Validation of a perioperative population factor VIII pharmacokinetic model with a large cohort of pediatric hemophilia a patients.

AIMS: Population pharmacokinetic (PK) models are increasingly applied to perform individualized dosing of factor VIII (FVIII) concentrates in haemophilia A patients. To guarantee accurate performance of a population PK model in dose individualization, validation studies are of importance. However, external validation of population PK models requires independent data sets and is, therefore, seldomly performed. Therefore, this study aimed to validate a previously published population PK model for FVIII concentrates administrated perioperatively. METHODS: A previously published population PK model for FVIII concentrate during surgery was validated using independent data from 87 children with severe haemophilia A with a median (range) age of 2.6 years (0.03-15.2) and body weight of 14 kg (4-57). First, the predictive performance of the previous model was evaluated with MAP Bayesian analysis using NONMEM v7.4. Subsequently, the model parameters were (re)estimated using a combined dataset consisting of the previous modelling data and the data available for the external validation. RESULTS: The previous model underpredicted the measured FVIII levels with a median of 0.17 IU mL-1 . Combining the new, independent and original data, a dataset comprising 206 patients with a mean age of 7.8 years (0.03-77.6) and body weight of 30 kg (4-111) was obtained. Population PK modelling provided estimates for CL, V1, V2, and Q: 171 mL h-1  68 kg-1 , 2930 mL 68 kg-1 , 1810 mL 68 kg-1 , and 172 mL h-1  68 kg-1 , respectively. This model adequately described all collected FVIII levels, with a slight median overprediction of 0.02 IU mL-1 . CONCLUSIONS: This study emphasizes the importance of external validation of population PK models using real-life data.

Dosing of factor VIII concentrate by ideal body weight is more accurate in overweight and obese haemophilia A patients.

AIMS: Under- and, especially, overdosing of replacement therapy in haemophilia A patients may be prevented by application of other morphometric variables than body weight (BW) to dose factor VIII (FVIII) concentrates. Therefore, we aimed to investigate which morphometric variables best describe interindividual variability (IIV) of FVIII concentrate pharmacokinetic (PK) parameters. METHODS: PK profiling was performed by measuring 3 FVIII levels after a standardized dose of 50 IU kg-1 FVIII concentrate. A population PK model was constructed, in which IIV for clearance (CL) and central volume of distribution (V1) was quantified. Relationships between CL, V1 and 5 morphometric variables (BW, ideal BW [IBW], lean BW, adjusted BW, and body mass index [BMI]) were evaluated in normal weight (BMI < 25 kg m-2 ), overweight (BMI 25-30 kg m-2 ) and obese haemophilia A patients (BMI > 30 kg m-2 ). RESULTS: In total, 57 haemophilia A patients (FVIII≤0.05 IU mL-1 ) were included with median BW of 83 kg (range: 53-133) and median age of 48 years (range: 18-77). IBW best explained observed variability between patients, as IIV for CL and V1 was reduced from 45.1 to 37.6 and 26.% to 14.1%, respectively. CL, V1 and half-life were similar for all BMI categories. The national recommended dosing schedule did not result in adequate trough levels, both in case of dosing based on BW and IBW. However, dosing based on IBW prevented unnecessary high FVIII peaks. CONCLUSION: IBW is the most suitable morphometric variable to explain interindividual FVIII PK variability and is more appropriate to dose overweight and obese patients.

Adherence to direct oral anticoagulant treatment for atrial fibrillation in the Netherlands: A surveillance study.

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.

Rosuvastatin use increases plasma fibrinolytic potential: a randomised clinical trial.

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.

Quality performance for indirect Xa inhibitor monitoring in patients using international external quality data.

Objectives Chromogenic anti-activated factor X (FXa) assays are currently the "gold standard" for monitoring indirect anticoagulants. However, anti-FXa has been shown to vary according to the choice of reagents. In the present study, the performance of anti-FXa measurement was evaluated in order to gain more insight into the clinical applications. Furthermore, the longitudinal coefficient of variation (CV) was studied to investigate whether there is improvement over time. Methods Laboratory tests results were evaluated for samples spiked with unfractionated heparin (UFH), low-molecular-weight-heparin (LMWH), fondaparinux and danaparoid sodium. External quality assessment (EQA) data from multiple years were used from more than 100 laboratories. Results Comparison of the results for all methods showed significant differences in measured values between the frequently used methods (ANOVA: p < 0.001). The largest differences were observed for LMWH and UFH measurements. These differences may be caused by differences in method composition, such as the addition of dextran sulphate. Substantial interlaboratory variation in anti-FXa monitoring was observed for all parameters, particularly at low concentrations. Our results showed that below 0.35 IU/mL, the CVs for UFH and LMWH increase dramatically and results below this limit should be used with caution. Conclusions Our study demonstrates that the choice of the anti-FXa method is particularly important for UFH and LMWH measurement. The variation in measurements may have an effect on clinical implications, such as therapeutic ranges. Furthermore, the longitudinal EQA data demonstrated a constant performance and, in at least 50% of the cases, improvement in the CV% of the anti-Xa results over time.

Accuracy assessment of consecutive test strip lots for whole blood INR point-of-care instruments: clarifying the role of frozen plasma pools.

Background In the Netherlands, each new lot of test strips for the CoaguChek XS is validated by a group of collaborating centers. The purpose of this study was to assess the accuracy of the international normalized ratio (INR) measured with consecutive test strip lots and the suitability of frozen plasma pools for accuracy evaluation. Methods Each year, a particular lot of CoaguChek XS test strips is used as reference lot. The reference lots have been validated with the International Standard for thromboplastin rTF/09, yielding a mathematical relationship (R1) between reference lot INR and International Standard INR. New lots are compared to the reference lot using patients' capillary blood samples, yielding a relationship (R2) between the new lot INR and the reference lot INR. INRs of the blood samples were within the 1.5-4.5 interval. In parallel, three frozen plasmas pools are analyzed with the test strips. The distance of each plasma point to the line of relationship R2 was assessed. Results Fifty-four test strip lots have been evaluated during 3 years (2014-2016). Mean INR differences between test strip lot and International Standard rTF/09 varied between -0.14 and +0.20 (-4% and +8%, respectively). A positive trend with strip lot sequence number was observed (p<0.001). In several cases, the distance of the frozen plasmas to the whole blood relationship (R2) was greater than the critical value for commutability. Conclusions Using whole blood, all evaluated test strip lots met the analytical bias criterion of ±10%. Frozen plasma pools behave differently compared to whole blood and are not suitable for assessing absolute accuracy of new CoaguChek XS test strips.

Multi-dose drug dispensing as a tool to improve medication adherence: A study in patients using vitamin K antagonists.

PURPOSE: Multi-dose drug dispensing (MDD) is a dosing aid that provides patients with disposable bags containing all drugs intended for 1 dosing moment. MDD is believed to increase medication adherence, but studies are based on self-reported data, and results may depend on socially desirable answers. Therefore, our purpose was to determine the effect of MDD on medication adherence in non-adherent patients taking vitamin K antagonists (VKAs), and to compare with instructing patients on medication use. METHODS: We conducted a before-after study in non-adherent patients where MDD was the exposure and change in adherence after MDD initiation was the outcome (within patient comparison). Time in therapeutic range (TTR) was selected as a measure for adherence, as this reflects stability of VKA treatment. To analyze whether MDD improved adherence as compared with standard care (ie, letters or calls from nurses of the anticoagulation clinic), non-adherent patients without MDD were also followed to estimate their TTR change over time (between patient comparison). RESULTS: Eighty-three non-adherent VKA patients started using MDD. The median TTR was 63% before MDD and 73% 6 months after MDD. The within patient TTR increased on average by 13% (95%CI 6% to 21%) within 1 month after starting MDD and remained stable during the next 5 months. The TTR of MDD-patients increased 10% (95%CI 2% to 19%) higher as compared with non-MDD patients within 1 month but was similar after 4 months (TTR difference 3%, 95%CI -2% to 9%). CONCLUSIONS: Adherence improved after initiation of MDD. Compared with instructing patients, MDD was associated with better adherence within 1 month but was associated with similar improvement after 4 months.

Statins and Risk of Bleeding: An Analysis to Evaluate Possible Bias Due to Prevalent Users and Healthy User Aspects.

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.

A randomized trial of genotype-guided dosing of acenocoumarol and phenprocoumon.

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.).

Recurrence risk after anticoagulant treatment of limited duration for late, second venous thromboembolism.

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.

Genetic polymorphisms and major bleeding risk during vitamin K antagonists treatment: The BLEEDS case-cohort.

BACKGROUND: Major bleeding occurs annually in 1%-3% of patients on vitamin K antagonists (VKAs), despite close monitoring. Genetic variants in proteins involved in VKA response may affect this risk. AIM: To determine the association of genetic variants (cytochrome P450 enzymes 2C9 [CYP2C9] and 4F2 [CYP4F2], gamma-glutamyl carboxylase [GGCX]) with major bleeding in VKA users, separately and combined, including vitamin K epoxide reductase complex subunit-1 (VKORC1). METHODS: A case-cohort study was established within the BLEEDS cohort, which includes 16,570 patients who initiated VKAs between 2012 and 2014. We selected all 326 major bleeding cases that occurred during 17,613 years of follow-up and a random subcohort of 978 patients. We determined variants in CYP2C9, CYP4F2, GGCX, VKORC1 and evaluated the interaction between variant genotypes. Hazard ratios for major bleeding with 95% confidence intervals (95% CI) were estimated by weighted Cox regression. RESULTS: Genotype was determined in 256 cases and 783 subcohort members. Phenprocoumon was the most prescribed VKA for both cases and the subcohort (78% and 75%, respectively). Patients with major bleeding were slightly older than subcohort patients. CYP4F2-TT carriership was associated with a 1.6-fold (95% CI 0.9-2.8) increased risk of major bleeding compared with CC-alleles, albeit not statistically significant. For the CYP2C9 and GGCX variants instead, the major bleeding risk was around unity. Carrying at least two variant genotypes in CYP2C9 (poor metabolizer), CYP4F2-TT, and VKORC1-AA was associated with a 4.0-fold (95%CI 1.4-11.4) increased risk, while carriers of both CYP4F2-TT and VKORC1-AA had a particularly increased major bleeding risk (hazard ratio 6.7, 95% CI 1.5-29.8) compared with carriers of CC alleles in CYP4F2 and GG in VKORC1. However, the number of major bleeding cases in carriers of multiple variants was few (8 and 5 patients, respectively). CONCLUSIONS: CYP4F2 polymorphism was associated with major bleeding, especially in combination with VKORC1 genetic variants. These variants could be considered to further personalize anticoagulant treatment.

Selective Serotonin Reuptake Inhibitor Use and Risk of Major Bleeding during Treatment with Vitamin K Antagonists: Results of A Cohort Study.

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.

Patients' and health care providers' perspectives on quality of hemophilia care in the Netherlands: a questionnaire and interview study.

Background: Hemophilia care has improved greatly because of advances in treatment options and comprehensive care. In-depth insight into the perspectives of persons with hemophilia and health care providers on their care may provide targets for further improvements. Objectives: To assess satisfaction of the hemophilia population with their care, to explore factors determining care satisfaction, and to identify areas for potential health care improvements, including digital health tools. Methods: First, to assess care satisfaction and factors determining satisfaction and health care improvements, data from a nationwide, cross-sectional questionnaire among 867 adult and pediatric Dutch persons with hemophilia A or B were analyzed. This included the Hemophilia Patient Satisfaction Scale questionnaire, Canadian Hemophilia Outcomes Kids' Life Assessment Tool satisfaction questions, a visual analog scale satisfaction score, and open questions. Second, to further explore factors determining satisfaction and health care improvements, semistructured interviews were conducted with 19 persons with hemophilia or their parents and 18 health care providers. Results: High care satisfaction was found, with an overall median Hemophilia Patient Satisfaction Scale score of 12 (IQR, 6-21). Participants in the interviews reported that patient-professional interactions, availability of care, and coordination of care were major factors determining satisfaction. Suggested health care improvements included improved information provision and coordination of care, especially shared care with professionals not working within comprehensive care centers. Participants suggested that digital health tools could aid in this. Conclusion: Satisfaction with hemophilia care is high among persons with hemophilia in the Netherlands, although several potential improvements have been identified. Accentuating these is especially relevant in the current era of treatment innovations, in which we might focus less on other aspects of care.

Inhibitor incidence after intensive FVIII replacement for surgery in mild and moderate haemophilia A: a prospective national study in the Netherlands.

Inhibitor development is currently the most severe complication in mild/moderate haemophilia A patients, causing increased bleeding tendency, hospitalization and mortality. It has been suggested that receiving high doses of factor VIII (FVIII) concentrates for surgical procedures is an important risk factor for inhibitor development in these patients. The current multicentre study aimed to determine prospectively the incidence of inhibitor development after intensive FVIII replacement therapy for surgical procedures in patients with mild/moderate haemophilia A. All consecutive patients with mild/moderate haemophilia A were included when they required at least 10 000 iu of FVIII concentrates (or 250 iu/kg) for 5 or more days for a surgical procedure. Potential clinical risk factors for inhibitor development and results of inhibitor tests were collected. Forty-six patients with a median age of 54 years (interquartile range, 40-59 years) were included in the study. F8 genotyping revealed 20 different missense mutations. Patients received either recombinant (65%) or plasma-derived FVIII concentrates (35%) by intermittent bolus injections (41%) or continuous infusion (57%). Two patients developed a low titre inhibitor post-operatively. The incidence of inhibitor development following intensive treatment for surgery in this unselected prospective cohort of mild/moderate haemophilia A patients was 4% (95% confidence interval, 0·5-14·8).

Evaluation of the effect of statin use on the acenocoumarol and phenprocoumon maintenance dose.

BACKGROUND: Statins and coumarins are prescribed in combination on a regular basis. Some case reports suggested that statins might affect the dose requirements of coumarins. The aim of the study was to investigate whether acenocoumarol and phenprocoumon maintenance doses are influenced by statin use. METHODS: The Pre-EU-PACT database was used, which contains information on 471 acenocoumarol and 624 phenprocoumon users. The influence of individual statins on the acenocoumarol and phenprocoumon maintenance dose was investigated by comparing unadjusted and adjusted mean differences of the maintenance dose between statin and non-statin users. RESULTS: Lower adjusted acenocoumarol dose requirements were observed for patients using atorvastatin, simvastatin, pravastatin, and rosuvastatin. These patients had a reduction in adjusted mean acenocoumarol maintenance dose of 0.11, 0.29, 0.38, and 0.69 mg/day, respectively, compared with a mean adjusted dose of 2.60 mg/day for the patients not using a statin. There was no significant effect of statin use on unadjusted and adjusted phenprocoumon maintenance dose (p=0.23 and p=0.35, respectively). CONCLUSIONS: Mean acenocoumarol maintenance dosages were decreased when acenocoumarol is co-administered with the different statins. Statin use does not affect phenprocoumon maintenance doses significantly.

Loading and maintenance dose algorithms for phenprocoumon and acenocoumarol using patient characteristics and pharmacogenetic data.

AIMS: Polymorphisms in CYP2C9 and VKORC1 influence patients' phenprocoumon (PHE) and acenocoumarol (ACE) dose requirements. To provide physicians with tools to estimate the patient's individual dose, we aimed to develop algorithms for PHE and ACE. METHODS AND RESULTS: In two Dutch anticoagulation clinics, data on age, sex, height, weight, co-medication, coumarin derivative doses, and international normalized ratio values were obtained from 624 patients taking PHE and 471 taking ACE. Single nucleotide polymorphisms relevant to coumarin derivative dosing on the CYP2C9 and VKORC1 genes were determined. Using multiple linear regression, we developed genotype-guided and non-genotype-guided algorithms to predict the maintenance dose with patient characteristics and genetic information. In addition, loading doses were derived from the calculated maintenance doses. We performed external validation in an independent data set with 229 PHE and 168 ACE users. CYP2C9 and VKORC1 genotype, weight, height, sex, age, and amiodarone use contributed to the maintenance dose of PHE and ACE. The genotype-guided algorithms explained 55.9% (PHE) and 52.6% (ACE) of the variance of the maintenance dose, the non-genetic algorithms 17.3% (PHE) and 23.7% (ACE). Validation in an independent data set resulted in an explained variation of 59.4% (PHE) and 49.0% (ACE) for the genotype-guided algorithms and for 23.5% (PHE) and 17.8% (ACE) for the non-genotype-guided algorithms, without height and weight as parameters. CONCLUSION: To our knowledge, these are the first genotype-guided loading and maintenance dose algorithms for PHE and ACE using large cohorts. The utility of these algorithms will be tested in randomized controlled trials.

The Immediate Effect of COVID-19 Vaccination on Anticoagulation Control in Patients Using Vitamin K Antagonists.

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.

Inter- and intra-individual concentrations of direct oral anticoagulants: The KIDOAC study.

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.