Perioperative replacement therapy in haemophilia B: An appeal to "B" more precise.

INTRODUCTION: Haemophilia B is caused by a deficiency of coagulation factor IX (FIX) and characterized by bleeding in muscles and joints. In the perioperative setting, patients are treated with FIX replacement therapy to secure haemostasis. Targeting of specified FIX levels is challenging and requires frequent monitoring and adjustment of therapy. AIM: To evaluate perioperative management in haemophilia B, including monitoring of FIX infusions and observed FIX levels, whereby predictors of low and high FIX levels were assessed. METHODS: In this international multicentre study, haemophilia B patients with FIX < 0.05 IU mL-1 undergoing elective, minor or major surgical procedures between 2000 and 2015 were included. Data were collected on patient, surgical and treatment characteristics. Observed FIX levels were compared to target levels as recommended by guidelines. RESULTS: A total of 255 surgical procedures were performed in 118 patients (median age 40 years, median body weight 79 kg). Sixty percent of FIX levels within 24 hours of surgery were below target with a median difference of 0.22 IU mL-1 [IQR 0.12-0.36]; while >6 days after surgery, 59% of FIX levels were above target with a median difference of 0.19 IU mL-1 [IQR 0.10-0.39]. Clinically relevant bleeding complications (necessity of a second surgical intervention or red blood cell transfusion) occurred in 7 procedures (2.7%). CONCLUSION: This study demonstrates that targeting of FIX levels in the perioperative setting is complex and suboptimal, but although this bleeding is minimal. Alternative dosing strategies taking patient and surgical characteristics as well as pharmacokinetic principles into account may help to optimize and individualize treatment.

Facilitating the implementation of pharmacokinetic-guided dosing of prophylaxis in haemophilia care by discrete choice experiment.

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.

Statin use decreases coagulation in users of vitamin K antagonists.

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.

An ultrapure plasma-derived monoclonal antibody-purified factor IX concentrate (Nonafact®), results of phase III and IV clinical studies.

Nonafact(®), an ultrapure, monoclonal antibody-purified factor IX concentrate (FIX) was developed to minimize risk of thrombotic complications and viral transmission. To investigate the pharmacokinetics, efficacy and safety, phase III/IV studies were performed in the Netherlands and Poland from 1996 to 2007. The mean half-life, in vivo response and recovery of Nonafact(®) were 18.7 (SD 2.0) h, 1.1 (SD 0.2) IU dL(-1) per IU kg(-1) b.w. of FIX infused and 49% (SD 10%), respectively. Eleven surgical procedures were performed in eight patients. During two surgeries, both high-risk, blood loss was observed. No postoperative bleeding occurred. The in vivo recovery of FIX was higher than expected. In the phase III follow-up study, 26 previously treated patients (PTP) were included with a median follow-up of 1130 days. From the 1617 minor bleedings, 80.5% was stopped after a single infusion. In the phase IV study thirteen patients were treated for a median study period of 737 days. In the two follow-up studies the investigators rated the effect of Nonafact(®) as excellent/good in 95% of major bleedings. Surgeries for which Nonafact(®) was given prophylactically were without bleeding problems. In total more than 10 million units of Nonafact(®) were used during almost 120 person-years. Only one minor adverse event was reported. No inhibitors, viral transmissions and thrombogenic events occurred. In conclusion, Nonafact(®) is safe and provides excellent haemostasis in haemophilia B patients treated for spontaneous bleeding or undergoing surgical procedures. Due to the excellent in vivo recovery characteristic, treatment with Nonafact(®) is cost saving compared to other FIX products.

Major differences in clinical presentation, diagnosis and management of men and women with autosomal inherited bleeding disorders.

BACKGROUND: In recent years, more awareness is raised about sex-specific dilemmas in inherited bleeding disorders. However, no large studies have been performed to assess differences in diagnosis, bleeding phenotype and management of men and women with bleeding disorders. Therefore, we investigated sex differences in a large cohort of well-defined patients with autosomal inherited bleeding disorders (von Willebrand disease (VWD), rare bleeding disorders (RBDs) and congenital platelet defects (CPDs)). METHODS: We included patients from three nationwide cross-sectional studies on VWD, RBDs and CPDs in the Netherlands, respectively the WiN, RBiN and TiN study. In all studies a bleeding score (BS) was obtained, and patients filled in an extensive questionnaire on the management and burden of their disorder. FINDINGS: We included 1092 patients (834 VWD; 196 RBD; 62 CPD), of whom 665 (60.9%) were women. Women were more often referred because of a bleeding diathesis than men (47.9% vs 36.6%, p = 0.002). Age of first bleeding was similar between men and women, respectively 8.9 ± 13.6 (mean ±sd) years and 10.6 ± 11.3 years (p = 0.075). However, the diagnostic delay, which was defined as time from first bleeding to diagnosis, was longer in women (11.6 ± 16.4 years) than men (7.7 ± 16.6 years, p = 0.002). Similar results were found when patients referred for bleeding were analyzed separately. Of women aging 12 years or older, 469 (77.1%) had received treatment because of sex-specific bleeding. INTERPRETATION: Women with autosomal inherited bleeding disorders are more often referred for bleeding, have a longer diagnostic delay, and often require treatment because of sex-specific bleeding. FUNDING: The WiN study was supported (in part) by research funding from the Dutch Hemophilia Foundation (Stichting Haemophilia), Shire (Takeda), and CSL Behring (unrestricted grant).

[The interaction between anticoagulant therapy with vitamin K-antagonists and treatment with antibiotics: a practical recommendation]. / De interactie tussen antistollingstherapie met vitamine K-antagonisten en behandeling met antibiotica: een praktische aanbeveling.

--In users of vitamin K-antagonists (VKA), antibiotics can lead to excessive anticoagulation. --It is unclear what the optimal policy is for prevention of an excessive anticoagulant effect during use of antibiotics. --This article describes the increased sensitivity to VKA during use of antibiotics, and also provides a practical recommendation for the correct method for use of antibiotics in combination with VKA treatment. --During use of antibiotics for more than one day, the prothrombin time-'international normalized ratio' (PTT-INR) must be checked both after 3 and after 7 days, and the dose of VKA must be adapted if necessary. --Use of co-trimoxazole for more than one day should, if possible, be avoided.

Characteristics and quality of oral anticoagulation treatment in pediatric patients in the Netherlands based on the CAPS cohort.

Essentials The knowledge of quality and safety of acenocoumarol and phenprocoumon use in children is limited. We used data from a multicenter retrospective follow-up study in children in the Netherlands. The quality of anticoagulation control in the first month of use was low, but improved thereafter. No thromboembolic events occurred, however bleeding events occurred in 1-3 out of 10 patients. SUMMARY: Background The use of vitamin-K antagonists in pediatric patients is rare and information on the quality and safety of treatment with acenocoumarol and phenprocoumon is limited. Objectives To assess the quality, safety and effectiveness during the first year of acenocoumarol and phenprocoumon treatment in pediatric patients in the Netherlands. Methods The Children Anticoagulation and Pharmacogenetics Study (CAPS) was designed as a multicenter retrospective follow-up study. Patients who used acenocoumarol or phenprocoumon at an age of ≤ 18 years, were selected from four pediatric hospitals and one anticoagulation clinic in the Netherlands. The quality of treatment was assessed by calculating the percentage of time in therapeutic INR range (TTR) for the first month and for every 3 months of use during the first year of treatment. Effectiveness and safety were assessed by the number of thromboembolic and bleeding events. Results In total, 213 patients participated, of whom 187 (155 acenocoumarol; 32 phenprocoumon) were included in this analysis. The mean TTR was 47.0% and 51.4% in the first month of use for acenocoumarol and phenprocoumon, respectively. After the first 3 months the mean TTR for both VKAs was above 64%. In 14.6% (acenocoumarol) and 31.3% (phenprocoumon) of the patients a bleeding event occurred during the first year of treatment; no thromboembolic events were reported. Conclusions The quality of anticoagulation treatment was low during the first month of use and leaves room for improvement. After the first month it increased to an acceptable level. However, bleeding events occurred frequently during the first year.

Population pharmacokinetics of factor IX in hemophilia B patients undergoing surgery.

Essentials Factor IX (FIX) dosing using body weight frequently results in under and overdosing during surgery. We aimed to establish a population pharmacokinetic (PK) model describing the perioperative FIX levels. Population PK parameter values for clearance and V1 were 284 mL h-170 kg-1 and 5450 mL70 kg-1. Perioperative PK parameters differ from those during non-surgical prophylactic treatment. SUMMARY: Background Hemophilia B is a bleeding disorder characterized by a deficiency of coagulation factor IX (FIX). In the perioperative setting, patients receive FIX concentrates to ensure hemostasis. Although FIX is usually dosed according to bodyweight, under- and overdosing occurs frequently during surgery. Aim The objective was to quantify and explain the interpatient variability of perioperatively administered plasma-derived (pd) and recombinant (r) FIX concentrates. Methods Data were collected from 118 patients (median age, 40 years [range, 0.2-90]; weight, 79 kg [range, 5.3-132]) with moderate (28%) or severe hemophilia B (72%), undergoing 255 surgical procedures. Population pharmacokinetic (PK) parameters were estimated using nonlinear mixed-effect modeling in NONMEM. Results Measured perioperative FIX level vs. time profiles were adequately described using a three-compartment PK model. For a typical 34-year-old patient receiving rFIX, clearance (CL), intercompartmental clearance (Q2, Q3), distribution volume of the central compartment (V1) and peripheral compartments (V2, V3) plus interpatient variability (%CV) were: CL, 284 mL h-170 kg-1 (18%); V1, 5450 mL70 kg-1 (19%); Q2, 110 mL h-170 kg-1; V2, 4800 mL70 kg-1; Q3, 1610 mL h-170 kg-1; V3, 2040 mL70 kg-1. From 0.2 years, CL and V1 decreased 0.89% and 1.15% per year, respectively, until the age of 34 years. Patients receiving pdFIX exhibited a lower CL (11%) and V1 (17%) than patients receiving rFIX. Interpatient variability was successfully quantified and explained. Conclusions The estimated perioperative PK parameters of both pdFIX and rFIX are different from those reported for prophylactic treatment. The developed model may be used to apply PK-guided dosing of FIX concentrates during surgery.

The pediatric acenocoumarol dosing algorithm: the Children Anticoagulation and Pharmacogenetics Study.

Essentials A pediatric pharmacogenetic dosing algorithm for acenocoumarol has not yet been developed. We conducted a multicenter retrospective follow-up study in children in the Netherlands. Body surface area and indication explained 45.0% of the variability in dose requirement. Adding the genotypes of VKORC1, CYP2C9 and CYP2C18 to the algorithm increased this to 61.8%. SUMMARY: Background The large variability in dose requirement of vitamin K antagonists is well known. For warfarin, pediatric dosing algorithms have been developed to predict the correct dose for a patient; however, this is not the case for acenocoumarol. Objectives To develop dosing algorithms for pediatric patients receiving acenocoumarol with and without genetic information. Methods The Children Anticoagulation and Pharmacogenetics Study was designed as a multicenter retrospective follow-up study in Dutch anticoagulation clinics and children's hospitals. Pediatric patients who used acenocoumarol between 1995 and 2014 were selected for inclusion. Clinical information and saliva samples for genotyping of the genes encoding cytochrome P450 (CYP) 2C9, vitamin K epoxide reductase complex subunit 1 (VKORC1), CYP4F2, CYP2C18 and CYP3A4 were collected. Linear regression was used to analyze their association with the log mean stable dose. A stable period was defined as three or more consecutive International Normalized Ratio measurements within the therapeutic range over a period of ≥ 3 weeks. Results In total, 175 patients were included in the study, of whom 86 had a stable period and no missing clinical information (clinical cohort; median age 8.9 years, and 49% female). For 80 of these 86 patients, genetic information was also available (genetic cohort). The clinical algorithm, containing body surface area and indication, explained 45.0% of the variability in dose requirement of acenocoumarol. After addition of the VKORC1, CYP2C9, and CYP2C18 genotypes to the algorithm, this increased to 61.8%. Conclusions These findings show that clinical factors had the largest impact on the required dose of acenocoumarol in pediatric patients. Nevertheless, genetic factors, and especially VKORC1, also explained a significant part of the variability.

VKORC1 and CYP2C9 genotypes and phenprocoumon anticoagulation status: interaction between both genotypes affects dose requirement.

In a prospective follow-up study of the effects of VKORC1 and CYP2C9 genotypes on the anticoagulation status of patients, we assessed the CYP2C9 and the VKORC1 C1173T genotypes of patients during the initial 6 months of phenprocoumon treatment. We used linear regression models and Cox proportional hazard models to determine the effects of the VKORC1 and CYP2C9 genotypes on phenprocoumon dose requirements, overanticoagulation, and time to achieve stability. Allele frequencies of interest within the cohort (N=281) were 40.8% VKORC1 T-1173, 12.8% CYP2C9*2, and 6.9% CYP2C9*3. In patients with the VKORC1 CC genotype, carriers of a CYP2C9 polymorphism needed dosages that were nearly 30% lower than those for CYP2C9*1/*1 patients (P<0.001). In patients with a VKORC1 polymorphism, differences between carriers of a CYP2C9 polymorphism and CYP2C9*1/*1 were far smaller and largely not statistically significant. A larger part of the variability in dose requirement was explained by the VKORC1 genotype than by the CYP2C9 genotype (28.7% and 7.2%, respectively). Carriers of a combination of a CYP2C9 polymorphism and a VKORC1 polymorphism had a strongly increased risk of severe overanticoagulation (hazard ratio (HR) 7.20, P=0.002). Only carriers of a CYP2C9*2 allele had a decreased chance to achieve stability compared to CYP2C9*1/*1 patients (HR 0.61, P=0.004). In conclusion, the VKORC1 genotype modifies the effect of the CYP2C9 genotype on phenprocoumon dose requirements. A combination of polymorphisms of both genotypes is associated with a strongly increased risk of overanticoagulation, whereas delayed stabilization is mainly associated with the CYP2C9 genotype.

Daily vitamin K supplementation improves anticoagulant stability.

BACKGROUND: One of the causes of unstable anticoagulant control in patients using vitamin K antagonists is a fluctuating intake of vitamin K. Research suggests that patients with a low dietary intake of vitamin K have a less stable anticoagulant control than patients with a higher intake. OBJECTIVES: To study whether supplementation with a low daily dose of vitamin K improves anticoagulant control. METHODS: We performed a double-blind, randomized, placebo-controlled trial. 200 patients of the Leiden anticoagulation clinic, who used the vitamin K antagonist phenprocoumon, were randomized to receive either adjusted-dose phenprocoumon and 100 mug vitamin K once daily or adjusted-dose phenprocoumon and a placebo. Treatment duration was 24 weeks. The primary outcome was the percentage of time the International Normalized Ratio was within the therapeutic range. RESULTS: The time in the therapeutic range was 85.5% in the placebo group and 89.5% in the vitamin K group (adjusted difference 3.6%; 95% CI -0.8% to 8.0%). The time below the therapeutic range was 3.1% in the placebo group and 2.1% in the vitamin K group (adjusted difference -0.7%; 95% CI -2.5% to 1.1%) and the time above the therapeutic range was 11.4% in the placebo group and 8.5% in the vitamin K group (adjusted difference -2.9%; 95% CI -6.9% to 1.1%). The relative risk (RR) of a maximal stability in the vitamin K group compared to the placebo group was 1.8 (95%, CI 1.1-2.7). CONCLUSION: Supplementation of vitamin K antagonists with 100 mug vitamin K improves stability of anticoagulant therapy. Because the risk of side effects is inversely related to anticoagulant stability, such an improvement is likely to reduce the number of bleeding and thrombotic events.

The quality of oral anticoagulant therapy and recurrent venous thrombotic events in the Leiden Thrombophilia Study.

BACKGROUND: The International Normalized Ratio (INR) target range is a relatively narrow range in which the efficacy of oral anticoagulant treatment, i.e. prevention of extension and recurrence of thrombosis, is balanced with the risk of hemorrhagic complications. Over the years, different INR target ranges have been implemented for individual indications, depending on their thrombotic potential. In most of the studies defining these INR targets, the treatment of the patients was aimed at a certain INR range, but in the analysis no account was taken of the time that the patients spent within this range in reality. METHODS: The Leiden Thrombophilia Study (LETS) is a population-based case-control study on risk factors for venous thrombosis, in which many genetic and acquired factors have been investigated. Our aim was to investigate the effect of the quality of the oral anticoagulant therapy for the initial venous thrombosis and its relationship with recurrence of thrombosis. Quality of anticoagulation was defined as the time spent at various INR levels during treatment, and we focused on the effect of sustained intensities above a certain INR in preventing recurrences later on. RESULTS: Two hundred and sixty-six patients with a total follow-up of 2495 patient-years were studied. The mean duration of the initial anticoagulant therapy was 194.5 days (range 48-4671). During follow-up, 58 recurrences were diagnosed (cumulative recurrence rate of 21.8% over 9 years). The mean INR during initial therapy was 2.90, with 90.3% [95% confidence interval (CI) 88.4-92.3%] of the time being spent above an INR of 2.0, and 39.1% (95% CI 35.5-42.7%) above an INR of 3.0. Patients who spent more time below the target range, or who had a shorter duration of anticoagulation, did not experience a higher risk of recurrence after the initial period of anticoagulation had passed. CONCLUSION: Provided that oral anticoagulant treatment is adequately managed, according to international guidelines, recurrent thrombosis cannot be ascribed to variation in the primary treatment. Further attempts to reduce the risk of recurrence should therefore be aimed at identifying other explanatory factors, and subsequently fine-tuning the target ranges.

Improved control of oral anticoagulant dosing: a randomized controlled trial comparing two computer algorithms.

BACKGROUND: Efforts to improve dosing quality in oral anticoagulant control include the use of computer algorithms. As current algorithms are simplistic and give dosage proposals in a small fraction of patients, we developed an algorithm based on principles of system and control engineering that gives proposals in nearly all patients. OBJECTIVE: To evaluate the new algorithm in clinical practice. PATIENTS AND METHODS: We conducted a double-blind randomized controlled trial among 712 patients with an indication for long-term anticoagulant treatment at the Leiden Anticoagulation Clinic. We compared oral anticoagulant dosing supported by the new algorithm (ICAD) with the standard algorithm (TRODIS). RESULTS: The percentage of time spent in the therapeutic range was similar for the new and standard algorithm groups, 79.8% vs. 80.2% (difference 0.4%, 95% CI: -1.7-2.6%). The new algorithm produced a dosage proposal in 97.5% of visits, and the standard algorithm in 60.8% (difference 36.7%, 95% CI: 35.4-38.0%). Of proposals of the new algorithm, 79.3% were accepted by the physician vs. 90.9% for the standard algorithm (difference 11.6%, 95% CI: 10.2-13.0%). This implies that the new algorithm gave an acceptable proposal in 77.4% of all patient visits vs. 55.3% for the standard algorithm (difference 22.1%, 95% CI 20.4-23.8%). CONCLUSIONS: Substantially more dosage proposals were generated and accepted with the new than with the standard algorithm, and the new algorithm will therefore improve the efficiency of anticoagulant monitoring without loss of quality.

Relationship between neighborhood socioeconomic status and venous thromboembolism: results from a population-based study.

Essentials Literature on socioeconomic status (SES) and incidence of venous thromboembolism (VTE) is scarce. We assessed neighborhood SES with VTE risk in a population of over 1.4 million inhabitants. Higher neighborhood SES was associated with lower incidence of VTE. These findings are helpful to inform policy and resource allocation in health systems. SUMMARY: Background The association between socioeconomic status and arterial cardiovascular disease is well established. However, despite its high burden of disability-adjusted life years, little research has been carried out to determine whether socioeconomic status is associated with venous thromboembolism. Objective To determine if neighborhood socioeconomic status is associated with venous thromboembolism in a population-based study from the Netherlands. Methods We identified all patients aged 15 years and older with a first event of venous thromboembolism from inhabitants who lived in the urban districts of The Hague, Leiden and Utrecht in the Netherlands in 2008-2012. Neighborhood socioeconomic status was based on the status score, which combines educational level, income and unemployment on a four-digit postal code level. Incidence rate ratios of venous thromboembolism were calculated for different levels of neighborhood socioeconomic status, with adjustments for age and sex. Results A total of 7373 patients with a first venous thromboembolism (median age 61 years; 50% deep vein thrombosis) were identified among more than 1.4 million inhabitants. Higher neighborhood SES was associated with lower incidence of VTE. In the two highest status score groups (i.e. the 95-99th and > 99th percentile), the adjusted incidence rate ratios were 0.91 (95% confidence interval [CI], 0.84-1.00) and 0.80 (95% CI, 0.69-0.93), respectively, compared with the reference status score group (i.e. 30-70th percentile). Conclusions High neighborhood socioeconomic status is associated with a lower risk of first venous thromboembolism.

Age-stratified outcome of a genotype-guided dosing algorithm for acenocoumarol and phenprocoumon.

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.

Major bleeding risks of different low-molecular-weight heparin agents: a cohort study in 12 934 patients treated for acute venous thrombosis.

Essentials Low-molecular-weight-heparins (LMWH) kinetics differ which may result in different bleeding risks. A cohort of 12 934 venous thrombosis patients on LMWH was followed until major bleeding. The absolute major bleeding risk was low among patients registered at the anticoagulation clinic. Once-daily dosing was associated with a lower bleeding risk as compared with twice-daily. SUMMARY: Background Low-molecular-weight heparins (LMWHs) are considered members of a class of drugs with similar anticoagulant properties. However, pharmacodynamics and pharmacokinetics between LMWHs differ, which may result in different bleeding risks. As these agents are used by many patients, small differences may lead to a large effect on numbers of major bleeding events. Objectives To determine major bleeding risks for different LMWH agents and dosing schedules. Methods A cohort of acute venous thrombosis patients from four anticoagulation clinics who used an LMWH and a vitamin K antagonist were followed until they ceased LMWH treatment or until major bleeding. Exposures were classified according to different types of LMWHs and for b.i.d. and o.d. use. Cumulative incidences for major bleeding per 1000 patients and risk ratios were calculated and adjusted for study center. Results The study comprised 12 934 patients with a mean age of 59 years; 6218 (48%) were men. The cumulative incidence of major bleeding was 2.5 per 1000 patients (95% confidence interval [CI], 1.7-3.5). Enoxaparin b.i.d. or o.d. was associated with a relative bleeding risk of 1.7 (95% CI, 0.2-17.5) compared with nadroparin o.d. In addition, a nadroparin b.i.d. dosing schedule was associated with a 2.0-fold increased major bleeding risk (95% CI, 0.8-5.1) as compared with a nadroparin o.d. dosing schedule. Conclusions Absolute major bleeding rates were low for all LMWH agents and dosing schedules in a large unselected cohort. Nevertheless, twice-daily dosing with nadroparin appeared to be associated with an increased major bleeding risk as compared with once-daily dosing, as also suggested in a meta-analysis of controlled clinical trials.

Incidence of venous thrombosis in a large cohort of 66,329 cancer patients: results of a record linkage study.

BACKGROUND: The incidence of venous thrombosis (VT) for cancer patients is increased compared with patients without cancer, but estimations of the incidence for different types of cancer have rarely been made because of the low incidence of various types of cancer. Large registries offer an opportunity to study the risk of VT in large cohorts of cancer patients, which is essential in decisions on prophylactic anti-coagulant treatment. METHODS: This cohort study estimates the incidence of VT in cancer patients by using record linkage of a Cancer Registry and an Anticoagulation Clinic database in the Netherlands. Cumulative incidences in patients with different types of malignancies were estimated. We calculated relative risks (RRs) in relation to the presence of distant metastases and treatment. RESULTS: Tumors of the bone, ovary, brain, and pancreas are associated with the highest incidence of VT (37.7, 32.6, 32.1, and 22.7/1000/0.5 year). Patients with distant metastases had a 1.9-fold increased risk [RRadj: 1.9; 95% confidence interval (CI): 1.6-2.3]. Chemotherapy leads to a 2.2-fold increased risk (RR(adj): 2.2; 95% CI: 1.8-2.7) and hormonal therapy leads to a 1.6-fold increased risk (RRadj: 1.6; 95% CI: 1.3-2.1) compared with patients not using these treatment modalities. Patients with radiotherapy or surgery did not have an increased risk. CONCLUSIONS: We compared the overall incidences of VT in the first half year in our study to the risk of major bleeding as described in the literature. For patients with distant metastases, for several types of cancer, prophylactic anti-thrombotic treatment could be beneficial.

Thalidomide as treatment for digestive tract angiodysplasias.

An 80-year-old man with von Willebrand's disease was admitted with severe melaena. Despite suppletion with von Willebrand concentrate he continued to be dependent on blood transfusions. Endoscopic examination did not show a bleeding focus. Video capsule endoscopy showed active bleeding from angiodysplasias in the proximal section of the small intestine. Ultimately, treatment with thalidomide was initiated at a dose of 100 mg/day. Soon after starting treatment his stools became normal and his haemoglobin level stabilised. No bleeding problems occurred for 11 months, after which the thalidomide treatment was stopped because of the potential side effects. Two months later he again developed melaena and treatment with thalidomide was restarted with a successful outcome. Trying to lower the dose to 50 mg resulted in rebleeding after three months with stabilisation after increasing the dose to 100 mg again. Monotherapy with thalidomide improves the clinical picture but may not be sufficient in the long term. Additional therapy, such as argon plasma coagulation or the use of the novel drug lenalidomide, might be necessary.

Optimization of vitamin K antagonist drug dose finding by replacement of the international normalized ratio by a bidirectional factor: validation of a new algorithm.

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.