Search

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: 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.)

Essentials The role of statins in hemostasis and venous thromboembolism (VTE) prophylaxis is not clear. This trial assessed whether rosuvastatin use affects thrombin generation in patients with VTE. Endogenous thrombin potential and peak were decreased by 10% and 5% with rosuvastatin therapy. These results provide basis for trials on the efficacy of statins in reducing recurrent VTE risk. SUMMARY: Background Statin therapy could form an alternative prophylactic treatment for venous thromboembolism (VTE) if statins are proven to downregulate hemostasis and prevent recurrent VTE, without increasing bleeding risk. Objectives The STAtins Reduce Thrombophilia (START) trial investigated whether statin affects coagulation in patients with prior VTE. Patients/methods After anticoagulation withdrawal, patients were randomized to rosuvastatin 20 mg day -1 for 4 weeks or no intervention. Plasma samples taken at baseline and at the end of the study were analyzed employing thrombin generation assay. Results and conclusions The study comprised 126 rosuvastatin users and 119 non-users. Mean age was 58 years, 61% were men, 49% had unprovoked VTE and 75% had cardiovascular (CV) risk factors. Endogenous thrombin potential (ETP) increased from baseline to end of study in non-statin users (mean 97.22 nm*min; 95% CI, 40.92-153.53) and decreased in rosuvastatin users (mean -24.94 nm*min; 95% CI, -71.81 to 21.93). The mean difference in ETP change between treatments was -120.24 nm*min (95% CI, -192.97 to -47.51), yielding a 10.4% ETP reduction by rosuvastatin. The thrombin peak increased in both non-statin (mean 20.69 nm; 95% CI, 9.80-31.58) and rosuvastatin users (mean 8.41 nm; 95% CI -0.86 to 17.69). The mean difference in peak change between treatments was -11.88 nm (95% CI, -26.11 to 2.35), yielding a 5% peak reduction by rosuvastatin. Other thrombin generation parameters did not change substantially. The reduction in ETP and peak by rosuvastatin was more pronounced in the subgroups of participants with CV risk factors and with unprovoked VTE. We conclude that rosuvastatin reduces thrombin generation potential in patients who had VTE., (© 2018 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals, Inc. on behalf of International Society on Thrombosis and Haemostasis.)

Aim: To study the effects of clinical and genetic factors on the phenprocoumon dose requirement in pediatric patients and to develop a dosing algorithm., Methods: Pediatric patients who used phenprocoumon were invited to participate in a retrospective follow-up study. Clinical information and genotypes of genetic variations in CYP2C9, VKORC1, CYP4F2, CYP2C18 and CYP3A4 were collected and tested with linear regression for association with phenprocoumon dose requirement., Results: Of the 41 patients included in the analysis, age, VKORC1, CYP2C9*2/*3 and CYP3A4*1B were statistically significantly associated with dose requirement, and together explained 80.4% of the variability in phenprocoumon dose requirement., Conclusion: Our study reveals that age and genetic variations explain a significant part of the variability in phenprocoumon dose requirement in pediatric patients.

Aims: Observational studies indicate that statins reduce the risk of recurrent venous thrombosis (VT). However, trials have not been performed and the mechanism is unknown. We aimed to determine whether statin therapy improves the coagulation profile in patients with prior VT., Methods and Results: Randomized clinical trial (NCT01613794). Patients were randomized to rosuvastatin 20 mg/day for 4 weeks or no intervention. Blood was drawn at baseline and at end of study. The primary outcome was factor (F) VIII:C. In total, five coagulation factors were measured: FVIII:C, von Willebrand factor:Ag, FVII:C, FXI:C, and D-dimer. Among 247 randomized participants, mean age was 58 years, 62% were women and 49% had unprovoked VT. For all tested coagulation factors, mean levels were clearly decreased at end of study in rosuvastatin users, whereas they hardly differed in non-statin users. Results were most consistent for FVIII:C where mean FVIII:C levels were 7.2 IU/dL [95% CI (confidence interval) 2.9-11.5] lower in rosuvastatin users, while among non-users, no change in FVIII:C was observed (mean difference -0.1; 95% CI -3.0 to 2.9). The mean age and sex adjusted difference in FVIII:C change was -6.7 IU/dL (95% CI -12.0 to -1.4) in rosuvastatin users vs. non-users. Subgroup analyses revealed that the decrease in coagulation factors by rosuvastatin was more pronounced in participants with unprovoked VT and in those with cardiovascular risk factors., Conclusion: Rosuvastatin 20 mg/day substantially improved the coagulation profile among patients with prior VT. These results suggest that statin therapy might be beneficial in patients at risk of recurrent VT.

Essentials The EU-PACT trial was used to investigate age on the interaction between coumarins and genotype. The results support the use of genotype-guided dosing for phenprocoumon in patients < 75 years. For patients ≥ 75 years the phenprocoumon algorithm should be revised and further tested. No influence of comorbidities and co-current drug use was found that could explain the differences., Summary: Background Age seemed to affect the interaction between coumarins and genotype in the acenocoumarol and phenprocoumon arm of the European Pharmacogenetics of Anticoagulant Therapy (EU-PACT) trial. Objectives To investigate the effect of genotype-guided dosing stratified by age and the potential factors causing a difference. Patients/Methods Data from the acenocoumarol/phenprocoumon arm of the EU-PACT trial were used. The percentages of time below the therapeutic range, time above the therapeutic range and time in the therapeutic range (TTR) during the initial 12 weeks of therapy were compared between the genotype-guided group and the control group among younger (< 75 years) and older (≥ 75 years) patients by the use of independent t-tests, and adjusted for sex, height, weight and co-medications by the use of linear regression. Results Among younger phenprocoumon users, TTR during the first 12 weeks in the genotype-guided group (n = 55) was 9.5% (95% confidence interval [CI] 1.3 to 17.8) higher than in the control group (n = 63), with a remarkably lower percentage of time above this range (difference: - 9.6%, 95% CI - 19.0 to - 0.2) and a similar time below this range. Older patients dosed by the genotype-guided algorithm (n = 24) spent more time above the range (difference: 27.5%, 95% CI 12.9 to 42.0). For acenocoumarol users, there were no significant differences between the genotype-guided and control groups for most outcomes, except for a lower percentage of time below the range among older patients. Conclusions The genotype-guided algorithm for phenprocoumon in the EU-PACT trial benefitted younger patients more, but for older patients the algorithm needs to be revised and tested in further research., (© 2016 International Society on Thrombosis and Haemostasis.)

Background: Risk scores for patients who are at high risk for major bleeding complications during treatment with vitamin K antagonists (VKAs) do not perform that well. BLEEDS was initiated to search for new biomarkers that predict bleeding in these patients., Objectives: To describe the outline and objectives of BLEEDS and to examine whether the study population is generalizable to other VKA treated populations., Methods: A cohort was created consisting of all patients starting VKA treatment at three Dutch anticoagulation clinics between January-2012 and July-2014. We stored leftover plasma and DNA following analysis of the INR., Results: Of 16,706 eligible patients, 16,570 (99%) were included in BLEEDS and plasma was stored from 13,779 patients (83%). Patients had a mean age of 70 years (SD 14), 8713 were male (53%). The most common VKA indications were atrial fibrillation (10,876 patients, 66%) and venous thrombosis (3920 patients, 24%). 326 Major bleeds occurred during 17,613 years of follow-up (incidence rate 1.85/100 person years, 95%CI 1.66-2.06). The risk for major bleeding was highest in the initial three months of VKA treatment and increased when the international normalized ratio increased. These results and characteristics are in concordance with results from other VKA treated populations., Conclusion: BLEEDS is generalizable to other VKA treated populations and will permit innovative and unbiased research of biomarkers that may predict major bleeding during VKA treatment., Competing Interests: The authors have declared that no competing interests exist.

Purpose: The purpose of the study is to determine the immediate and long-term effect of statins on coagulation in patients treated with vitamin K antagonists (VKAs)., Methods: We selected patients on VKAs of two Dutch anticoagulation clinics who initiated treatment with a statin between 2009 and 2013. Patients who initiated or stopped concomitant drugs that interact with VKAs or were hospitalised during follow-up were excluded. The VKA dosage (mg/day) after statin initiation was compared with the last VKA dosage before the statin was started. Immediate and long-term differences in VKA dosage (at 6 and 12 weeks) were calculated with a paired student t test., Results: Four hundred thirty-five phenprocoumon users (mean age 70 years, 60 % men) and 303 acenocoumarol users (mean age 69 years, 58 % men) were included. After start of statin use, the immediate phenprocoumon dosage was 0.02 mg/day (95 % CI, 0.00 to 0.03) lower. At 6 and 12 weeks, these phenprocoumon dosages were 0.03 (95 % CI, 0.01 to 0.05) and 0.07 mg/day (95 % CI, 0.04 to 0.09) lower as compared with the dosage before first statin use. In acenocoumarol users, VKA dosage was 0.04 mg/day (95%CI, 0.01 to 0.07) (immediate effect), 0.10 (95 % CI, 0.03 to 0.16) (at 6 weeks), and 0.11 mg/day (95 % CI, 0.04 to 0.18) (after 12 weeks) lower., Conclusions: Initiation of statin treatment was associated with an immediate and long-term minor although statistically significant decrease in VKA dosage in both phenprocoumon and acenocoumarol users, which suggests that statins may have anticoagulant properties., Competing Interests: Compliance with ethical standards Sources of funding N. van Rein was supported by Innovative Coagulation Diagnostics at the Center for Translational Molecular Medicine [grant number 01C-201] and W.M. Lijfering is a Postdoc of the Netherlands Heart Foundation [grant number 2011 T 12]. Conflict of interest The authors declare that they have no conflict of interest.

Patients receiving vitamin K-antagonists are monitored by regular assessment of the International Normalized Ratio (INR). There are two popular methods for therapeutic control of anticoagulation in patient groups: 1) Time in Therapeutic Range (TTR) assessed by linear interpolation of successive INR measurements; 2) the cross-sectional proportion (CSP) of all patients' last INRs within range. The purpose of the present study is to compare the two methods using data from 53 Dutch Thrombosis Centres and to develop a semi-quantitative model for TTR based on different types of INR change. Different groups of around 400,000 patients in four consecutive years were evaluated: patients in the induction phase, short-term, long-term, low-target range, high-target range, receiving either acenocoumarol or phenprocoumon, and performing self-management. Each Centre provided TTR and CSP results for each patient group. TTR and CSP were compared using the Wilcoxon signed-rank test. Separately, we analysed the relationship between consecutive INR results regarding in or out of range and their frequency of occurrence in patients of two different cohorts. Good correlation was observed between TTR and CSP (correlation coefficient 0.694-0.950 in low-target range). In long-term acenocoumarol patients (low-target range) the median TTR was significantly higher than CSP (80.0 % and 78.7 %, respectively; p<0.001). In long-term phenprocoumon patients (low-target range) there was no significant difference between median TTR (83.0 %) and median CSP (82.6 %). In conclusion, the correlation between TTR assessed by linear interpolation and CSP was good. TTR assessed by linear interpolation was higher than CSP in patients on acenocoumarol.

Unlabelled: Essentials Statins, especially rosuvastatin, may reduce venous thrombosis risk, but the mechanism is unclear. We performed a randomized trial investigating the effect of rosuvastatin on platelet reactivity. Thromboxane-A2 mediated platelet aggregation was measured before and after rosuvastatin therapy. Rosuvastatin did not inhibit thromboxane-mediated platelet aggregation in venous thrombosis patients., Summary: Background Statins may exert a protective effect against the risk of venous thrombosis (VT), but the mechanism is unclear. Objectives In this open-label, randomized clinical trial (www.clinicaltrials.gov NCT01613794), we aimed to determine the ex vivo effect of rosuvastatin on platelet reactivity in patients with a history of VT. Methods Platelet reactivity, in platelet reaction units (PRUs), was measured at baseline and after 28 days with VerifyNow, which uses arachidonic acid to determine thromboxane-mediated platelet aggregation, in 50 consecutive patients included in our study (25 receiving rosuvastatin and 25 without intervention). Results Forty-seven of 50 (94.0%) consecutively enrolled patients had two valid PRU measurements. The mean PRUs in rosuvastatin users were 609 at baseline and 613 at the end of the study (mean change 5; 95% confidence interval [CI] - 18 to 27). The mean PRUs in non-users were 620 at baseline and 618 at the end of the study (mean change - 2; 95% CI - 15 to 12). The mean difference in PRU change between users and non-users was 6 (95% CI - 20 to 33). After exclusion of patients who used antiplatelet medication, or had thrombocytopenia, similar results were obtained, i.e. no apparent effect of rosuvastatin on PRUs, with a mean difference in PRU change between users and non-users of - 1 (95% CI - 20 to 19). Conclusions Rosuvastatin does not affect platelet reactivity when arachidonic acid is used as an agonist in patients with a history of VT., (© 2016 International Society on Thrombosis and Haemostasis.)

Purpose To assess the correlation of intraocular retinoblastoma tumor size measured with magnetic resonance (MR) imaging in the prediction of histopathologically determined metastatic risk factors (postlaminar optic nerve invasion and massive choroidal invasion). Materials and Methods The ethics committee approved this retrospective multicenter study with a waiver of informed consent. The study population included 370 consecutive patients with retinoblastoma (375 eyes) who underwent baseline MR imaging, followed by primary enucleation from 1993 through 2014. Tumor sizes (maximum diameter and volume) were measured independently by two observers and correlated with histopathologic risk factors. Receiver operating characteristic curves were used to analyze the diagnostic accuracy of tumor size, and areas under the curve were calculated. Logistic regression analysis was performed to evaluate potential confounders. Results Receiver operating characteristic analysis of volume and diameter, respectively, yielded areas under the curve of 0.77 (95% confidence interval [CI]: 0.70, 0.85; P < .0001) and 0.78 (95% CI: 0.71, 0.85; P < .0001) for postlaminar optic nerve invasion (n = 375) and 0.67 (95% CI: 0.57, 0.77; P = .0020) and 0.70 (95% CI: 0.59, 0.80; P = .0004) for massive choroidal tumor invasion (n = 219). For the detection of co-occurring massive choroidal invasion and postlaminar optic nerve invasion (n = 219), volume and diameter showed areas under the curve of 0.81 (95% CI: 0.70, 0.91; P = .0032) and 0.83 (95% CI: 0.73, 0.93; P = .0016), respectively. Conclusion Intraocular tumor size shows a strong association with postlaminar optic nerve invasion and a moderate association with massive choroidal invasion. These findings provide diagnostic accuracy measures at different size cutoff levels, which could potentially be useful in a clinical setting, especially within the scope of the increasing use of eye-salvage treatment strategies. (©) RSNA, 2015 Online supplemental material is available for this article.

Statins are said to protect against a wide range of diseases. We studied to what extent potential bias influences the results of studies on beneficial side effects of statins. We selected 8,188 atrial fibrillation patients who started treatment with anticoagulants at the Leiden Anticoagulation Clinic in the Netherlands between 2003 and 2009 and experienced 1,683 minor and 451 major bleeds during 18,105 person-years of follow-up. Statins were associated with a risk reduction of 9% for bleeds (hazard ratio = 0.91, 95% confidence interval: 0.82, 1.00). Additionally, analyses were stratified by age, incident users (patients who started statins during follow-up, i.e., an inception cohort), and prevalent statin users (statin users at baseline), as restriction to incident users avoids overoptimistic risk estimates. After stratification, the protective associations disappeared or reversed (range of hazard ratios = 0.99-3.22), except for patients aged 75 years or older. This remaining association could be due to another bias as, according to guidelines, in the elderly, statins should be prescribed only to those with a reasonable life expectancy. This could have resulted in a comparison of fit statin users with less fit nonstatin users (healthy user effect). The apparent protective association of statins on bleeds may be due to bias. We recommend stratification by age and incident and prevalent statin use when studying associations of statins with disease outcomes to avoid overoptimistic risk estimates., (© The Author 2016. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: After diagnosis of cancer-associated VTE, guidelines recommend considering the continuation of anticoagulant treatment until the patient is cured of cancer, although the safety of stopping anticoagulant treatment after the patient is cured has never been evaluated., Methods: We conducted a cohort study in consecutive patients in whom cancer-associated VTE was diagnosed at the Leiden University Medical Center between January 2001 and January 2010 and monitored for the effect of cancer treatment, occurrence of recurrent VTE, major hemorrhage, and death., Results: Of the 358 patients with cancer-associated VTE, anticoagulant treatment was continued until the death of 207 patients. In another 12 patients anticoagulant treatment was continued because of an alternative indication despite their being cured of cancer. Anticoagulant treatment was stopped in 50 patients for reasons other than major hemorrhage despite active cancer, in 21 patients after major hemorrhage, and in 68 patients after they had been cured of cancer. Among these 68 patients, 10 patients received a diagnosis of symptomatic recurrent VTE during a cumulative follow-up of 311 years, resulting in an incidence rate of 3.2 per 100 patient-years (95% CI, 1.5-5.9). Seven of these 10 patients with recurrent VTE experienced a cancer relapse during follow-up. For the 50 patients who stopped anticoagulant treatment despite active cancer the recurrent VTE incidence rate was 19 per 100 patient-years (11 events during 59 years of follow-up; 95% CI, 9.3-33)., Conclusions: Our data support the recommendation to stop anticoagulant treatment of cancer-associated VTE in patients cured of cancer. A cancer relapse seems to be a strong risk factor for recurrent symptomatic VTE., (Copyright © 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Unlabelled: Essentials Minor bleeding is associated with subsequent major bleeding in patients treated with vitamin K antagonists. This study confirms that patients with minor bleeds have a 2.5-fold increased risk of major bleeds. A case-crossover analysis revealed that the increased risk is due to fixed underlying risk factors. Future research may unveil these unknown fixed risk factors and improve major bleeding risk scores., Summary: Background Patients who have a minor bleed during treatment with vitamin K antagonists (VKAs) have a 3-fold increased risk of subsequent major bleeding. The nature of the underlying risk factors is largely unknown. Objectives To indicate why patients with minor bleeds are at increased risk of subsequent major bleeds (e.g. are risk factors of a transient or a fixed nature). Methods Patients who started VKA treatment between 2003 and 2013 were included. Exposure was from the minor bleed until 3 months later. We used two analyses: a Cox model which we adjusted for several known risk factors, and a case-crossover (CCO) design, which corrects for all fixed risk factors (such as chronic diseases and genes) as patients are compared with themselves. The combination of both analyses gives insight into whether the association of minor with major bleeds is a result of fixed or transient risk factors. Results Out of 26 130 patients who were included and followed for '61 672 patient years', 7194 experienced a minor bleed and 913 a major bleed. The Cox model indicated that patients with minor bleeds had a 2.5-fold increased risk of experiencing subsequent major bleeding after adjustment for known risk factors, whereas the CCO gave risk estimates around unity (odds ratio, 0.9; 95% confidence interval, 0.5-1.5). Conclusions The combination of both analyses indicates that minor bleeds are markers for fixed and currently unknown risk factors for major bleeding events., (© 2016 International Society on Thrombosis and Haemostasis.)

Background: Point-of-care (POC) international normalized ratio (INR) monitoring by healthcare professionals could eliminate the need for venous blood sampling in non-self-monitoring (NSM) patients on vitamin K antagonists (VKA). However, few studies have investigated the impact of POC INR monitoring on the quality of treatment in these patients and real-world data on this issue are lacking., Objectives: To investigate the safety, efficacy and quality of anticoagulant control during POC INR monitoring as compared with laboratory INR monitoring in NSM patients., Methods: We performed a retrospective cohort study using data from the anticoagulation clinic of the Star-Medical Diagnostic Center (Rotterdam, the Netherlands). Patients who received treatment with VKA between 29 May 2012 and 29 May 2014 were eligible. Percentage of time in therapeutic range (TTR) and incidence rates of major clinical events (all-cause mortality, hospitalization, major bleeding and ischemic stroke) were compared for the year before and year after introduction of POC monitoring. Cox proportional hazard models were used to estimate hazard ratios and 95% confidence intervals for major clinical events between exposure groups., Results: In total, 1973 patients during the 1-year laboratory-monitoring observation period and 1959 patients during the 1-year POC-monitoring observation period were included. Median TTR was significantly lower during POC monitoring (77.9%; 95% CI, 67.2-87.4) than during laboratory INR monitoring (81.0%; 95% CI, 71.1-90.5). Adjusted hazard ratios for major clinical events were all around unity., Conclusions: Although associated with lower TTR, POC INR monitoring is a safe and effective alternative to laboratory INR monitoring in NSM patients on VKA., (© 2016 International Society on Thrombosis and Haemostasis.)

Unlabelled: ESSENTIALS: We developed a new algorithm to optimize vitamin K antagonist dose finding. Validation was by comparing actual dosing to algorithm predictions. Predicted and actual dosing of well performing centers were highly associated. The method is promising and should be tested in a randomized trial., Background: Oral vitamin K antagonists (VKAs) have a narrow therapeutic window and thus require frequent monitoring of its intensity by the international normalized ratio (INR). Improvement of VKA dosing defined as more time in therapeutic range (TTR) can reduce thrombotic disease and bleeding. Computerized decision support programs (CDSs) are used to optimize VKA dosing, but the effects are heterogeneous. CDSs significantly improve the proportion of time in the therapeutic INR range for initiation therapy but not the quality of anticoagulant management in an outpatient setting. One of the major problems of VKA dose finding is that the INR is a ratio and does not present linearity. We developed a new dose-finding algorithm, based on a novel bidirectional factor (BF). This BF is linear transformation of the nonlinear INR., Methods: We compared the outcomes of the new algorithm, called BF-N, with dose finding performed at three highly ranked Dutch anticoagulation centers, using both acenocoumarol and phenprocoumon., Results: The outcomes of the BF-N algorithm showed a linear correlation with VKA doses of the three centers (y = 1.001x, r(2) 0.999 for acenocoumarol and y = 0.999x, r(2) 0.999 for phenprocoumon), with a standard deviation of 3.83%. The rate of automated dosage proposals increased to 100%., Conclusion: The BF-N algorithm performs well in real-life settings and increases the rate of automated dosage proposals. The algorithm can be easily built into existing CDSs. Experienced staff remains necessary for complicated situations. The new algorithm needs to be evaluated in a prospective trial., (© 2015 International Society on Thrombosis and Haemostasis.)

Unlabelled: ESSENTIALS: Targeting of factor VIII values is a challenge during perioperative replacement therapy in hemophilia. This study aims to identify the extent and predictors of factor VIII underdosing and overdosing. Blood group O predicts underdosing and is associated with perioperative bleeding. To increase quality of care and cost-effectiveness of treatment, refining of dosing is obligatory., Background: Perioperative administration of factor VIII (FVIII) concentrate in hemophilia A may result in both underdosing and overdosing, leading to respectively a risk of bleeding complications and unnecessary costs., Objectives: This retrospective observational study aims to identify the extent and predictors of underdosing and overdosing in perioperative hemophilia A patients (FVIII levels < 0.05 IU mL(-1))., Patients and Methods: One hundred nineteen patients undergoing 198 elective, minor, or major surgical procedures were included (median age 40 years, median body weight 75 kg). Perioperative management was evaluated by quantification of perioperative infusion of FVIII concentrate and achieved FVIII levels. Predictors of underdosing and (excessive) overdosing were analyzed by logistic regression analysis. Excessive overdosing was defined as upper target level plus ≥ 0.20 IU mL(-1)., Results: Depending on postoperative day, 7-45% of achieved FVIII levels were under and 33-75% were above predefined target ranges as stated by national guidelines. A potential reduction of FVIII consumption of 44% would have been attained if FVIII levels had been maintained within target ranges. Blood group O and major surgery were predictive of underdosing (odds ratio [OR] 6.3, 95% confidence interval [CI] 2.7-14.9; OR 3.3, 95% CI 1.4-7.9). Blood group O patients had more bleeding complications in comparison to patients with blood group non-O (OR 2.02, 95% CI 1.00-4.09). Patients with blood group non-O were at higher risk of overdosing (OR 1.5, 95% CI 1.1-1.9). Additionally, patients treated with bolus infusions were at higher risk of excessive overdosing (OR 1.8, 95% CI 1.3-2.4)., Conclusion: Quality of care and cost-effectiveness can be improved by refining of dosing strategies based on individual patient characteristics such as blood group and mode of infusion., (© 2015 International Society on Thrombosis and Haemostasis.)

Introduction: Patients', parents' and providers' preferences with regard to medical innovations may have a major impact on their implementation., Aim: To evaluate barriers and facilitators for individualized pharmacokinetic (PK)-guided dosing of prophylaxis in haemophilia patients, parents of young patients, and treating professionals by discrete choice experiment (DCE) questionnaire., Patients/methods: The study population consisted of patients with haemophilia currently or previously on prophylactic treatment with factor concentrate (n = 114), parents of patients aged 12-18 years (n = 19) and haemophilia professionals (n = 91). DCE data analysis was performed, taking preference heterogeneity into account., Results: Overall, patients and parents, and especially professionals were inclined to opt for PK-guided dosing of prophylaxis. In addition, if bleeding was consequently reduced, more frequent infusions were acceptable. However, daily dosing remained an important barrier for all involved. 'Reduction of costs for society' was a facilitator for implementation in all groups., Conclusions: To achieve implementation of individualized PK-guided dosing of prophylaxis in haemophilia, reduction of bleeding risk and reduction of costs for society should be actively discussed as they are motivating for implementation; daily dosing is still reported to be a barrier for all groups. The knowledge of these preferences will enlarge support for this innovation, and aid in the drafting of implementable guidelines and information brochures for patients, parents and professionals., (© 2015 John Wiley & Sons Ltd.)

Introduction: Introducing point-of-care (POC) INR measurement to monitor anticoagulant therapy may be beneficial for both patients and anticoagulation clinics. However, agreement between POC and laboratory INR results is still unclear, especially at sub- and supratherapeutic levels. Therefore we investigated the analytical and clinical agreement between POC INR results of the Coaguchek XS and laboratory INR results of the STA-R Evolution., Materials and Methods: Paired POC and laboratory INR results were obtained and analyzed in 3257 patients aged 18-104 years between August 2008 and March 2014., Results: Mean difference between POC and laboratory results ranged from -0.18 (95%CI -0.20;-0.16) INR point for POC results 2.0-3.0, up to 1.14 (95%CI 0.87;1.42) INR point for POC results 7.1-8.0. In the therapeutic range (POC INR 2.0-4.0), mean difference between POC and laboratory results was -0.13 (95%CI -0.15;-0.12) INR point. At subtherapeutic (POC INR <2.0) and supratherapeutic (POC INR >4.0) INR levels, mean differences were -0.13 (95%CI -0.15;-0.11) and 0.72 (95%CI 0.63;0.80) INR point, respectively. Clinical agreement regarding therapeutic range was present in 92.0% (POC within range), 67.7% (POC below range) and 87.6% (POC above range) of the paired measurements. We observed ≥15% INR difference between the POC and laboratory result in 14.8% (POC INR 2.0-4.0), 17.0% (POC INR<2.0) and 47.8% (POC INR >4.0) of the paired measurements., Conclusions: POC and laboratory INR results were strongly correlated within the therapeutic range and differences between results become larger with increasing INR. Clinical disagreement between laboratory and POC results occurs often at both sub- and supratherapeutic INR levels., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Haemophilia A is an X-linked inherited, rare bleeding disorder, caused by a deficiency of coagulation factor VIII (FVIII). Previous studies in prophylactic dosing have demonstrated that FVIII consumption can be significantly reduced by individualising dosing based on combined analysis of individual pharmacokinetic (PK) profiling and population PK data (Bayesian analysis). So far, no studies have been performed that address perioperative concentrate consumption using iterative PK-guided dosing based on a PK population model. The "OPTI-CLOT" trial is an open-label, prospective, multicentre randomised controlled superiority trial (RCT), aiming to detect a 25 % difference in perioperative FVIII concentrate consumption with iterative Bayesian PK-guided dosing in comparison to the standard dosing procedure. Sixty haemophilia A patients ≥ 12 years of age, with FVIII plasma levels ≤ 0.05 IUml(-1) will be included requiring FVIII replacement therapy administered either by continuous or bolus infusion for an elective, low or medium risk surgical procedure. The proposed study aims to investigate a novel perioperative iterative PK-guided dosing strategy, based on a recently constructed perioperative PK population model. This model will potentially decrease underdosing and overdosing of clotting factor concentrate and is expected to overall reduce FVIII consumption by minimally 25 %. Moreover, participating hospitals will gain experience with PK-guided dosing, facilitating future implementation of this intervention which is expected to optimise current care and reduce costs of treatment.

Background: It has not been investigated how much the use of clinical factors in a dosing algorithm improves the percentage of time in therapeutic range (TTR). The present study aimed to compare the effect of dosing algorithms for acenocoumarol and phenprocoumon including clinical patient characteristics with standard care in the Netherlands., Setting: The pre-EU-PACT study, an observational study in the Netherlands, was used to obtain standard care data. Data from the Dutch patients in the EU-PACT trial (comparing the use of a clinical algorithm with and without genetic information) was used for the clinical dosing algorithm., Methods: For both acenocoumarol and phenprocoumon, the percentage of time in, below and above therapeutic International Normalized Ratio (INR) range during 12weeks after treatment initiation were assessed in both studies., Results: During the weeks 2-12, the clinical dosing algorithm of acenocoumarol (80 patients) led to a higher TTR (74.3% versus 68.0% in range 2.0-3.5, 95% Confidence interval [CI] difference: 0.5% to 11.8%), and a reduced percentage of time below INR 2 and above INR 3.5, compared with standard care (272 patients). For phenprocoumon, compared with standard care (484 patients), 80 patients treated by the dosing algorithm did not obtained a significantly higher TTR in range 2.0-3.5 or a lower percentage of time above 3.5, however, they spent more time with INR below 2., Conclusion: The use of a clinical dosing algorithm for acenocoumarol seemed to improve the quality of anticoagulation therapy during the treatment of initial 2-12 weeks. For phenprocoumon, there was no statistically difference in anticoagulation control., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Prospective studies on the relationship between course of cannabis use and clinical outcome in patients with non-affective psychotic disorders are inconclusive. The current study examined whether (1) persistent, recently started, discontinued and non-cannabis-using patients with a psychotic disorder differed with regard to illness outcome at 3-year follow-up, and (2) whether timing of cannabis discontinuation was associated with course of clinical outcome., Method: This 3-year follow-up study was part of a multi-center study in the Netherlands and Belgium (Genetic Risk and Outcome of Psychosis; GROUP). We used mixed-model analyses to investigate the association between pattern of cannabis use and symptoms, global functioning and psychotic relapse., Results: In our sample of 678 patients, we found persistent users to have more positive and general symptoms, worse global functioning and more psychotic relapses compared with non-users and discontinued users [Positive and Negative Syndrome Scale (PANSS) positive, p < 0.001; PANSS general, p < 0.001; Global Assessment of Functioning (GAF) symptoms, p = 0.017; GAF disability, p < 0.001; relapses, p = 0.038]. Patients who started using cannabis after study onset were characterized by worse functioning at baseline and showed an increase in general symptoms (including depression and anxiety) at the 3-year follow-up (p = 0.005). Timing of cannabis discontinuation was not associated with clinical outcome., Conclusions: These findings suggest that cannabis use in patients with a psychotic disorder has a long-lasting negative effect on illness outcome, particularly when persistent. Treatment should focus on discouraging cannabis use.

Background: Schizophrenia is highly comorbid with cannabis use disorders (CUDs), and this comorbidity is associated with an unfavourable course. Early onset or frequent cannabis use may influence brain structure. A key question is whether comorbid CUDs modulate brain morphology alterations associated with schizophrenia., Methods: We used surface-based analysis to measure the brain volume, cortical thickness and cortical surface area of a priori-defined brain regions (hippocampus, amygdala, thalamus, caudate, putamen, orbitofrontal cortex, anterior cingulate cortex, insula, parahippocampus and fusiform gyrus) in male patients with schizophrenia or related disorders with and without comorbid CUDs and matched healthy controls. Associations between age at onset and frequency of cannabis use with regional grey matter volume were explored., Results: We included 113 patients with (CUD, n = 80) and without (NCUD, n = 33) CUDs and 84 controls in our study. As expected, patients with schizophrenia (with or without a CUD) had smaller volumes of most brain regions (amygdala, putamen, insula, parahippocampus and fusiform gyrus) than healthy controls, and differences in cortical volume were mainly driven by cortical thinning. Compared with the NCUD group, the CUD group had a larger volume of the putamen, possibly driven by polysubstance use. No associations between age at onset and frequency of use with regional grey matter volumes were found., Limitations: We were unable to correct for possible confounding effects of smoking or antipsychotic medication., Conclusion: Patients with psychotic disorders and comorbid CUDs have larger putamen volumes than those without CUDs. Future studies should elaborate whether a large putamen represents a risk factor for the development of CUDs or whether (poly)substance use causes changes in putamen volume.

Objective: The HAS-BLED score enables a risk estimate of major bleeds in patients with atrial fibrillation on vitamin K-antagonists (VKA) treatment, but has not been validated for patients with venous thromboembolism (VTE). We analyzed whether the HAS-BLED score accurately identifies patients at high risk of major bleeds during VKA treatment for acute VTE., Methods: Medical records of 537 patients with acute VTE (primary diagnosis pulmonary embolism in 223, deep vein thrombosis in 314) starting VKA treatment between 2006-2007 were searched for items on the HAS-BLED score and the occurrence of major bleeds during the first 180 days of follow-up. The hazard ratio (HR) for the occurrence of major bleeds comparing non-high with high-risk patients as defined by a HAS-BLED score ≥ 3 points was calculated using Cox-regression analysis., Results: Major bleeds occurred in 11/537 patients (2.0%, 5.2/100 person years, 95% CI 2.8-9.2). Cumulative incidences of major bleeds were 1.3% (95% CI 0.1-2.5) in the non-high (HAS-BLED < 3) and 9.6% (95%CI 2.2-17.0) in the high-risk group (HAS-BLED ≥ 3), (p <0.0001 by Log-Rank test), with a HR of 8.7 (95% CI 2.7-28.4). Of the items in the HAS-BLED score, abnormal renal function (HR 10.8, 95% CI 1.9-61.7) and a history of bleeding events (HR 10.4, 95% CI 2.5-42.5) were independent predictors of major bleeds during follow-up., Conclusion: Acute VTE patients with a HAS-BLED score ≥ 3 points are at increased risk of major bleeding. These results warrant for correction of the potentially reversible risk factors for major bleeding and careful International Normalized Ratio monitoring in acute VTE patients with a high HAS-BLED score.

Background: Portable point-of-care (POC) instruments for determination of the whole blood prothrombin time (PT) have been available for the last three decades. Recently, two novel POC instruments for PT and International Normalized Ratio (INR) determination in whole blood have been manufactured. The purpose of this study was to compare INR values obtained with the novel instruments (microINR® and ProTime InRhythm™) to the INR determined with the international standard for thromboplastin rTF/09., Materials and Methods: In 60 patients treated with vitamin K-antagonists, venous whole blood was analysed with four different types of POC instruments including the novel ones. In the same patients, citrated plasma was analysed with the international standard rTF/09 and the manual tilt tube technique for clotting time determination. We assessed the bias of the INR read from the POC instruments relative to the international standard. To study the imprecision of the two novel POC instruments, duplicate INR determinations were performed., Results: The results obtained with the two novel POC instruments were positively correlated with those of the international standard rTF/09. However, there was a significant bias between INR read from the novel instruments and the INR determined with rTF/09 (P < 0.001). The mean bias was -13.7% (MicroINR) and -9.3% (InRhythm). The imprecision coefficient of variation in venous blood was 5.0% and 5.1%, respectively., Conclusion: The imprecision of the two novel instruments is acceptable with respect to the average within-subject variation of the INR. The accuracy of the systems is borderline and should be improved by the manufacturers., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Patients with a second venous thromboembolism generally receive anticoagulant treatment indefinitely, although it is known that the recurrence risk diminishes over time while the risk of hemorrhage persists with continued anticoagulation and increases with age. Based on these arguments and limited evidence for indefinitely prolonged treatment, the Dutch guidelines recommend considering treatment of a limited duration (i.e. 12 months) for a 'late' second venous thromboembolism, defined by a second venous thromboembolism diagnosed more than 1 year after discontinuing treatment for a first event. It is hypothesized that the risk of continued anticoagulation might outweigh the benefits in such circumstances. We evaluated this management in daily practice. Since 2003, limited duration of treatment was systematically considered at our hospital in consecutive patients, in whom we determined the recurrence risk. Of 131 patients with late second venous thromboembolism, 77 were treated for a limited duration, of whom 26 developed a symptomatic third venous thromboembolism thereafter during a cumulative follow-up of 277 years, resulting in an incidence rate of 9.4/100 patient-years (95% confidence interval: 6.1-14). The incidence rates in patients with unprovoked and provoked venous thromboembolism were 12/100 patient-years (95% confidence interval: 7.4-19) and 5.6/100 patient-years (95% confidence interval: 2.2-12), respectively [adjusted hazard ratio 2.8 (95% confidence interval: 1.1-7.2)]. The recurrence risk after treatment of limited duration for 'late' second venous thromboembolism exceeded the risk of hemorrhage associated with extended anticoagulation. Most patients may, therefore, be better served by treatment of indefinite duration, although the risk-benefit ratio of extended anticoagulation should be weighed for every patient., (Copyright© Ferrata Storti Foundation.)

Background: Vitamin K1 (VK1) reverses the effects of vitamin K antagonists (VKAs). The literature shows that the bioavailability from solutions might be higher than that from tablets, possibly resulting in different effects., Objectives: To compare the bioavailability and effect on the International Normalized Ratio (INR) of 5-mg VK1 tablets and solution in three randomized clinical trials., Methods and Results: The bioavailability was determined in a crossover trial with 25 healthy volunteers. VK1 plasma concentrations were assessed at 0, 2, 4, 5, 6, 8, 10 and 24 h, and the area under the curve was higher in the solution group than in the tablet group (mean difference 365 μg L(-1) h, 95% confidence interval [CI] 230-501, P < 0.0001). In the other two trials, the effects of both formulations on the INR were measured at 0, 24 and 48 h. In the second trial, on 72 patients on phenprocoumon with planned invasive procedures, both formulations were similarly effective, because all patients reached an INR of < 2.0, which was the primary endpoint. In the last trial, on 72 patients on phenprocoumon with an INR of 7.0-11.0, the INR decreased slightly more in the solution group (4.7, 95% CI 4.3-5.1) than in the tablet group (4.2, 95% CI 3.8-4.6). The solution group had a 3.3-fold increased likelihood (95% CI 0.7-15.1) of reaching an INR of < 2.0 at 48 h. Additionally, the increases in VK1 concentrations were similar (tablets, 3.2 μg L(-1) ; solution, 3.4 μg L(-1) ; P = 0.99) after 24 h., Conclusions: VK1 tablets are at least as clinically effective as the solution in countering VKAs., (© 2014 International Society on Thrombosis and Haemostasis.)

Background: Little is known about the effect of stimulant use (amphetamines, cocaine, ecstasy) on cognitive functioning in schizophrenia patients. The current study examined (1) whether recency and frequency of stimulant use is associated with cognitive functioning and (2) whether these associations differ between psychotic patients, their unaffected siblings and controls., Method: Participants completed a comprehensive cognitive test battery. Stimulant use was assessed by urinalysis and by the Composite International Diagnostic Interview (CIDI). Using random effects regression models, the main effects of Stimulant Use and the interaction with Diagnostic Status on cognitive functioning were assessed., Results: The interaction term between Stimulant Use and Diagnostic Status was not significant for any of the cognitive outcome variables, indicating similar effects of stimulant use in all three groups. Recent stimulant users showed more errors deficit in verbal learning in comparison to never users (Cohen's d = -0.60, p < 0.005). Lifetime frequent stimulant use was significantly associated with worse immediate and delayed verbal recall, working memory and acquired knowledge (Cohen's d = -0.22 to -0.29, p < 0.005). Lifetime infrequent stimulant use was not associated with significant cognitive alterations in comparison to never use., Conclusions: The presence of cognitive deficits associated with lifetime stimulant use is dependent on the frequency of use, with no observed deficits in infrequent users and modest negative effects in frequent users.

Background: Anticoagulant therapy with vitamin K antagonists (VKAs) is affected by interaction of the VKAs with a large number of other drugs. Although metformin is generally not considered to interact with VKAs, we observed a decrease in INR after starting metformin treatment in patients using the VKA phenprocoumon., Objectives: To investigate the influence of metformin use on the dosage of phenprocoumon and INR in stably anticoagulated patients., Patients: We used the database of the Anticoagulation Clinic Leiden for this study. In a population of 369 patients screened, 27 consecutive patients using phenprocoumon were prescribed metformin during the study period (1 January 2007 to 1 March 2009), without use of other concomitant medications or medical interventions that could influence the INR., Results: The mean phenprocoumon dosage increased from 2.13 to 2.37 mg per day within 6 weeks (mean increase, 0.23 mg; 95% CI, 0.12-0.34) and 2.49 mg per day within 3 months (mean increase, 0.36 mg; 95% CI, 0.24-0.48) after starting metformin. The mean INR decreased from 2.88 to 2.26 (mean decrease, 0.63; 95% CI, 0.41-0.85) within 6 weeks and 2.54 (mean decrease, 0.35; 95% CI, 0.24-0.48) within 3 months after starting metformin., Conclusions: This study shows that clinicians should be aware that metformin treatment may lead to an increased optimal dosage of phenprocoumon., (© 2014 International Society on Thrombosis and Haemostasis.)

Background: Observational evidence suggests that the use of a genotype-guided dosing algorithm may increase the effectiveness and safety of acenocoumarol and phenprocoumon therapy., Methods: We conducted two single-blind, randomized trials comparing a genotype-guided dosing algorithm that included clinical variables and genotyping for CYP2C9 and VKORC1 with a dosing algorithm that included only clinical variables, for the initiation of acenocoumarol or phenprocoumon treatment in patients with atrial fibrillation or venous thromboembolism. The primary outcome was the percentage of time in the target range for the international normalized ratio (INR; target range, 2.0 to 3.0) in the 12-week period after the initiation of therapy. Owing to low enrollment, the two trials were combined for analysis. The primary outcome was assessed in patients who remained in the trial for at least 10 weeks., Results: A total of 548 patients were enrolled (273 patients in the genotype-guided group and 275 in the control group). The follow-up was at least 10 weeks for 239 patients in the genotype-guided group and 245 in the control group. The percentage of time in the therapeutic INR range was 61.6% for patients receiving genotype-guided dosing and 60.2% for those receiving clinically guided dosing (P=0.52). There were no significant differences between the two groups for several secondary outcomes. The percentage of time in the therapeutic range during the first 4 weeks after the initiation of treatment in the two groups was 52.8% and 47.5% (P=0.02), respectively. There were no significant differences with respect to the incidence of bleeding or thromboembolic events., Conclusions: Genotype-guided dosing of acenocoumarol or phenprocoumon did not improve the percentage of time in the therapeutic INR range during the 12 weeks after the initiation of therapy. (Funded by the European Commission Seventh Framework Programme and others; EU-PACT ClinicalTrials.gov numbers, NCT01119261 and NCT01119274.).