in guidelines., Methods: Prescriptions for drugs used in diabetes treatment during a 5-year study period were obtained from electronic databases. Patients initiating T2DM treatment during the study period were included. An SAS analysis tool was developed to create episodes of use of drug classes, which resulted in treatment patterns., Findings: A total of 253,530 patients initiating T2DM treatment during the study period were included; 52% to 55% were male, and the mean age ranged from 62 to 67 years. Metformin was the most common initial treatment in all countries. After initial therapy, most patients in the Netherlands, Spain, and the United Kingdom switched to a combination of metformin + a sulfonylurea derivative (SU). In Italy, metformin in combination with an SU was outnumbered by "other treatment," mainly because of repaglinide use. In France, treatments including dipeptidyl peptidase-4 inhibitors were most frequent as second- and fourth-line treatment. Metformin monotherapy was again most commonly observed as the third line of treatment in all countries. Fourth treatment was a combination of metformin + an SU in the Netherlands and Spain; in the United Kingdom and France, dipeptidyl peptidase-4 inhibitors were the most frequently used fourth line of treatment., Implications: This study provides a comprehensive overview of T2DM treatment patterns among patients initiating T2DM treatment in 5 European countries. There were differences, especially regarding the uptake of newer incretin-based treatments, which are usually prescribed as a second and/or third treatment in agreement with local guidelines. These variations reflect the differences between the national guidelines of these countries., (Copyright © 2017 Elsevier HS Journals, Inc. All rights reserved.)

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

Introduction: Antipsychotic drugs (APDs) are used to treat several mental illnesses. Some APDs have long been known to be associated with QT prolongation, potentially leading to torsades de pointes (TdP) and sudden cardiac death (SCD). In 2005, thioridazine was withdrawn because of the risk of SCD, bringing further attention to the arrhythmogenic potential of APDs., Aim: The aim of the current study was to evaluate the use of APDs in five European countries during the years 1996-2010., Methods: A cohort study was conducted using prescription/dispensing data from seven healthcare databases [the AARHUS University Hospital Database (Denmark), the German Pharmacoepidemiological Research Database (GePaRD) (Germany), Health Search Database/Thales (HSD) and Emilia Romagna Regional Database (ERD) (Italy), PHARMO Database Network and Integrated Primary Care Information (IPCI) (the Netherlands) and The Health Improvement Network (THIN) (the UK), covering a population of 27 million individuals. The annual prescription rate of APDs was measured overall and for individual medications. APDs were classified as torsadogenic according to the Arizona-CERT list. All analyses were stratified by age, gender and calendar year., Results: A total of 559 276 person-years (PYs) of exposure to APDs was captured. The crude annual prescription rate of APD use ranged from 3.0/1000 PYs in ERD to 7.7/1000 PYs in AARHUS. Among APDs with established torsadogenic potential, thioridazine was the most frequently used medication in the UK. Haloperidol was commonly prescribed in Italy and the Netherlands. The use of APDs with torsadogenic potential was much higher in elderly patients., Conclusions: Substantial use of APDs with torsadogenic potential has been reported in Europe in recent years, in spite of increasing concerns about their arrhythmogenic potential. This use was even greater in elderly patients, who are at higher risk of SCD., (© 2016 The British Pharmacological Society.)

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

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

Introduction: In a protein C deficient family, we recently identified a candidate gene, CADM1, which interacted with protein C deficiency in increasing the risk of venous thrombosis (VT). This study aimed to determine whether CADM1 variants also interact with protein C pathway abnormalities in increasing VT risk outside this family., Materials and Methods: We genotyped over 300 CADM1 variants in the population-based MEGA case-control study. We compared VT risks between cases with low protein C activity (n=194), low protein S levels (n=23), high factor VIII activity (n=165) or factor V Leiden carriers (n=580), and all 4004 controls. Positive associations were repeated in all 3496 cases and 4004 controls., Results: We found 22 variants which were associated with VT in one of the protein C pathway risk groups. After mutual adjustment, six variants remained associated with VT. The strongest evidence was found for rs220842 and rs11608105. For rs220842, the odds ratio (OR) for VT was 3.2 (95% CI 1.2-9.0) for cases with high factor VIII activity compared with controls. In addition, this variant was associated with an increased risk of VT in the overall study population (OR: 1.5, 95% CI 1.0-2.2). The other variant, rs11608105, was not associated with VT in the overall study population (OR: 1.0, 95% CI 0.8-1.1), but showed a strong effect on VT risk (OR: 21, 95% CI 5.1-88) when combined with low protein C or S levels., Conclusions: In a population-based association study, we confirm a role for CADM1 variants in increasing the risk of VT by interaction with protein C pathway abnormalities., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

In thrombophilic families, protein S deficiency is clearly associated with venous thrombosis. We aimed to determine whether the same holds true in a population-based case-control study (n = 5317). Subjects were regarded protein S deficient when protein S levels were < 2.5th percentile of the controls. Free and total protein S deficiency was not associated with venous thrombosis: free protein S < 53 U/dL, odds ratio [OR] 0.82 (95% confidence interval [CI], 0.56-1.21) and total protein S < 68 U/dL, OR 0.90 (95% CI, 0.62-1.31). When lower cutoff values were applied, it appeared that subjects at risk of venous thrombosis could be identified at levels < 0.10th percentile of free protein S (< 33 U/dL, OR 5.4; 95% CI, 0.61-48.8). In contrast, even extremely low total protein S levels were not associated with venous thrombosis. PROS1 was sequenced in 48 subjects with free protein S level < 1st percentile (< 4 6 U/dL), and copy number variations were investigated in 2718 subjects, including all subjects with protein S (free or total) < 2.5th percentile. Mutations in PROS1 were detected in 5 patients and 5 controls reinforcing the observation that inherited protein S deficiency is rare in the general population. Protein S testing and PROS1 testing should not be considered in unselected patients with venous thrombosis.

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

Results of trials with new oral anticoagulant drugs and vitamin K antagonists (VKA) might not be directly applicable to Dutch clinical practice due to the high level of control of anticoagulation in the Netherlands. In addition, the Dutch method for assessing anticoagulation control uses cross-sectional international normalised ratio (INR) test results while the method used in the trials is based on person-time. To enable comparisons, the two calculation methods were applied to INR data of a cohort of 5422 atrial fibrillation patients treated with VKA. Overall, 74% of test results and 77% of person-time were in the therapeutic range [2.0-3.5]. For the narrower target INR interval [2.5-3.5], 59% of test results and 61% of person-time were in range. It was only between two and six months after the start of treatment that the percentage of person-time in range was lower than the percentage of test results in range. Control of anticoagulation, expressed as a percentage of person-time spent in range, in this Dutch dataset was similar to recent trials with new oral anticoagulants, although it should be noted that the Dutch INR target is higher than the target in these trials. INR control as estimated by the two calculation methods (cross-sectional and longitudinal) was similar.

There are no risk models available yet that accurately predict a person's risk for developing venous thrombosis. Our aim was therefore to explore whether inclusion of established thrombosis-associated single nucleotide polymorphisms (SNPs) in a venous thrombosis risk model improves the risk prediction. We calculated genetic risk scores by counting risk-increasing alleles from 31 venous thrombosis-associated SNPs for subjects of a large case-control study, including 2712 patients and 4634 controls (Multiple Environmental and Genetic Assessment). Genetic risk scores based on all 31 SNPs or on the 5 most strongly associated SNPs performed similarly (areas under receiver-operating characteristic curves [AUCs] of 0.70 and 0.69, respectively). For the 5-SNP risk score, the odds ratios for venous thrombosis ranged from 0.37 (95% confidence interval [CI], 0.25-0.53) for persons with 0 risk alleles to 7.48 (95% CI, 4.49-12.46) for persons with more than or equal to 6 risk alleles. The AUC of a risk model based on known nongenetic risk factors was 0.77 (95% CI, 0.76-0.78). Combining the nongenetic and genetic risk models improved the AUC to 0.82 (95% CI, 0.81-0.83), indicating good diagnostic accuracy. To become clinically useful, subgroups of high-risk persons must be identified in whom genetic profiling will also be cost-effective.

Venous thrombosis (VT) is one of the leading causes of maternal death in the western world, but the genetic causes of pregnancy-related VT are insufficiently understood. The aim of this study was to investigate the association between common genetic variations in candidate genes and pregnancy-related VT. We undertook a hospital based case-control study of women with VT during pregnancy or puerperium; controls were women giving birth without having VT. Single nucleotide polymorphisms (SNPs) were selected in 49 pre-specified candidate genes involved in coagulation, inflammation, and hormonal metabolism in 313 cases and 353 controls. We found new associations between SNPs and total pregnancy-related VT in the genes encoding coagulation factors V and VIII, and p-selectin. Additional new associations between SNPs and antenatal VT were found in the genes encoding the epidermal growth factor receptor, the pregnane X receptor, and protein S. Of 21 SNPs previously associated with thrombotic disease, rs2289252 in F11 and rs3917643 in F3 were associated with pregnancy-related VT, while rs4524 in F5 was associated with antenatal VT., (© 2012 Blackwell Publishing Ltd.)

Background: We evaluated 10 single-nucleotide polymorphisms (SNPs) identified in three European case-control studies as risk factors for venous thrombosis., Objectives: We sought to replicate the positive findings from this report among Whites and to evaluate the association of these SNPs with venous thrombosis for the first time among Blacks., Patient/methods: These SNPs were evaluated in a case-control study of deep vein thrombosis and pulmonary embolism that included 1076 cases and 1239 controls. About 50% of subjects were African Americans. We measured plasma factor (F) XI on a subset of subjects., Results: Among Whites, positive findings for rs13146272 in the CYP4V2 gene, for rs3087505 in the KLKB1 gene and for rs3756008 and rs2036914 in the F11 gene were found. We did not find significant associations for rs2227589 in the SERPINC1 gene and for rs1613662 in the GP6 gene. Among Blacks, rs2036914 in F11 and rs670659 in RGS7 were related to venous thrombosis, but the study had limited statistical power for many SNPs. Among Blacks, plasma FXI was related to two SNPs and the OR relating to the 90th percentile of the control distribution of plasma FXI was 2.6 (95% CI, 1.4, 5.0)., Conclusions: Our study supports the finding that genetic variants in the F11 gene are risk factors for venous thrombosis among both Whites and Blacks, although the findings in Blacks require confirmation. A meta-analysis of five case-control studies indicates that rs2227589 in the SERPINC1 gene, rs13146272 in the CYP4V2 gene and rs1613662 in the GP6 gene are risk factors for venous thrombosis among Whites., (© 2011 International Society on Thrombosis and Haemostasis.)

Background: Recent studies have found associations between deep vein thrombosis (DVT) and single nucleotide polymorphisms (SNPs) in a 4q35.2 locus that contains genes encoding factor XI (F11), a cytochrome P450 family member (CYP4V2), and prekallikrein (KLKB1)., Objective: We investigated which of the common SNPs in this locus are independently associated with DVT., Methods: The study populations were the Leiden Thrombophilia Study (LETS) (443 DVT cases and 453 controls) and the Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis (MEGA study) (2712 DVT cases and 4634 controls). We assessed the association between DVT and 103 SNPs in a 200 kb region using logistic regression., Results: We found that two SNPs (rs2289252 and rs2036914 in F11) were independently associated with DVT. After adjusting for age, sex, and the other SNP, the odds ratios (risk vs. non-risk homozygotes) of these two SNPs were 1.49 for rs2289252 (95% CI, 1.25-1.76) and 1.33 for rs2036914 (95% CI, 1.11-1.59). We found that rs2289252 was also associated with FXI levels, as has been previously reported for rs2036914; these two SNPs remained associated with DVT with somewhat attenuated risk estimates after adjustment for FXI levels., Conclusion: Two SNPs, rs2289252 and rs2036914 in F11, appear to independently contribute to the risk of DVT, a contribution that is explained at least in part by an association with FXI levels.

Protein C (PC) deficiency increases the risk of venous thrombosis (VT) among members of Kindred Vermont II but fails to fully account for the inheritance pattern. A genome scan of the pedigree supported the presence of a prothrombotic gene on chromosome 11q23 (nominal P < .0001), with weaker support on chromosomes 10p12 (P < .0003) and 18p11.2-q11 (P < .0007). Resequencing of 109 genes in the linkage regions identified 5030 variants in a sample of 20 kindred members. Of 16 single nucleotide polymorphisms in 6 genes tested in the larger family set, only single nucleotide polymorphisms in cell adhesion molecule 1 (CADM1) associated with VT. Among the 8 CADM1 single nucleotide polymorphisms genotyped in the complete sample, rs6589488 was most strongly supported (P < .000007), but the association was limited to the PC-deficient subset of the sample (P < .000001). Haplotype analysis narrowed the region containing the causative variant to the coding region of the CADM1 gene. CADM1 gene expression analyzed in blood outgrowth endothelial cells cultured from family members was decreased compared with control subjects, lending phenotypic support to this conclusion. Finally, we have for the first time demonstrated CADM1 in endothelial cells, where it appears to be selectively involved in endothelial cell migration, suggesting a role in endothelial barrier repair.

Background: We recently reported the association between the Malmö sequence variant in F9 (rs6048) and deep vein thrombosis., Design and Methods: We aimed to study whether the association between F9 Malmö and deep vein thrombosis is explained by linkage disequilibrium with nearby single-nucleotide polymorphisms, and whether the association is explained biologically by F9 Malmö affecting factor IX antigen levels or activation of factor IX. We investigated the association of F9 Malmö and 28 nearby single-nucleotide polymorphisms with deep vein thrombosis in men from two case-control studies, LETS (n=380) and MEGA (n=1,469). We assessed the association of F9 Malmö with factor IX antigen level in male control subjects from LETS (n=191) and two subsets of MEGA (n=823 and n=484) and the association with endogenous thrombin potential in LETS control men. We studied the association between F9 Malmö and factor IX activation peptide in 1,199 healthy middle-aged men from the NPHS-II cohort., Results: In the combined LETS and MEGA studies, the odds ratio (95% confidence interval) for the G allele of F9 Malmö, compared with the A allele, was 0.80 (0.69-0.93). One single-nucleotide polymorphism in F9, rs422187, was strongly linked to F9 Malmö (r(2)=0.94) and was similarly associated with deep vein thrombosis. No other single-nucleotide polymorphism or haplotype tested was more strongly associated. Factor IX antigen level, factor IX activation peptide levels and endogenous thrombin potential did not differ between F9 Malmö genotypes., Conclusions: The F9 Malmö sequence variant was the most strongly associated with deep vein thrombosis among common single-nucleotide polymorphisms in the region. However, the biological mechanism by which F9 Malmö affects risk remains unknown.

Background: A positive family history of venous thrombosis may reflect the presence of genetic risk factors. Once a risk factor has been identified, it is not known whether family history is of additional value in predicting an individual's risk. We studied the contribution of family history to the risk of venous thrombosis in relation to known risk factors., Methods: In the Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis, a population-based case-control study, we collected blood samples and information about family history and environmental triggers from 1605 patients with a first venous thrombosis and 2159 control subjects., Results: A total of 505 patients (31.5%) and 373 controls (17.3%) reported having 1 or more first-degree relatives with a history of venous thrombosis. A positive family history increased the risk of venous thrombosis more than 2-fold (odds ratio [95% confidence interval], 2.2 [1.9-2.6]) and up to 4-fold (3.9 [2.7-5.7]) when more than 1 relative was affected. Family history corresponded poorly with known genetic risk factors. Both in those with and without genetic or environmental risk factors, family history remained associated with venous thrombosis. The risk increased with the number of factors identified; for those with a genetic and environmental risk factor and a positive family history, the risk was about 64-fold higher than for those with no known risk factor and a negative family history., Conclusions: Family history is a risk indicator for a first venous thrombosis, regardless of the other risk factors identified. In clinical practice, family history may be more useful for risk assessment than thrombophilia testing.

Objective: Carriers of the factor V Leiden mutation (FVL-carriers) have a substantially increased risk of deep venous thrombosis (DVT), whereas the risk of pulmonary embolism (PE) is only mildly increased compared with noncarriers. So far few studies have investigated possible mechanisms for this so-called FVL paradox., Methods and Results: Consecutive patients with a first DVT or PE were included in a large population-based case-control study (MEGA study). Patients, aged 18 to 70 years, provided a questionnaire, DNA (n=3313), or plasma (n=1474). Surgery, injury, and travel were considered thrombosis-provocative. Of 2063 patients with isolated DVT, 20% were FVL-carrier, as were 8% of the 885 patients with isolated PE. Among DVT patients, FVL-carriers had their thrombi more often proximal and a higher number of affected veins than noncarriers. No differences were observed between FVL-carriers and noncarriers in time between provocation and diagnosis, in vitro coagulation time, and thrombus density. Compared with patients with both DVT and PE, isolated DVT patients more often had thrombi located distally and had a similar number of affected veins. Compared with isolated PE patients, isolated DVT patients had a similar time between provocation and diagnosis, and similar in vitro coagulation time and thrombus density., Conclusions: Although some effects were differential for FVL-carriers and noncarriers, and some were differential for PE and DVT patients, none of the potential mechanisms offered a clear explanation.

Context: The genetic causes of deep vein thrombosis (DVT) are not fully understood., Objective: To identify single-nucleotide polymorphisms (SNPs) associated with DVT., Design, Setting, and Patients: We used 3 case-control studies of first DVT. A total of 19 682 gene-centric SNPs were genotyped in 443 cases and 453 controls from the Leiden Thrombophilia Study (LETS, 1988-1992). Twelve hundred six SNPs associated with DVT were reinvestigated in the Multiple Environmental and Genetic Assessment of Risk Factors for Venous Thrombosis study (MEGA-1, 1999-2004) in a subset of 1398 cases and 1757 controls. Nine SNPs associated with DVT in both LETS and MEGA-1 were investigated a third time in 1314 cases and 2877 controls from MEGA-2, a second subset of MEGA. Additional SNPs close to one SNP in CYP4V2 were genotyped in LETS and MEGA-1., Main Outcome Measure: Odds ratios (ORs) for DVT were estimated by logistic regression. False discovery rates served to investigate the effect of multiple hypothesis testing., Results: Of 9 SNPs genotyped in MEGA-2, 3 were strongly associated with DVT (P < .05; false discovery rate < or =.10): rs13146272 in CYP4V2 (risk allele frequency, 0.64), rs2227589 in SERPINC1 (risk allele frequency, 0.10), and rs1613662 in GP6 (risk allele frequency, 0.84). The OR for DVT per risk allele was 1.24 (95% confidence interval [95%CI], 1.11-1.37) for rs13146272, 1.29 (95% CI, 1.10-1.49) for rs2227589, and 1.15 (95% CI, 1.01-1.30) for rs1613662. In the region of CYP4V2, we identified 4 additional SNPs (in CYP4V2, KLKB1, and F11) that were also associated with both DVT (highest OR per risk allele, 1.39; 95% CI, 1.11-1.74) and coagulation factor XI level (highest increase per risk allele, 8%; 95% CI, 5%-11%)., Conclusions: We identified SNPs in several genes that were associated with DVT. We also found SNPs in the region around the SNP in CYP4V2 (rs13146272) that were associated with both DVT and factor XI levels. These results show that common genetic variation plays an important role in determining thrombotic risk.

Various pathways lead to the development of venous thrombosis. Risk factors are common and can be genetic or acquired. Since the identification of factor V Leiden and prothrombin 20210 G-->A, the field of genetic epidemiology has developed rapidly and many new genetic variants have been described in the past decade. However, the association with venous thrombosis is often unclear and conflicting results have been reported in various studies. The aim of this review is to describe these candidate predictors of venous thrombosis and to put these in perspective.

Objective: Women with a moderate intake of alcohol have higher concentrations of sex steroids in serum, and higher risk of developing breast cancer, compared to non-drinkers. In the present study, we investigate the relationships between alcohol consumption and serum levels of sex steroids and sex-hormone binding globulin (SHBG) in 790 pre- and 1,291 post-menopausal women, who were part of the European Prospective Investigation into Cancer and Nutrition (EPIC)., Methods: Serum levels of testosterone (T), androstenedione (Delta4), dehydroepiandrosterone sulphate (DHEAS), estrone (E1), estradiol (E2) and SHBG were measured by direct immunoassays. Free T (fT) and free E2 (fE2) were calculated according to mass action laws. Current alcohol intake exposure to alcohol was assessed from dietary questionnaires., Results: Pre-menopausal women who consumed more than 25 g/day of alcohol had about 30% higher DHEAS, T and fT, 20% higher Delta4 and about 40% higher E1, concentrations compared to women who were non-consumers. E2, fE2 and SHBG concentrations showed no association with current alcohol intake. In post-menopausal women, DHEAS, fT, T, Delta4, and E1 concentrations were between 10% and 20% higher in women who consumed more than 25 g/day of alcohol compared to non-consumers. E2 or fE2 were not associated with alcohol intake at all. SHBG levels were about 15% lower in alcohol consumers compared to non-consumers., Conclusion: This study supports the hypothesis of an influence of alcohol intake on sex hormone concentrations in blood.