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Fernanda A Orsi,1,2 Willem M Lijfering,2,3 Arnoud Van der Laarse,4,5 L Renee Ruhaak,4 Frits R Rosendaal,2 Suzanne C Cannegieter,2–3,6 Christa Cobbaert41Department of Clinical Pathology, School of Medical Sciences, University of Campinas (UNICAMP), Campinas, Brazil; 2Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands; 3Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands; 4Department of Clinical Chemistry and Laboratory Medicine, Leiden University Medical Center, Leiden, The Netherlands; 5Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands; 6Department of Internal Medicine, Section of Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, The NetherlandsPurpose: Apolipoproteins C-I, C-II, C-III and E have been associated with risk of arterial thrombotic diseases. We investigated whether these apolipoproteins have prothrombotic properties and are associated with risk of venous thromboembolism (VTE).Patients and methods: A total of 127 VTE patients and 299 controls were randomly selected from the Multiple Environmental and Genetic Assessment of Risk Factors for Venous Thrombosis study (1999–2004), in the Netherlands. The apolipoproteins were quantified using mass spectrometry (LC/MS/MS), and their levels were analyzed as continuous variable (per SD increase).Results: In controls, increases in levels of apolipoproteins were associated with increases in levels of vitamin K-dependent factors, factor XI, antithrombin and clot lysis time. Additionally, increasing apolipoproteins C-III and E levels were associated with higher factor VIII and von Willebrand factor levels. Levels of C-reactive protein were not associated with any apolipoprotein. The age- and sex-adjusted odds ratios of apolipoproteins E, C-III, CII and CI to the risk of venous thrombosis were 1.21 (95% CI, 0.98–1.49), 1.19 (95% CI, 0.99–1.44), 1.24 (95% CI, 0.95–1.61) and 1.06 (95% CI, 0.87–1.30) per SD increase, respectively. These odds ratios did not attenuate after adjustments for statin use, estrogen use, BMI, alcohol use, and self-reported diabetes.Conclusions: Levels of apolipoproteins C-I, C-II, C-III and E are associated with those of several coagulation factors. However, whether these apolipoproteins are also associated with an increased risk of VTE remains to be established.Keywords: thrombosis, proteomics, lipids, cholesterol, coagulation, risk factors

Objective: The aim of this time-trend analysis is to estimate long-term excess mortality and associated cardiovascular risk for abdominal aortic aneurysm (AAA) patients after elective repair while addressing the changes in AAA management and patient selection over time., Background: Despite the intensification of endovascular aneurysm repair and cardiovascular risk management, Swedish population data suggest that AAA patients retain a persistently high long-term mortality after elective repair. The question is whether this reflects suboptimal treatment, a changing patient population over time, or a national phenomenon., Methods: Nationwide time-trend analysis including 40,730 patients (87% men) following elective AAA repair between 1995 and 2017. Three timeframes were compared, each reflecting changes in the use of endovascular aneurysm repair and intensification of cardiovascular risk management. Relative survival analyses were used to estimate disease-specific excess mortality. Competing risk of death analysis evaluated the risk of cardiovascular versus noncardiovascular death. Sensitivity analysis evaluated the impact of changes in patient selection over time., Results: Short-term excess mortality significantly improved over time. Long-term excess mortality remained high with a doubled mortality risk for women (relative excess risk=1.87, 95% CI: 1.73-2.02). Excess mortality did not differ between age categories. The risk of cardiovascular versus noncardiovascular death remained similar over time, with a higher risk of cardiovascular death for women. Changes in patient population (ie, older and more comorbid patients in the latter period) marginally impacted excess mortality (2%)., Conclusions: Despite changes in AAA care, patients retain a high long-term excess mortality after elective repair with a persistent high cardiovascular mortality risk. In this, a clear sex - but no age - disparity stands out., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Colorectal cancer (CRC) is the third most prevalent cancer type. CRC-patients are at increased risk of venous and arterial thromboembolism (TE), but the magnitude of the risks, their predictors and consequences are not exactly known., Objectives: We aimed to determine incidence, predictors and prognosis of TE after incident CRC in a large, unselected population., Methods: Using data from Statistics Netherlands and the Netherlands Comprehensive Cancer Organization, all incident CRC-patients were identified between 2013 and 2018 plus a sample of 1:2 age- and sex-matched control subjects. Incidence rates and cumulative incidences for TE were estimated. Predictor variables for TE were explored by univariable Cox regression. The association between TE and all-cause mortality was evaluated by multivariable time-dependent Cox regression., Results: 68,238 incident CRC-patients were matched to 136,476 controls. CRC-patients had a 1-year cumulative venous TE (VTE) incidence of 1.93 % (95%CI 1.83-2.04), versus 0.24 % (95%CI 0.21-0.27) in controls (HR 8.85; 95%CI 7.83-9.99). For arterial TE (ATE), this was 2.74 % (95%CI 2.62-2.87) in CRC versus 1.88 % (95%CI 1.81-1.95) in controls (HR 1.57; 95%CI 1.47-1.66). Cancer stage, surgery, chemotherapy and asthma were predictors for VTE, whereas age, prior ATE and Parkinson's disease were predictors for ATE. CRC patients with TE had an increased risk of all-cause mortality (VTE HR; 3.68 (95%CI 3.30-4.10, ATE HR; 3.05 (95%CI 2.75-3.39)) compared with CRC-patients without TE., Conclusions: This Dutch nationwide cohort study adds detailed knowledge on the risk of VTE and ATE, their predictors and prognosis in CRC-patients. These findings may drive TE prophylactic management decisions., Competing Interests: Declaration of competing interest Q. Chen is supported by the Chinese Government Scholarship (No. 201906380148) for his PhD at the Leiden University Medical Center. Prof. Dr. Klok has received research support from Bayer, Bristol-Myers Squibb, Actelion, Boston Scientific, Leo Pharma, The Netherlands Organization for Health Research and Development, The Dutch Thrombosis Association, The Dutch Heart Foundation and the Horizon Europe program, all outside this work and paid to his institution., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Elevated levels of coagulation factors (F) II (FII), FV, FVII, FIX, FX, and FXI have often been related with coronary heart disease, ischemic stroke, and venous thrombosis (VT). However, there are few studies on their associations with all-cause mortality., Objective: We explored whether elevated levels of FII, FV, FVII, FIX, FX, and FXI are associated with an increased risk of death in patients who had VT and in individuals from the general population., Methods: We followed 1919 patients with previous VT and 2800 age- and sex-matched community controls in whom coagulation factor levels were measured. A high coagulation factor was defined as the >90th percentile of normal in the controls. Cox regression analyses were adjusted for age and sex and for being a patient with VT or being a control subject., Results: The median age at time of enrolment was 48 years for both patients and controls, and slightly more women than men were followed. Over a median follow-up of 6.1 years for patients and 5.0 years for controls, there were 79 and 60 deaths in patient and controls respectively. There was no association of FII, FV, FVII, FIX, FX, and FXI with all-cause mortality in patients or in control individuals., Conclusions: Elevated levels of FII, FV, FVII, FIX, FX, and FXI levels may not be associated with an increased risk of all-cause mortality. Only for cardiac death, an association with high FX and FXI was found, which confirms the findings of previous studies, but numbers were small., (© 2023 The Author(s).)

Importance: The temporal trend in adverse events regarding stroke prevention for nonvalvular atrial fibrillation (NVAF) in the direct oral anticoagulant (DOAC) era was rarely investigated comprehensively, especially taking into account potential changes in patient characteristics and anticoagulation treatment., Objective: To investigate time trends in patient characteristics, anticoagulation treatment, and prognosis of patients with incident NVAF in the Netherlands., Design, Setting, and Participants: This retrospective cohort study assessed patients with incident NVAF initially recognized within a hospitalization between 2014 and 2018, using data from Statistics Netherlands. Participants were followed-up for 1 year from the hospital admission at which the incident NVAF diagnosis was made or until death, whichever occurred first. Data were analyzed from January 15, 2021, to March 8, 2023., Exposure: Calendar year of the incident NVAF diagnosis, according to which the participants were categorized into 5 cohorts., Main Outcomes and Measures: Outcomes of interest were baseline patient characteristics, anticoagulation treatment, and occurrence of ischemic stroke or major bleeding within the 1-year follow-up after incident NVAF., Results: Between 2014 and 2018, 301 301 patients (mean [SD] age, 74.2 [11.9] years; 169 748 [56.3%] male patients) experienced incident NVAF in the Netherlands, each of whom was categorized into 1 of 5 cohorts by calendar year. Baseline patient characteristics were broadly the same between cohorts with a mean (SD) CHA2DS2-VASc (congestive heart failure, hypertension, age ≥75 years [doubled], diabetes, stroke [doubled], vascular disease, age 65 to 74 years, and sex category [female]) score of 2.9 (1.7). The median (IQR) proportion of days covered by OACs (ie, vitamin K antagonists or DOACs) within the 1-year follow-up increased from 56.99% (0%-86.30%) to 75.62% (0%-94.52%), and DOACs increased from 5102 patients (13.5%) to 32 314 patients (72.0%) among those who received OACs, gradually replacing VKAs as the first choice of OACs. Over the course of the study, there were statistically significant decreases in the 1-year cumulative incidence of ischemic stroke (from 1.63% [95% CI, 1.52%-1.73%] to 1.39% [95% CI, 1.30%-1.48%) and major bleeding (from 2.50% [95% CI, 2.37%-2.63%] to 2.07% [95% CI, 1.96%-2.19%]), and the association was consistent after adjusting for baseline patient characteristics and excluding those with preexisting chronic anticoagulation., Conclusions and Relevance: This cohort study of patients with incident NVAF diagnosed between 2014 and 2018 in the Netherlands found similar baseline characteristics, increased OAC use with DOACs being favored over time, and improved 1-year prognosis. Comorbidity burden, potential underuse of anticoagulation medications, and specific subgroups of patients with NVAF remain directions for future investigations and further improvement.

Background: The STAtins Reduce Thrombophilia trial showed that, in patients with prior venous thrombosis, rosuvastatin decreased various coagulation factor levels., Objectives: Here, we investigated the hypothesis that statins decrease coagulation factor levels through shared mechanisms of synthesis or regulatory pathways with apolipoproteins., Methods: We measured the levels of apolipoprotein (Apo)A-I, A-II, A-IV, (a), B-100, B-total, C-I, C-II, C-III, and E in patients (n = 126) randomized to 28 days of rosuvastatin use. We assessed the association between apolipoproteins and coagulation factors at baseline using linear regression. The mean difference in apolipoprotein levels between baseline and after 28 days of rosuvastatin use was determined through linear regression, adjusting for age, sex, and body mass index. Coagulation factors were added to this model to determine if the lowering of apolipoproteins by rosuvastatin was linked with coagulation factor levels., Results: At baseline, levels of all apolipoproteins, except Apo(a), were positively associated with FVII, FIX, and FXI. Apolipoproteins levels, except for ApoA-I, A-IV, and Apo(a), were decreased after 28 days of rosuvastatin. ApoB-100 showed the largest mean decrease of -0.43 g/L (95% CI = -0.46 to -0.40). The decrease in ApoC-I and C-III levels was associated with a decrease in FVII, whereas the decrease in apoA-II, B-100, and B-total was associated with a decrease in FXI. The decrease in apolipoproteins was neither associated with FVIII or vWF decrease nor with endogenous thrombin potential changes., Conclusions: Rosuvastatin decreases the level of several apolipoproteins, but this decrease was associated only with a decrease in FVII and XI and not with FVIII/vWF., (© 2023 The Author(s).)

Background:  Selective serotonin reuptake inhibitors (SSRIs) may increase the risk of major bleeding by decreasing platelet function or decreasing vitamin K antagonist (VKA) metabolism via cytochrome P450 (CYP) inhibition., Aims:  To determine whether SSRIs are associated with major bleeding during VKA treatment and investigate the possible mechanisms., Methods:  In this cohort study, information on SSRI use and bleeding complications was obtained from patient records of VKA initiators between 2006 and 2018 from two anticoagulation clinics. Conditional logistic regression and time-dependent Cox regression were used to estimate the effect of SSRIs on a high international normalized ratio (INR ≥ 5) within 2 months after SSRI initiation and on major bleeding during the entire period of SSRI use, respectively. SSRI use was stratified for (non-)CYP2C9 inhibitors., Results:  A total of 58,918 patients were included, of whom 1,504 were SSRI users. SSRI initiation versus nonuse was associated with a 2.41-fold (95% confidence interval [CI]: 2.01-2.89) increased risk for a high INR, which was 3.14-fold (95% CI: 1.33-7.43) among CYP2C9-inhibiting SSRI users. The adjusted hazard ratio of major bleeding was 1.22 (95% CI: 0.99-1.50) in all SSRI users and 1.31 (95% CI: 0.62-2.72) in CYP2C9-inhibiting SSRI users compared with nonusers., Conclusion:  SSRI use is associated with an increased risk of high INR and might be associated with major bleeding. The risk of a high INR was slightly more elevated for CYP2C9-inhibiting SSRI users, suggesting there might be a pharmacokinetic interaction (by CYP2C9 inhibition) next to a pharmacodynamic effect of SSRIs on platelet activation., Competing Interests: None declared., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/).)

Patients with venous thrombosis (VT) are at increased risk of future arterial cardiovascular disease (CVD) (i.e., myocardial infarction, ischemic stroke or peripheral artery disease). We investigated whether shared risk factors for VT and CVD are associated with the levels of procoagulant factors (fibrinogen, factor VIII, and von Willebrand factor), and whether the relationship between these risk factors and subsequent CVD was mediated through these procoagulant factors in patients with VT. In a follow-up study consisting of 4956 patients with VT, 2176 patients (44%) provided blood samples and were linked to the Dutch Hospital registry of Statistics Netherlands to identify hospital admissions or procedures for subsequent CVD. In total, 52 CVD events occurred over a follow-up of 11,124 years, with an incidence rate of 4.7 per 1000 patient years (95% confidence intervals 3.5-6.1). Increasing age, male sex, smoking history, major illnesses, dyslipidemia, and impaired fasting glucose levels were associated with increased CVD risk. Procoagulant factor levels were also associated with CVD risk. When adjusted for these procoagulant factors, the association between the risk factors and CVD attenuated partially. This study provides evidence that procoagulant factors can partially explain the association between increased risks of subsequent CVD in patients with previous VT., Competing Interests: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported., (© 2022 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)

Background: Opioid overdoses are increasing in the Netherlands, and there may be other harms associated with prescription opioid use. We investigated the relationship between prescription opioid use and unplanned ICU admission and death., Methods: This is an analysis of linked government registries of the adult Dutch population (age ≥18 years) alive on January 1, 2018. The co-primary outcomes were ICU admission and death up to 1 year. Crude event rates and event-specific adjusted hazard rates (aHRs) with 95% confidence intervals (CIs) were calculated using multivariable analysis for people with and without exposure to an opioid prescription., Results: We included 13 813 173 individuals, of whom 32 831 were admitted to the ICU and 152 259 died during the 1 year follow-up. Rates of ICU admission and death amongst people who reimbursed an opioid prescription were 5.87 and 62.2 per 1000 person-years, and rates of ICU admission and death in those without a prescription were 2.03 and 6.34, respectively. Exposed individuals had a higher rate of both ICU admission (aHR 2.53; 95% CI: 2.45-2.60) and death (aHR 7.11; 95% CI: 7.02-7.19) compared with unexposed individuals. Both outcomes were more frequent amongst prescription opioid users across a range of subgroups., Conclusions: The rate of ICU admission and death was higher amongst prescription opioid users than non-users in the full cohort and in subgroups. These findings represent an important public health concern., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background and Purpose: Numbers on opioid prescriptions over time in arthroplasty patients are currently lacking. Therefore we determined the annual opioid prescribing rate in patients who received a hip/knee arthroplasty (HA/KA) between 2013 and 2018., Patients and Methods: The Dutch Foundation for Pharmaceutical Statistics, which provides national coverage of medication prescriptions, was linked to the Dutch Arthroplasty Register, which provides arthroplasty procedures. The opioid prescription rates were expressed as the number of defined daily dosages (DDD) and morphine milligram equivalent (MME) per person year (PY) and stratified for primary and revision arthroplasty. Amongst subgroups for age (< 75; ≥ 75 years) and sex for primary osteoarthritis arthroplasties, prescription rates stratified for opioid type (weak/strong) and prevalent preoperative opioid prescriptions (yes/no) were assessed., Results: 48,051 primary KAs and 53,964 HAs were included, and 3,540 revision KAs and 4,118 HAs. In 2013, after primary KA 58% were dispensed ≥ 1 opioid within the first year; this increased to 89% in 2018. For primary HA these numbers increased from 38% to 75%. In KAs the prescription rates increased from 13.1 DDD/PY to 14.4 DDD/PY, mainly due to oxycodone prescriptions (2.9 DDD/PY to 7.3 DDD/PY), while tramadol decreased (7.3 DDD/PY to 4.6 DDD/PY). The number of MME/PY also increased (888 MME/PY to 1224 MME/PY). Similar changes were observed for HA and revision arthroplasties. Irrespective of joint, prescription of opioid medication increased over time, with highest levels in groups with preoperative opioid prescriptions while weak opioid prescriptions decreased., Interpretation: In the Netherlands, between 2013 and 2018 postoperative opioid prescriptions after KA and HA increased, mainly due to increased oxycodone prescriptions with highest levels after surgeries with preoperative prescriptions.

Background: Lower-leg injury and knee arthroscopy are both associated with venous thromboembolism (VTE). The mechanism of VTE in both situations is unknown, including the role of procoagulant microparticles. This may provide useful information for individualizing thromboprophylactic treatment in both patient groups., Objective: We aimed to study the effect of (1) lower-leg trauma and (2) knee arthroscopy on procoagulant phospholipid-dependent (PPL) activity plasma levels., Methods: POT-(K)CAST trial participants who did not develop VTE were randomly selected for the current study. Plasma was collected shortly after lower-leg trauma or before and after knee arthroscopy. For aim 1, samples of 67 patients with lower-leg injury were compared with control samples (preoperative samples of 74 patients undergoing arthroscopy). Linear regression was used to obtain mean ratios (natural logarithm retransformed data), adjusted for age, sex, body mass index, infections, and comorbidities. For aim 2, pre- and postoperative samples of 49 patients undergoing arthroscopy were compared using paired t tests. PPL activity was measured using modified activated factor X-dependent PPL clotting assay., Results: For aim 1, PPL activity levels were almost threefold higher in patients with lower-leg injury compared with controls, that is, mean ratio, 2.82 (95% confidence interval [CI], 1.98-4.03). For aim 2, postoperative PPL activity levels did not change significantly, that is, mean change, -0.72 mU/mL (95% CI, -2.03 to 0.59)., Conclusion: Lower-leg trauma was associated with increased plasma levels of PPL activity, in contrast to knee arthroscopy. Lower-leg trauma triggers the release of procoagulant microparticles., (© 2022 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis (ISTH).)

Background: Whether certain activities can trigger spontaneous intracerebral hemorrhage (ICH) remains unknown. Insights into factors that trigger vessel rupture resulting in ICH improves knowledge on the pathophysiology of ICH. We assessed potential trigger factors and their risk for ICH onset., Methods: We included consecutive patients diagnosed with ICH between July 1, 2013, and December 31, 2019. We interviewed patients on their exposure to 12 potential trigger factors (eg, Valsalva maneuvers) in the (hazard) period soon before onset of ICH and their normal exposure to these trigger factors in the year before the ICH. We used the case-crossover design to calculate relative risks (RR) for potential trigger factors., Results: We interviewed 149 patients (mean age 64, 66% male) with ICH. Sixty-seven (45%) had a lobar hemorrhage, 60 (40%) had a deep hemorrhage, 19 (13%) had a cerebellar hemorrhage, and 3 (2%) had an intraventricular hemorrhage. For ICH in general, there was an increased risk within an hour after caffeine consumption (RR=2.5 [95% CI=1.8-3.6]), within an hour after coffee consumption alone (RR=4.8 [95% CI=3.3-6.9]), within an hour after lifting >25 kg (RR=6.6 [95% CI=2.2-19.9]), within an hour after minor head trauma (RR=10.1 [95% CI=1.7-60.2]), within an hour after sexual activity (RR=30.4 [95% CI=16.8-55.0]), within an hour after straining for defecation (RR=37.6 [95% CI=22.4-63.4]), and within an hour after vigorous exercise (RR=21.8 [95% CI=12.6-37.8]). Within 24 hours after flu-like disease or fever, the risk for ICH was also increased (RR=50.7 [95% CI=27.1-95.1]). Within an hour after Valsalva maneuvers, the RR for deep ICH was 3.5 (95% CI=1.7-6.9) and for lobar ICH the RR was 2.0 (95% CI=0.9-4.2)., Conclusions: We identified one infection and several blood pressure related trigger factors for ICH onset, providing new insights into the pathophysiology of vessel rupture resulting in ICH.

Background: Venous thromboembolism (VTE) is a frequent cardiovascular disease with severe complications, including recurrence and death. There is a great need for alternative prophylactic treatment options as anticoagulation is accompanied by increased bleeding risk. Statins are reported to reduce the risk of incident and recurrent VTE, but the mechanisms are elusive. Procoagulant phospholipids (PPL), and phosphatidylserine in particular, are crucial for efficient coagulation activation, but no studies have investigated the effect of statin treatment on plasma PPL activity., Objectives: To investigate the impact of rosuvastatin treatment on plasma PPL activity and levels of extracellular vesicles (EVs)., Patients/methods: Patients with a history of VTE (≥18 years) allowed to stop anticoagulant treatment were randomized to either 20 mg/day of rosuvastatin treatment or no treatment for 28 days in the Statins Reduce Thrombophilia (NCT01613794) trial. Plasma samples were collected at baseline and study end. PPL activity was measured in samples from 245 participants using a factor Xa-dependent clotting assay and EV levels by flow cytometry., Results: Rosuvastatin treatment yielded an overall 22% (95% confidence interval [CI] -38.2 to -5.8) reduction in PPL activity, and 37% (95% CI -62.9 to -11.2) reduction in PPL activity in participants with a history of pulmonary embolism. The effect of rosuvastatin on plasma PPL activity was not explained by changes in total cholesterol nor change in levels of total- or platelet-derived EVs., Conclusions: Rosuvastatin treatment caused a substantial decrease in plasma PPL activity, suggesting that a PPL-dependent attenuation of coagulation activation may contribute to a reduced VTE risk following statin treatment., (© 2021 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.)

Background:  In January 2021, the Dutch vaccination program against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was started. Clinical studies have shown that systemic reactions occur in up to 50% of vaccine recipients. Therefore, COVID-19 vaccination could affect anticoagulation control, potentially leading to an increased risk of thrombotic events and bleeding complications., Aims:  This article investigates whether the BNT162b2 vaccine affects anticoagulation control in outpatients using vitamin K antagonists (VKAs)., Methods:  A case-crossover study was performed in a cohort of outpatient VKA users from four Dutch anticoagulation clinics who received a BNT162b2 vaccine. International normalized ratio (INR) results and VKA dosages before the first vaccination, the reference period, were compared with those after the first and second vaccination., Results:  A total of 3,148 outpatient VKA users were included, with a mean age (standard deviation) of 86.7 (8.7) years, of whom 43.8% were male, 67.0% used acenocoumarol, and 33.0% phenprocoumon. We observed a decrease of 8.9% of INRs within range in the standard intensity group (target INR 2.0-3.0). There was both an increased risk of supratherapeutic (odds ratio [OR] = 1.34 [95% confidence interval [CI] 1.08-1.67]) and subtherapeutic levels (OR = 1.40 [95% CI 1.08-1.83]) after first vaccination. In the high-intensity group (target INR 2.5-3.5), the risk of a supratherapeutic INR was 2.3 times higher after first vaccination (OR = 2.29 [95% CI 1.22-4.28]) and 3.3 times higher after second vaccination (OR = 3.25 [95% CI 1.06-9.97])., Conclusion:  BNT162b2 was associated with an immediate negative effect on anticoagulation control in patients treated with VKAs, so it is advisable to monitor the INR shortly after vaccination, even in stable patients., Competing Interests: C.V., J.S.B., M.C.N., F.J..v.d.M., A.J.W.G., Y.C.F.M., S.C.C., and W.M.L. have no conflicts of interest to declare. M.J.H.A.K. has received unrestricted grants paid to the department for research outside this work from Bayer and Daiichi Sankyo, and has received a speaker's fee paid to the department from Bayer., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/).)

Background: Non-valvular atrial fibrillation (NVAF) patients are advised to switch from a vitamin K antagonist (VKA) to direct oral anticoagulant (DOAC) when time in therapeutic range (TTR) is low., Objective: To examine if pre-switch TTR determines persistence patterns in NVAF patients who are switched from a VKA to DOAC., Patients/methods: Adult NVAF patients from three Dutch anticoagulation clinics who were newly switched from a VKA to DOAC between July 1, 2013 and September 30, 2018 were stratified by pre-switch TTR levels. DOAC prescription records were examined to determine persistence patterns according to a 100-day prescription gap. Cumulative incidences of non-persistence to DOAC were estimated using the cumulative incidence competing risk method. The association of pre-switch TTR levels with DOAC non-persistence was evaluated by Cox regression models., Results: A total of 3696 NVAF patients were included, of whom 690 (18.7%) had a pre-switch TTR ≤ 45%. After switching from VKA to DOAC, 14.0% (95% confidence interval [CI] 11.3-17.0%) of the patients with a pre-switch TTR ≤ 45% became non-persistent to DOAC within 1 year, while 9.8% (95% CI 8.7-11.0%) did in those with a pre-switch TTR > 45%. In a multivariable model, a pre-switch TTR ≤ 45% was associated with a higher risk of non-persistence to DOAC (adjusted hazard ratio 1.55, 95% CI 1.22-1.97). Results were similar when using other cut-off points (60% or 70%) to define a low TTR., Conclusion: NVAF patients switching from VKA to DOAC due to a low pre-switch TTR saw a worse persistence pattern to DOAC after the switch compared to patients with a high pre-switch TTR., (© 2021 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.)

Objective: Many prescribed and over-the-counter medications, for example, non-steroidal anti-inflammatory drugs (NSAIDs) are associated with upper gastrointestinal bleeding (UGIB). Recently, a decrease in prescribing of NSAIDs was observed in the Netherlands, but whether a similar decreasing trend could be observed in the incidence of severe UGIB (either fatal or requiring hospitalisation), contingent on medication prescription, is unknown., Design: We conducted a cohort study using Dutch national statistics on pharmacy claims, hospitalisation and mortality between 2013 and 2018. We explored the incidence of sex-specific and age-specific severe UGIB in four (sub)populations: (A) total population, (B) without a filled prescrption for NSAIDs, (C) without filled prescriptions for NSAIDs and antithrombotic agents, (D) without any risk factors for UGIB., Results: The cumulative incidence of severe UGIB did not decrease throughout the study period, regardless of the subgroup analysis. In the total population, it was 199 per 100 000 inhabitants (95% CI 197 to 201) in 2013-2014 and 260 (95% CI 258 to 263) in 2017-2018. The absolute risk of severe UGIB was 50% lower in the subgroup B than in the full cohort. It decreased further by 50% in the subgroup D when compared with subgroup B. The risk of severe UGIB was 1.5-1.9 fold higher in young women than in young men; an indication of over-the-counter NSAIDs use being more prevalent in women than men in this age group., Conclusion: We found no evidence to support a relationship between reduced prescribing of NSAIDs and the incidence of severe UGIB in the Netherlands since 2013. The relationship was also not observed when we removed the effect of risk factors., Competing Interests: Competing interests: All authors have completed the Conflict of Interest Statement form and declare: no support from any private organisation for the submitted work; AD has received research grants and personal fees from MSD, grants from Medasense, grants from Grunenthal, personal fees from Trevena, grants from AMO Pharma, grants from Center for Human Drug Research, outside the submitted work; no other relationships or activities that could appear to have influenced the submitted work., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Direct oral anticoagulants (DOACs) do not require concentration monitoring. However, whether DOAC concentrations are stable and their variation between and within patients is not well studied., Methods: Patients on vitamin K antagonists (VKA) who switched to rivaroxaban, apixaban, or dabigatran were included between 2018 and 2020. Blood was drawn at DOAC trough and peak concentrations at week 0, 2, and 8. Plasma drug concentrations were determined by anti-factor Xa concentrations (rivaroxaban, apixaban) or diluted thrombin time (dabigatran). Inter- and intra-individual variability was assessed by calculating the coefficient of variation (CV). Linear regression models were employed to evaluate associations between DOAC trough concentrations and previous VKA dosage, creatinine clearance, and body mass index (BMI)., Results: One hundred fifty-two patients were included, of whom 96 (63%) were male and with a mean age of 73.9 ± 8.4 years. For the inter-individual variability, the CV ranged between 48% and 81% for trough values and between 25% and 69% for peak values among patients using the recommended DOAC dose. Intra-individual variability was substantially lower, as here the CV ranged between 18% and 33% for trough values and between 15% and 29% for peak values among patients using the recommended DOAC dose. Previous VKA dosage and creatinine clearance were inversely associated with DOAC trough concentrations. No association was found between BMI and DOAC trough concentrations., Conclusion: Inter-individual variability of DOAC concentrations was higher than intra-individual variability. Lower previous VKA dosage and creatinine clearance were associated with higher DOAC trough concentrations. These findings support further study into an optimal target range, in which the risks of both bleeding and thrombosis are minimal., (© 2021 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.)

Aims: Persistence with direct oral anticoagulants (DOACs) has become a concern in non-valvular atrial fibrillation (NVAF) patients, but whether this affects prognosis is rarely studied. We investigated the persistence with oral anticoagulants (OACs) and its association with prognosis among a nationwide cohort of NVAF patients., Methods and Results: DOAC-naive NVAF patients who started to use DOACs for ischaemic stroke prevention between 2013 and 2018 were included using Dutch national statistics. Persistence with OACs was determined based on the presence of a 100-day gap between the last prescription and the end of study period. In 93 048 patients, 75.7% had a baseline CHA2DS2-VASc score of ≥2. The cumulative incidence of persistence with OACs was 88.1% [95% confidence interval (CI) 87.9-88.3%], 82.6% (95% CI 82.3-82.9%), 77.7% (95% CI 77.3-78.1%), and 72.0% (95% CI 71.5-72.5%) at 1, 2, 3, and 4 years after receiving DOACs, respectively. Baseline characteristics associated with better persistence with OACs included female sex, age range 65-74 years, permanent atrial fibrillation, previous exposure to vitamin K antagonists, stroke history (including transient ischaemic attack), and a CHA2DS2-VASc score ≥2. Non-persistence with OACs was associated with an increased risk of the composite outcome of ischaemic stroke and ischaemic stroke-related death [adjusted hazard ratio (aHR) 1.79, 95% CI 1.49-2.15] and ischaemic stroke (aHR 1.58, 95% CI 1.29-1.93) compared with being persistent with OACs., Conclusion: At least a quarter of NVAF patients were non-persistent with OACs within 4 years, which was associated with poor efficacy of ischaemic stroke prevention. The identified baseline characteristics may help identify patients at risk of non-persistence., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Coagulopathy has been reported in severely ill patients with coronavirus disease 2019 (COVID-19). It is unclear whether outpatients with COVID-19 who are treated with vitamin K antagonists (VKAs) have unstable anticoagulation., Objective: To assess the stability of VKA therapy in patients with COVID-19 through a case-crossover study., Methods: Between February and July 2020, we included patients who tested positive for COVID-19 from two anticoagulant clinics in the Netherlands. We collected international normalized ratios (INRs) determined between 26 weeks before infection and 12 weeks after. Time in therapeutic range (TTR) and the variance growth rate (VGR) were calculated within patients., Results: Fifty-one patients with COVID-19 (mean age, 84 years) were included, of whom 15 (29%) were men. Mean TTR in the 26 weeks before COVID-19 was 80% (95% confidence interval [CI], 75-85) compared to 59% (95% CI, 51-68) in the 6 weeks after infection. Mean TTR difference was -23% (95% CI, -32 to -14) with a time above therapeutic range of 38% (95% CI, 30-47) in the 6 weeks after infection. The TTR rose again to 79% (95% CI, 69-89) between 6 and 12 weeks after infection. Also, VGR increased, with a mean increase of 4.8 (95% CI, 2.1-7.5) in the 6 weeks after infection. In the 26 weeks before infection, we registered 19 of 641 (3%) of INR ≥5.0 compared with 35 of 247 (14%) in the 6 weeks after (risk ratio, 4.4; 95% CI, 2.7-7.3)., Conclusions: COVID-19 is associated with a strong decrease in TTR and in therapeutic stability in patients taking VKAs. Additional monitoring in these patients is advised to maximize therapeutic stability., (© 2021 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis (ISTH).)

Background: Prescribing practice of pain medication is changing in the Netherlands; opioids are used more often instead of nonsteroidal anti-inflammatory drugs (NSAIDs), therefore we aimed to compare the use of pain medication with Slovenia which has stringent prescribing rules for strong opioids. Methods: We conducted a cohort study into national prescription databases of the Netherlands and Slovenia covering pharmacy claims between January 1, 2013 and December 31, 2019. In the analysis about 17 million Dutch and 2 million Slovenian residents were included. Findings: The use of opioids and NSAIDs was higher in Slovenia than in the Netherlands. More frequent use of opioids in Slovenia could be almost entirely explained by weak opioids (about 6% of the population), whereas they were prescribed 50% less frequently in the Netherlands. The opioid use has increased by about 20% in the Netherlands (4.85 and 6.00% of the population in 2013 and 2018, respectively), and the majority of this increase could be explained by strong opioids (4.05% in 2018), specifically, by oxycodone whose use increased by more than 2-fold between 2013 and 2019. In comparison, oxycodone was seldomly used in Slovenia (about 0.3% of the population received a prescription in a year). Interpretation: When medication use is controlled by stringent prescribing rules, like for strong opioids in Slovenia, the use is lower as compared to when such rules do not exist., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Bedene, Strmljan, van Dorp, Udovič, Lijfering, Niesters, Rosendaal, Dahan and Fürst.)

Background: Adherence to direct oral anticoagulants (DOACs) in patients with atrial fibrillation in every day practice may be less than in clinical trials., Aims: To assess adherence to DOACs in atrial fibrillation patients in every day practice and identify predictors for non-adherence., Methods: Individual linked dispensing data of atrial fibrillation patients who used DOACs were obtained from the Foundation for Pharmaceutical Statistics covering the Netherlands between 2012 and 2016. One year adherence to DOAC was calculated for initial DOAC as proportion of days covered (PDC) ≥80% and the association between clinical variables and adherence was assessed using logistic regression. In addition, we measured non-persistence, that is, patients who completely stopped their initial DOAC within 1 year follow-up., Results: A total of 4797 apixaban-, 20 454 rivaroxaban- and 18 477 dabigatran users were included. The mean age was 69 years (n = 43 910), which was similar for the DOAC types. The overall proportion of patients with PDC ≥80% was 76%, which was highest for apixaban- (87%), followed by dabigatran- (80%) and rivaroxaban (69%) users. Multivariable analyses revealed that age ≤60 years, no concomitant drug use were predictors for non-adherence. Of atrial fibrillation patients who continued treatment, 97% had a PDC ≥80%, compared with only 56% for those who discontinued their DOAC treatment within 1 year., Conclusions: Non-adherence to DOACs was associated with age ≤60 years and no concomitant drugs use. Non-adherence was higher in patients who later discontinued DOAC treatment. Results of our study support research into interventions to improve adherence., (© 2021 The Authors. Pharmacoepidemiology and Drug Safety published by John Wiley & Sons Ltd.)

Background: Statins are a potential treatment for venous thromboembolism (VTE) prophylaxis complementary to conventional anticoagulants without associated bleeding complications. This study aimed to compare pro-thrombotic activities of different classes of lipid-lowering drugs in an active comparator design and determine whether there is a relation between statin versus fibrate/niacin use and pro-coagulant factor outcomes., Methods: This is a cross-sectional analysis of participants from the Netherlands Epidemiology of Obesity study using any class of lipid-lowering drugs, including any types of statins, niacin, and fibrates. We performed linear regression analyses to determine fibrinogen, factor (F) VIII, FIX, and FXI activity in statins versus fibrate/niacin users and adjusted for age, sex, tobacco smoking, body mass index (BMI), hypertension, diabetes, and prevalent cardiovascular disease., Results: Among 1043 participants, the mean age was 58.4 ± 5.2 years, 61% were men, and the mean BMI was 31.3 ± 4.5 kg/m 2 . Clinical characteristics were balanced between statin and fibrate/niacin users. Statin users had lower mean FXI (18.3 IU/dL, 95% confidence interval (CI) 9.4 to 27.3) levels compared to fibrate/niacin users. The level of FVIII (15.8 IU/dL, 95% CI - 0.003 to 31.6), and FIX (11.3 IU/dL, 95% CI - 0.4 to 23.2) were lower in statin users than fibrate/niacin users with marginal statistical significance., Conclusion: Current statin use was associated with lower plasma levels of FXI than fibrate/niacin use. The effects on coagulation factors may, in part, explain the benefit of statin therapy rendered in primary and secondary prevention of VTE.

Glucocorticoid treatment increases venous thromboembolism (VTE) risk. Whether this is due to the medication or the underlying disease, or affects the risk of VTE recurrence, has been difficult to determine. The aim of our present study was to quantify the risk for first and recurrent VTE associated with oral glucocorticoids use, considering the underlying disease. A total of 2547 patients with VTE from the Multiple Environmental and Genetic Assessment of Risk Factors for Venous Thrombosis (MEGA) study were linked to the Dutch Pharmaceutical Statistics register. The risk of first VTE during periods of exposure with oral glucocorticoids was estimated by the self-controlled case series method and that of recurrent VTE was examined in a cohort design. The incidence rate ratio (IRR) of first VTE in the period of glucocorticoid treatment was 3·51 [95% confidence interval (CI) 2·55-4·80]. This IRR was 2·53 (95% CI 1·10-5·72) in the week before treatment started, 5·28 (95% CI 2·89-9·53) in the first 7 days of treatment, remained elevated afterwards and decreased to 1·55 (95% CI 0·85-3·12) after 6 months, as compared to unexposed periods. The hazard ratio for recurrence was 2·72 (95% CI 1·64-4·78) in treatment periods as compared with no treatment. The increased risk of VTE associated with oral glucocorticoid treatment is due to a combined effect of the treatment and the underlying disease, remaining high during the first months of prescription., (© 2021 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Background: Short-term follow-up of COVID-19 patients reveals pulmonary dysfunction, myocardial damage and severe psychological distress. Little is known of the burden of these sequelae, and there are no clear recommendations for follow-up of COVID-19 patients.In this multi-disciplinary evaluation, cardiopulmonary function and psychological impairment after hospitalization for COVID-19 are mapped., Methods: We evaluated patients at our outpatient clinic 6 weeks after discharge. Cardiopulmonary function was measured by echocardiography, 24-hours ECG monitoring and pulmonary function testing. Psychological adjustment was measured using questionnaires and semi-structured clinical interviews. A comparison was made between patients admitted to the general ward and Intensive care unit (ICU), and between patients with a high versus low functional status., Findings: Eighty-one patients were included of whom 34 (41%) had been admitted to the ICU. New York Heart Association class II-III was present in 62% of the patients. Left ventricular function was normal in 78% of patients. ICU patients had a lower diffusion capacity (mean difference 12,5% P  = 0.01), lower forced expiratory volume in one second and forced vital capacity (mean difference 14.9%; P <0.001; 15.4%; P <0.001; respectively). Risk of depression, anxiety and PTSD were 17%, 5% and 10% respectively and similar for both ICU and non-ICU patients., Interpretation: Overall, most patients suffered from functional limitations. Dyspnea on exertion was most frequently reported, possibly related to decreased DLCOc. This could be caused by pulmonary fibrosis, which should be investigated in long-term follow-up. In addition, mechanical ventilation, deconditioning, or pulmonary embolism may play an important role., Competing Interests: There is no conflict of interest for the present manuscript., (© 2021 The Author(s).)

Background: Von Willebrand factor (VWF) levels are regulated by genetic and acquired factors. The acquired factors are mostly related to age and could be mediators of the age effect on VWF levels., Objectives: To disentangle the role of genetic (sex, blood group) and acquired factors (comorbidities, body mass index, reduced kidney function, hormone use, and inflammation) in regulating von Willebrand factor antigen (VWF:Ag) and factor VIII activity (FVIII:C) levels in the normal population., Methods: Analysis were performed in a large population sample (2923 individuals) from the Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis (MEGA study), after exclusion of individuals with active cancer and women who were pregnant or within nine months postpartum. The increase of VWF:Ag and FVIII:C with age was evaluated by linear regression after the age of 40 years. Analyses were adjusted for acquired factors and stratified for sex and blood group., Results: VWF:Ag and FVIII:C increased with age: increase per decade of age for VWF:Ag 18 IU/dL (95%CI 15-20) and for FVIII:C 12 IU/dL (95%CI 10-14). After adjustment for acquired factors, the increase per decade was 13 IU/dL (95%CI 10-16) for VWF:Ag and 9 IU/dL (95%CI 6-11) for FVIII:C. The stratified analysis for blood group showed higher increase in the non-O group, but these differences were annulled after adjustment for acquired factors., Conclusions: VWF:Ag and FVIII:C increase with age. Carriers of blood group non-O present a steeper increase of VWF:Ag and FVIII:C with age, that is mediated by acquired factors., (Copyright © 2020. Published by Elsevier Ltd.)

Background:  Major bleeding occurs in 1 to 3% of patients treated with oral anticoagulants per year. Biomarkers may help to identify high-risk patients. A proposed marker for major bleeding while using anticoagulants is soluble thrombomodulin (sTM)., Methods:  Plasma was available from 16,570 patients of the BLEEDS cohort that consisted of patients who started treatment with vitamin K antagonists between 2012 and 2014. A case-cohort study was performed including all patients with a major bleed ( n  = 326) during follow-up and a random sample of individuals selected at baseline ( n  = 652). Plasma sTM levels were measured and stratified by percentiles. Patients were also categorized by international normalized ratio (INR). Adjusted hazard ratios (for age, sex, hypertension, and diabetes) with 95% confidence intervals (CIs) were estimated by means of Cox regression., Results:  Plasma sTM levels were available for 263 patients with a major bleed and 538 control subjects. sTM levels were dose-dependently associated with risk of major bleeding, with a 1.9-fold increased risk (95% CI: 1.1-3.1) for levels above the 85th percentile versus the <25th percentile. A high INR (≥4) in the presence of high (≥70th percentile) sTM levels was associated with a 7.1-fold (95% CI: 4.1-12.3) increased risk of major bleeding, corresponding with a bleeding rate of 14.1 per 100 patient-years., Conclusion:  High sTM levels at the start of treatment are associated with major bleeding during vitamin K antagonist treatment, particularly in the presence of a high INR., Competing Interests: None declared., (Thieme. All rights reserved.)

Objective: Whether hepatic triglyceride content (HTGC) contributes to hypercoagulability beyond total body fat (TBF) and visceral adipose tissue (VAT) is unclear. We, therefore, aimed to investigate the association between HTGC and coagulation factors (F)I (fibrinogen), VIII, IX, and XI while adjusting for TBF and VAT. Approach and Results: In this cross-sectional analysis of the NEO study (Netherlands Epidemiology of Obesity; n=6671), a random subset of participants underwent magnetic resonance imaging and magnetic resonance spectroscopy to assess VAT and HTGC (n=2580). We excluded participants without complete imaging and coagulation assessment, and with history of liver disease, venous thrombosis, or on anticoagulation. Mean differences in coagulation factor levels across HTGC quartiles were estimated by linear regression adjusted for age, sex, ethnicity, education, alcohol intake, physical activity, smoking, estrogen, and menopause, in addition to TBF and VAT. Among the 1946 participants included, median HTGC was 2.66% (interquartile range: 1.34%-6.27%). Coagulation factor levels increased dose-dependently across HTGC quartiles. Mean differences between the fourth and first quartiles were 14.7 mg/dL (95% CI, 2.1-27.2) for fibrinogen, 6.7 IU/dL (95% CI, 0.5-12.9) for FVIII, 26.1 IU/dL (95% CI, 22.4-29.8) for FIX, and 8.6 IU/dL (95% CI, 4.6-12.6) for FXI. With further adjustment for TBF and VAT, the dose-response association of HTGC with FIX persisted, whereas associations with other factors disappeared., Conclusions: HTGC was associated with various coagulation factors, of which FIX remained associated with HTGC after adjustment for TBF and VAT. HTGC might contribute to venous thrombosis risk beyond total body and visceral fat through FIX levels.

Direct oral anticoagulants (DOACs) are increasingly used for treatment and prevention of thromboembolic diseases, used in fixed dose regimens. Although their safety and efficacy profiles are considered optimal, clinical events still occur. Given that anticoagulation treatment is a delicate balance between clotting and bleeding, it is possible that an optimal target spot exists where the effect of anticoagulation achieves both the lowest possible risk of bleeding and thrombosis. Other currently available anticoagulants (ie, vitamin K antagonists and heparins) provide important clues for this. If such a target spot exists, tailored DOAC therapy may further benefit patients. This opinion article summarizes the current available evidence that suggests that such a tailored strategy could work. It also describes research suggestions for conducting studies in patient populations such as patients with extremes of body weight or impaired kidney function to evaluate whether tailored treatment with DOACs could lead to better patient outcomes., (© 2020 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.)

Background: To evaluate the association between crowding and transmission of viral respiratory infectious diseases, we investigated the change in transmission patterns of influenza and COVID-19 before and after a mass gathering event (i.e., carnival) in the Netherlands., Methods: Information on individual hospitalizations related to the 2017/2018 influenza epidemic were accessed from Statistics Netherlands. The influenza cases were stratified between non-carnival and carnival regions. Distributions of influenza cases were plotted with time and compared between regions. A similar investigation in the early outbreak of COVID-19 was also conducted using open data from the Dutch National Institute for Public Health and the Environment., Results: Baseline characteristics between non-carnival and carnival regions were broadly similar. There were 13,836 influenza-related hospitalizations in the 2017/2018 influenza epidemic, and carnival fell about 1 week before the peak of these hospitalizations. The distributions of new influenza-related hospitalizations per 100,000 inhabitants with time between regions followed the same pattern with a surge of new cases in the carnival region about 1 week after carnival, which did not occur in the non-carnival region. The increase of new cases for COVID-19 in the carnival region exceeded that in the non-carnival region about 1 week after the first case was reported, but these results warrant caution as for COVID-19 there were no cases reported before the carnival and social measures were introduced shortly after carnival., Conclusion: In this study, a mass gathering event (carnival) was associated with aggravating the spread of viral respiratory infectious diseases.

: Venous thromboembolism (VTE) is a chronic disease. Strategies to assess groups at a high risk of recurrence are needed. We reported that patients without prior risk situation for VTE had an incidence rate ratio (IRR) three times higher when compared with those with this history. The aim of this study was to re-evaluate the cohort, with a longer follow-up and evaluated the association between the absence of a prior risk situation for VTE with an increased risk for recurrence. A total of 289 patients with a previous VTE were followed for 116 months. Patients were advised to attend the outpatients' clinic in case of suspected VTE recurrence. Incidence rates of recurrent thrombotic events were calculated as the number of events over the accumulated observation time. Recurrent VTE occurred in 52 (18%) patients. Patients with a provoked first event and positive prior risk situations for VTE had an incidence rate for recurrence of 1.2 [95% confidence interval (95% CI), 0.7-1.9] per 100 patient-years. The IRR of this subgroup compared with patients with a provoked event without prior risk situations for VTE was 0.9 (95% CI 0.4-2.4). IRR was 2.5 (95% CI, 1.3-4.9) in patients with an unprovoked event and positive prior risk situations and 5.9 (95% CI, 32.8-12.5) in patients with an unprovoked event and no prior risk situations compared with patients with a provoked event without other prior risk situations for VTE. Exposure to prior risk situations for VTE was a protective factor among those patients whose first VTE event was unprovoked.

It is not known whether the synergistic effect of genetic markers, increasing the risk of venous thrombosis (VT), and combined oral contraceptives (COC) use varies between different types of progestogens in these preparations. We investigated the joint effect of genetic risk factor, that is, F5 rs6025, F2 rs1799963, and FGG rs2066865 mutations, and different progestogens on the risk of VT. The constrained maximum likelihood estimation (CMLE) method was used to calculate joint effects, expressed as odds ratio (OR) with 95% confidence intervals [CI]. As the dose of estrogen is known to be a risk factor for VT, analyses were restricted to COC with 30 µg estrogen and each progestogen. Overall, the joint effect of COC and genetic variants was lowest for COC containing the progestogen levonorgestrel, albeit CIs were wide. The OR (95% CI) of the four different analyses (i.e. joint effect with F5 rs6025, F2 rs1799963, F5 rs6025 or F2 rs1799963 and FGG rs2066865) ranged between 7·4 (5·4-10·2) and 24·8 (12·3-50·0) for levonorgestrel. For gestodene the joint effect ranged between 11·7 (7·2-19·1) and 30·9 (10·6-89·9). Desogestrel and cyproterone acetate had the highest risk estimates: 14·6 (9·7-21·9) and 32·6 (13·2-80·6) and 15·5 (9·7-24·9) and 44·4 (16·9-116·3) respectively. In women with inherited thrombophilia, COC containing levonorgestrel were associated with the lowest risk of VT, albeit the CIs were wide., (© 2020 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Over the past decade opioid use has risen globally. The causes and consequences of this increase, especially in Europe, are poorly understood. We conducted a population-based cohort study using national statistics on analgesics prescriptions, opioid poisoning hospital admissions and deaths in the Netherlands from 2013 to 2017. Pain prevalence and severity was determined by using results of 2014-2017 Health Interview Surveys. Between 2013 and 2017 the proportion of residents receiving opioid prescription rose from 4.9% to 6.0%, and the proportion of those receiving NSAIDs decreased from 15.5% to 13.7%. Self-reported pain prevalence and severity remained constant, as 44.7% of 5,119 respondents reported no pain-impeded activities-of-daily-living in 2014 (aRR, 1.00 [95% CI, 0.95-1.06] in 2017 vs 2014). Over the observation period, the incidence of opioid poisoning hospitalization and death increased from 8.6 to 12.9 per 100,000 inhabitants. The incidence of severe outcomes related to opioid use increased, as 3.9% of 1,343 hospitalized for opioid poisoning died in 2013 and 4.6% of 2,055 in 2017. We demonstrated that NSAIDs prescription decreased and opioid prescription increased in the Netherlands since 2013, without an increase in pain prevalence and severity. Consequently, the incidence of severe outcomes related to opioids increased.

We conducted a study to assess the effect of rosuvastatin use on fibrinolysis in patients with previous venous thromboembolism (VTE). This was a post hoc analysis within the STAtins Reduce Thrombophilia (START) study (NCT01613794). Plasma fibrinolytic potential, fibrinogen, plasmin inhibitor, plasminogen activator inhibitor-1 (PAI-1) and thrombin-activatable fibrinolysis inhibitor (TAFI) were measured before and after four weeks of rosuvastatin or no treatment in participants with prior confirmed VTE, after ending anticoagulant therapy. In the non-rosuvastatin group (n = 121), plasma fibrinolytic potential and individual fibrinolysis parameters did not change at the end of the study versus the baseline, whereas in the rosuvastatin group (n = 126), plasma fibrinolytic potential increased: the mean clot lysis time decreased by 8·75 min (95% CI -13·8 to -3·72), and plasmin inhibitor levels and TAFI activity were lower at the end of the study (-0·05 U/ml; 95% CI -0·07 to -0·02 and -4·77%; 95% CI -6·81 to -2·73, respectively). PAI-1 levels did not change and fibrinogen levels were 0·17 g/l (95% CI 0·04-0·29) higher. In participants with prior VTE, rosuvastatin use led to an increased fibrinolytic potential compared with non-statin use. Our findings support the need for further studies on the possible role for statins in the secondary prevention of VTE., (© 2020 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Background: Since direct oral anticoagulants (DOACs) have been introduced for treatment and prevention of thromboembolic diseases, patients on vitamin K antagonists (VKA) have to decide whether to remain on VKA or switch to DOAC. The goal of this study was to evaluate treatment satisfaction, preferences, and concerns among those who already have switched from VKA to DOAC., Methods: A questionnaire was sent to 2920 former patients of three anticoagulation clinics in the Netherlands, who switched from VKA to DOAC (2016-2017). Questions concerned demographics, treatment satisfaction, concerns, perspectives on antidotes, and monitoring. To identify predictors for being concerned about adverse events, logistic regression was used to estimate crude- and adjusted (age and sex) odds ratios (OR) and 95% confidence intervals (95% CI)., Results: One thousand, three hundred ninety-nine questionnaires (response rate 48%) were used for analysis. DOAC treatment satisfaction was high (mean 8.8 of a maximum 10-point score). A quarter of patients expressed concerns about adverse events. Predictors for being concerned were age < 60 years (vs age > 75 years, OR 4.1, 95% CI 2.6-6.4), female sex (OR 1.3, 95% CI 1.0-1.6), and high education (OR 1.6, 95% CI 1.2-2.2). Fifty-nine percent of all patients indicated antidote availability as important, 73% would be willing to participate in DOAC monitoring., Conclusions: DOAC treatment satisfaction was high. A substantial number of patients expressed concerns about adverse events, especially women, patients aged < 60 years, or highly educated patients. Our findings among patients who already had switched to DOAC may assist in the process of shared decision-making when switching a patient from VKA to DOAC is considered., (© 2020 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.)

Background: Multiple studies have described a higher incidence of venous thromboembolism (VTE) in people living with an HIV infection (PWH). However, data on the risk of recurrent VTE in this population are lacking, although this question is more important for clinical practice. This study aims to estimate the risk of recurrent VTE in PWH compared to controls and to identify risk factors for recurrence within this population., Methods and Findings: PWH with a first VTE were derived from the AIDS Therapy Evaluation in the Netherlands (ATHENA) cohort (2003-2015), a nationwide ongoing cohort following up PWH in care in the Netherlands. Uninfected controls were derived from the Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis (MEGA) follow-up study (1999-2003), a cohort of patients with a first VTE who initially participated in a case-control study in the Netherlands who were followed up for recurrent VTE. Selection was limited to persons with an index VTE suffering from deep vein thrombosis in the lower limbs and/or pulmonary embolism (PE). Participants were followed from withdrawal of anticoagulation to VTE recurrence, loss to follow-up, death, or end of study. We estimated incidence rates, cumulative incidence (accounting for competing risk of death) and hazard ratios (HRs) using Cox proportional hazards regression, adjusting for age, sex, and whether the index event was provoked or unprovoked. When analyzing risk factors among PWH, the main focus of analysis was the role of immune markers (cluster of differentiation 4 [CD4]+ T-cell count). There were 153 PWH (82% men, median 48 years) and 4,005 uninfected controls (45% men, median 49 years) with a first VTE (71% unprovoked in PWH, 34% unprovoked in controls) available for analysis. With 40 VTE recurrences during 774 person-years of follow-up (PYFU) in PWH and 635 VTE recurrences during 20,215 PYFU in controls, the incidence rates were 5.2 and 3.1 per 100 PYFU (HR: 1.70, 95% CI 1.23-2.36, p = 0.003). VTE consistently recurred more frequently per 100 PYFU in PWH in all predefined subgroups of men (5.6 versus 4.8), women (3.6 versus 1.9), and unprovoked (6.0 versus 5.2) or provoked (3.1 versus 2.1) first VTE. After adjustment, the VTE recurrence risk was higher in PWH compared to controls in the first year after anticoagulant discontinuation (HR: 1.67, 95% CI 1.04-2.70, p = 0.03) with higher cumulative incidences in PWH at 1 year (12.5% versus 5.6%) and 5 years (23.4% versus 15.3%) of follow-up. VTE recurred less frequently in PWH who were more immunodeficient at the first VTE, marked by a better CD4+ T-cell recovery on antiretroviral therapy and during anticoagulant therapy for the first VTE (adjusted HR: 0.81 per 100 cells/mm3 increase, 95% CI 0.67-0.97, p = 0.02). Sensitivity analyses addressing potential sources of bias confirmed our principal analyses. The main study limitations are that VTEs were adjudicated differently in the cohorts and that diagnostic practices changed during the 20-year study period., Conclusions: Overall, the risk of recurrent VTE was elevated in PWH compared to controls. Among PWH, recurrence risk appeared to decrease with greater CD4+ T-cell recovery after a first VTE. This is relevant when deciding to (dis)continue anticoagulant therapy in PWH with otherwise unprovoked first VTE., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: CR reports grants from Gilead, Merck, and personal fees from Gilead, ViiV, Janssen-Cilag. JFBH and EDP report no conflicts of interest. YIGVT was employed by the Dutch National Health Institute during analysis and reporting on this study. CS reports grants from Netherlands Ministry of Health, Welfare and Sport, National Institute for Public Health and the Environment, Centre for Infectious Disease Control, during the conduct of the study. FW reports personal fees from Gilead Sciences, personal fees from ViiV Healthcare, outside the submitted work. PR reports independent scientific grant support to his institution from Gilead Sciences, Janssen Pharmaceuticals Inc., Merck & Co., Bristol-Myers Squibb, and ViiV Healthcare; fees to his institution for his participation on scientific advisory boards for Gilead Sciences ViiV Healthcare, Merck & Co., Teva pharmaceutical industries, and on a data safety monitoring committee for Janssen Pharmaceuticals Inc. BR reports grants from Gilead, grants from MSD, nonfinancial support from MSD, nonfinancial support from Gilead, nonfinancial support from BMS, nonfinancial support from Janssen-Cilag, nonfinancial support from ViiV, nonfinancial support from Abbvie, personal fees from Gilead, personal fees from ViiV, personal fees from Great-Lakes pharmaceuticals, outside the submitted work; and financial compensation payed to institution for advisory board participation organized by Gilead, ViiV, BMS, Janssen-Cilag, and MSD. KM received research support from Bayer, Sanquin, and Pfizer; speaker fees from Bayer, Sanquin, Boehringer Ingelheim, BMS, and Aspen; consulting fees from Uniqure (outside the submitted work, all fees go to the institution). WBW reports reimbursement payed to institution for investigator-initiated study from Janssen-Cilag, financial compensation payed to institution for multicenter study by GSK and catering of a symposium by Janssen-Cilag, all outside the submitted work. SCC is a member of the Editorial Board of PLOS Medicine. WML reports no conflicts of interest.

Background: The adipocyte-derived hormone leptin has been associated with altered blood coagulation in in vitro studies. However, it is unclear whether this association is relevant in vivo and to what extent this association is influenced by total body fat. Therefore, we aimed to examine the association between serum leptin and blood coagulation while taking total body fat into account in a population-based cohort study., Methods: We performed a cross-sectional analysis with baseline measurements of 5797 participants of the Netherlands Epidemiology of Obesity (NEO) study, a population-based cohort of middle-aged men and women. We examined associations between serum leptin concentration and coagulation factor concentrations and parameters of platelet activation in linear regression analyses. All analyses were adjusted for multiple covariates, including total body fat., Results: In multivariable adjusted analyses a 1 μg/L higher serum leptin concentration was associated with a 0.22 IU/dL (95% CI: 0.11, 0.32) higher FVIII concentration and a 0.20 IU/dL (95% CI: 0.14, 0.27) higher FIX concentration (3.5 IU/dL FVIII and 3.2 IU/dL FIX per SD leptin). Serum leptin concentration was not associated with FXI, fibrinogen, platelet count, mean platelet volume and platelet distribution width in multivariable adjusted analyses., Discussion: This study showed that serum leptin concentration was associated with higher concentrations of FVIII and FIX in an observational study, which could be clinically relevant., Competing Interests: Declaration of competing interest The authors state that they have no conflict of interest., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Many patients who used vitamin K antagonists (VKAs) for long-term prevention of thromboembolism are now actively switched to a direct oral anticoagulant (DOAC). Strict adherence to a DOAC is crucial for its success. However, therapy adherence and clinical factors that predict nonadherence are currently not well studied among patients who switched from a VKA to a DOAC., Methods: A questionnaire was developed and sent to 2920 former patients of 3 anticoagulation clinics in the Netherlands, who switched from a VKA to a DOAC between January 2016 and December 2017. Questions concerned demographics, treatment persistence, adherence, and the occurrence of bleeding or thromboembolic events on DOACs. To identify predictors for nonadherence, logistic regression models were used to estimate crude and age/sex-adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs)., Results: A total of 1399 questionnaires (response rate 48%) were used for analysis. DOAC treatment persistence (94%) and adherence (86%) rates were high. Several predictors of nonadherence were identified, including young age (OR, 5.9; 95% CI, 3.6-9.8 for <60 years compared to >75 years), low consultation frequency with a specialist (OR, 1.6; 95% CI, 1.1-2.2), a history of minor bleeding on DOACs (OR, 1.9; 95% CI, 1.3-2.8), and a twice-daily dosing regimen (OR, 1.9; 95% CI, 1.3-2.6)., Conclusions: Self-reported treatment persistence and adherence were high in our study population, and several predictors of nonadherence were identified. Factors that can be influenced (low consult frequency with medical specialist, daily dosing regimen) may be used to improve therapy adherence., (© 2020 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals, Inc on behalf of International Society on Thrombosis and Haemostasis.)

Background:  The benefit of periprocedural bridging with low-molecular-weight heparin (LMWH) in patients with atrial fibrillation has been contested by the publication of the BRIDGE trial., Objective:  This article determines whether publication of the BRIDGE trial has led to less bridging procedures and better patient outcomes (i.e., a composite of thromboembolism, major bleeding, and death) in patients undergoing invasive procedures at the Leiden Anticoagulation Clinic, the Netherlands., Methods:  We identified all procedures that required vitamin K antagonist interruption. Procedures were divided in a period before (2014-2016; 22 months) and after the publication of the BRIDGE trial (2016-2017; 22 months). Cumulative incidences 30 days postprocedure and relative risks of thromboembolic events, major bleeding, and mortality were calculated., Results:  A total of 4,892 and 4,237 eligible procedures were performed in 2014 to 2016 and 2016 to 2017, respectively. The cumulative incidence of thromboembolism was 0.5% in 2014 to 2016 compared with 0.3% in 2016 to 2017; adjusted odds ratio (OR) 0.60 (95% confidence interval [CI] 0.30-1.21). The cumulative incidence of major bleeding was 1.0% in the 2014 to 2016 period as compared with 1.3% in the 2016 to 2017 period; adjusted OR was 1.27 (95% CI 0.85-1.90). The adjusted OR of the composite endpoint was 1.05 (95% CI 0.74-1.48). The frequency of bridging with LMWH (14.8% in 2014-2016 vs. 16.6% in 2016-2017) as well as mean CHA 2 DS 2 -VASc scores of patients receiving bridging did not change after publication of the BRIDGE trial., Conclusion:  We showed that despite publication of the BRIDGE trial, the frequency of bridging with LMWH and patient outcomes regarding bleeding complications did not change., Competing Interests: None declared., (Georg Thieme Verlag KG Stuttgart · New York.)

Hypertension during pregnancy and preeclampsia are associated with increased arterial thrombotic risk in later life. Whether these complications are associated with risk of venous thromboembolism (VTE) on the short term after pregnancy and on the long term, that is, outside pregnancy, is largely unknown. We conducted a nationwide cohort study in women with at least 1 pregnancy and their first VTE risk by linking the Dutch perinatal registry (Perined) to anticoagulation clinics. We used Cox proportional hazard models to estimate hazard ratios (HRs) and corresponding 95% CI for VTE risk in women with hypertension during pregnancy, women with preeclampsia, compared with women with uncomplicated pregnancies (reference). A total of 1 919 918 women were followed for a median of 13.7 (interquartile range, 7.6-19.2) years for a total of 24 531 118 person-years in which 5759 first VTEs occurred; incidence rate: 2.3 (95% CI, 2.3-2.4) per 10 000 person-years. In the first pregnancy and 3-month postpartum period, VTE risk was higher in women with hypertension, HR, 2.0 (95% CI, 1.7-2.4), and highest among women with preeclampsia, HR, 7.8 (95% CI, 5.4-11.3), versus the reference group. On the long term, women with hypertension during pregnancy and preeclampsia had a higher VTE risk: HR, 1.5 (95% CI, 1.4-1.6) and HR, 2.1 (95% CI, 1.8-2.4), respectively, versus the reference group. When excluding events during pregnancy and postpartum, these HRs were 1.4 (95% CI, 1.3-1.5) and 1.6 (95% CI, 1.4-2.0), respectively. In conclusion, hypertension during pregnancy and preeclampsia are associated with an increased VTE risk during pregnancy and postpartum period and in the 13 years after.