Publications by authors named "Karina Meijer"

130 Publications

Fixed Versus Variable Dosing of Prothrombin Complex Concentrate for Bleeding Complications of Vitamin K Antagonists-The PROPER3 Randomized Clinical Trial.

Ann Emerg Med 2021 Sep 14. Epub 2021 Sep 14.

Department of Haematology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

Study Objective: To determine if a fixed dose of 1000 IU of 4-factor prothrombin complex concentrate (4F-PCC) is as effective as traditional variable dosing based on body weight and international normalized ratio (INR) for reversal of vitamin K antagonist (VKA) anticoagulation.

Methods: In this open-label, multicenter, randomized clinical trial, patients with nonintracranial bleeds requiring VKA reversal with 4F-PCC were allocated to either a 1,000-IU fixed dose of 4F-PCC or the variable dose. The primary outcome was the proportion of patients with effective hemostasis according to the International Society of Thrombosis and Haemostasis definition. The design was noninferiority with a lower 95% confidence interval of no more than -6%. When estimating sample size, we assumed that fixed dosing would be 4% superior.

Results: From October 2015 until January 2020, 199 of 310 intended patients were included before study termination due to decreasing enrollment rates. Of the 199 patients, 159 were allowed in the per-protocol analysis. Effective hemostasis was achieved in 87.3% (n=69 of 79) in fixed compared to 89.9% (n=71 of 79) in the variable dosing cohort (risk difference 2.5%, 95% confidence interval -13.3 to 7.9%, P=.27). Median door-to-needle times were 109 minutes (range 16 to 796) in fixed and 142 (17 to 1076) for the variable dose (P=.027). INR less than 2.0 at 60 minutes after 4F-PCC infusion was reached in 91.2% versus 91.7% (P=1.0).

Conclusion: The large majority of patients had good clinical outcome after 4F-PCC use; however, noninferiority of the fixed dose could not be demonstrated because the design assumed the fixed dose would be 4% superior. Door-to-needle time was shortened with the fixed dose, and INR reduction was similar in both dosing regimens.
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http://dx.doi.org/10.1016/j.annemergmed.2021.06.016DOI Listing
September 2021

[Switching from acenocoumarol to phenprocoumon: step in personalised anticoagulation?]

Ned Tijdschr Geneeskd 2021 09 9;165. Epub 2021 Sep 9.

UMC Groningen, afd. Hematologie, Groningen.

Acenocoumarol and phenprocoumon are vitamin K antagonists (VKA) with average half-lives of 11 hours and 160 hours, respectively. They are used to treat and prevent thrombosis in mechanical cardiac valve replacement, atrial fibrillation and venous thromboembolism. There are historical regional differences in preferred VKA in the Netherlands. Safe and effective treatment requires the international normalized ratios (INRs) to be in the therapeutic range, and stable. Theoretically, the longer-acting phenprocoumon would yield a higher time in therapeutic range (TTR) and lower INR variability. In practice, switching from acenocoumarol to phenprocoumon eventually improves INR variability and in some patients TTR as well. However, during the preceding transition period, INRs are more often volatile and supratherapeutic. Furthermore, switching to an alternative VKA could weaken integrated care, as other healthcare providers are less experienced with it. Healthcare providers must coordinate an intended switch with the anticoagulation clinic.
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September 2021

Design of the HEM-POWR study: a prospective, observational study of real-world treatment with damoctocog alfa pegol in patients with haemophilia A.

BMJ Open 2021 09 2;11(9):e044997. Epub 2021 Sep 2.

Center for Bleeding and Clotting Disorders, University of Minnesota Medical Center, Minneapolis, Minnesota, USA

Introduction: Haemophilia A is a rare bleeding disorder caused by defects in coagulation factor VIII (FVIII). Damoctocog alfa pegol (BAY 94-9027, Jivi, Bayer, Germany) is a site-specifically PEGylated, extended-half-life, recombinant FVIII, approved for use in previously treated patients (PTPs) aged ≥12 years with haemophilia A. However, a real-world evidence regarding routine clinical use of damoctocog alfa pegol is limited.

Methods And Analysis: HEM-POWR is a multinational, multicentre, non-interventional, prospective, postmarketing cohort study evaluating the effectiveness and safety of real-world treatment with damoctocog alfa pegol. Estimated enrolment is ≥200 PTPs with haemophilia A, receiving damoctocog alfa pegol (on-demand, prophylaxis or intermittent prophylaxis (as per local label)), observed for 36 months. Primary outcomes are total bleeding events and annualised bleeding rate; secondary outcomes include long-term safety, joint health, pharmacokinetics, patient-reported outcomes (PROs) from validated questionnaires and perioperative haemostasis. Where applicable, reasons for switching to damoctocog alfa pegol, choice of treatment regimen and dose will also be captured. Exploratory and descriptive statistical analyses will be performed, and will be stratified by parameters including, but not limited to, prophylaxis regimen and haemophilia severity. Patients can record bleeds and consumption in electronic (e) Diaries, ePROs, and can access non-promotional study information (videos explaining study procedures) via an online patient portal. Optionally, patients can enrol in the LIFE-ACTIVE substudy designed to investigate the relationship between activity (measured by the ActiGraph CP Insight watch) and effectiveness parameters collected from HEM-POWR.

Ethics And Dissemination: Study approval was obtained by local independent ethics committees and authorities in participating study centres across Europe, the Americas and Asia. Informed consent from patients or their legal representative is a requirement for participation. The study results will be submitted for publication in a peer-reviewed scientific journal and presented at scientific conferences.

Trial Registration Numbers: NCT03932201, EUPAS26416.

Protocol Version And Date: V.1.2, 27 September 2019.
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http://dx.doi.org/10.1136/bmjopen-2020-044997DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8413870PMC
September 2021

Factor V Leiden and the Risk of Bleeding in Patients With Acute Coronary Syndromes Treated With Antiplatelet Therapy: Pooled Analysis of 3 Randomized Clinical Trials.

J Am Heart Assoc 2021 09 28;10(17):e021115. Epub 2021 Aug 28.

Department of Cardiology St. Antonius Hospital Nieuwegein the Netherlands.

Background Whether factor V Leiden is associated with lower bleeding risk in patients with acute coronary syndromes using (dual) antiplatelet therapy has yet to be investigated. Methods and Results We pooled data from 3 randomized clinical trials, conducted in patients with acute coronary syndromes, with adjudicated bleeding outcomes. Cox regression models were used to obtain overall and cause-specific hazard ratios (HRs) to account for competing risk of atherothrombotic outcomes (ie, composite of ischemic stroke, myocardial infarction, and cardiovascular death) in each study. Estimates from the individual studies were pooled using fixed effect meta-analysis. The 3 studies combined included 17 623 patients of whom 969 (5.5%) were either heterozygous or homozygous (n=23) carriers of factor V Leiden. During 1 year of follow-up, a total of 1289 (7.3%) patients developed major (n=559) or minor bleeding. Factor V Leiden was associated with a lower risk of combined major and minor bleeding (adjusted cause-specific HR, 0.75; 95% CI, 0.56-1.00; =0.046; I=0%) but a comparable risk of major bleeding (adjusted cause-specific HR, 0.93; 95% CI, 0.62-1.39; =0.73; I=0%). Adjusted pooled cause-specific HRs for the association of factor V Leiden with atherothrombotic events alone and in combination with bleeding events were 0.75 (95% CI, 0.55-1.02; =0.06; I=0%) and 0.75 (95% CI, 0.61-0.92; =0.007; I=0%), respectively. Conclusions Given that the lower risk of bleeding conferred by factor V Leiden was not counterbalanced by a higher risk of atherothrombotic events, these findings warrant future assessment for personalized medicine such as selecting patients for extended or intensive antiplatelet therapy.
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http://dx.doi.org/10.1161/JAHA.120.021115DOI Listing
September 2021

Effect of lower VWF and FXI levels on levonorgestrel IUS and endometrial ablation treatment success in heavy menstrual bleeding: An exploratory study.

Haemophilia 2021 Nov 24;27(6):e756-e759. Epub 2021 Aug 24.

Department of Haematology, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands.

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http://dx.doi.org/10.1111/hae.14392DOI Listing
November 2021

Convenience and satisfaction in direct oral anticoagulant-treated patients with atrial fibrillation.

Res Pract Thromb Haemost 2021 Aug 17;5(6):e12577. Epub 2021 Aug 17.

Department of Haematology University of Groningen University Medical Center Groningen Groningen the Netherlands.

Background: Direct oral anticoagulants (DOACs) are the preferred anticoagulants for thromboprophylaxis in atrial fibrillation. We aimed to identify determinants of quality of life related to DOAC treatment to optimize DOAC treatment convenience and satisfaction.

Methods: We conducted a cross-sectional study in DOAC users. DOAC treatment-related convenience and satisfaction were measured by Perception of Anticoagulant Treatment Questionnaire. Higher scores are more favorable (range, 0-100). Patient-reported outcome measures and drug- and organization-related factors were collected. Multiple regression analyses were used to evaluate the association between these factors (ie, exposure variables) and DOAC treatment-related convenience and treatment satisfaction (ie, outcome variables).

Results: Of 1598 patients invited, 1035 responded, and 962 were included. The median convenience score was 98.1 (94.2-100.0), mean satisfaction score 66.5± 14.9. Twenty-four percent felt not well informed at the start of DOAC; 6.9% did not know who to turn to with questions. Multiple regression analyses showed that lacking sense of security, the predefined composite of receiving insufficient information at start of DOAC and/or not knowing who to turn to with questions was associated with lower convenience (regression coefficient, -1.29; 95% confidence interval [CI], -2.16 to -0.41). Bleeding, gastrointestinal complaints, and lower medication adherence were also associated with lower convenience. Missing sense of security (regression coefficient -6.59; 95% CI, -8.94 to -4.24) and bleeding without consultation were associated with lower treatment satisfaction.

Conclusions: Accessible interventions to improve DOAC care could be providing more instruction at treatment initiation and ensuring that patients know who to contact in case of problems.
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http://dx.doi.org/10.1002/rth2.12577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8371341PMC
August 2021

Unintentional guideline deviations in hospitalized patients with two or more antithrombotic agents: an intervention study.

Eur J Clin Pharmacol 2021 Dec 28;77(12):1919-1926. Epub 2021 Jul 28.

Pharmacy Foundation of Haarlem Hospitals, Haarlem, The Netherlands.

Purpose: Treatment schedules for antithrombotic therapy are complex, and there is a risk of inappropriate prescribing or continuation of antithrombotic therapy beyond the intended period of time. The primary aim of this study was to determine the frequency of unintentional guideline deviations in hospitalized patients. Secondary aims were to determine whether the frequency of unintentional guideline deviations decreased after intervention by a pharmacist, to determine the acceptance rate of the interventions and to determine the type of interventions.

Methods: We performed a non-controlled prospective intervention study in three teaching hospitals in the Netherlands. We examined whether hospitalized patients who used the combination of an anticoagulant plus at least one other antithrombotic agent had an unintentional guideline deviation. In these cases, the hospital pharmacist contacted the physician to assess whether this deviation was intentional. If the deviation was unintentional, a recommendation was provided how to adjust the antithrombotic regimen according to guideline recommendations.

Results: Of the 988 included patients, 407 patients had an unintentional guideline deviation (41.2%). After intervention, this was reduced to 22 patients (2.2%) (p < 0.001). The acceptance rate of the interventions was 96.6%. The most frequently performed interventions were discontinuation of an low molecular weight heparin in combination with a direct oral anticoagulant and discontinuation of an antiplatelet agent when there was no indication for the combination of an antiplatelet agent and an anticoagulant.

Conclusion: A significant number of hospitalized patients who used an anticoagulant plus one other antithrombotic agent had an unintentional guideline deviation. Intervention by a pharmacist decreased unintentional guideline deviations.
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http://dx.doi.org/10.1007/s00228-021-03185-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8585825PMC
December 2021

Quality of life in patients with pulmonary embolism treated with edoxaban versus warfarin.

Res Pract Thromb Haemost 2021 Jul 14;5(5):e12566. Epub 2021 Jul 14.

Daiichi Sankyo Pharma Development Basking Ridge NJ USA.

Background: Long-term sequelae of acute pulmonary embolism (PE) include decreased quality of life (QoL). Evidence suggests that adequacy of initial anticoagulant treatment in the acute phase of venous thrombosis has a key impact on late postthrombotic complications. We hypothesize that patients with acute PE treated with edoxaban for acute PE experience have improved QoL compared to those treated with warfarin.

Methods: Patients with PE who participated in the Hokusai-VTE trial were contacted between June 2017 and September 2020 for a single long-term follow-up visit. Main outcomes were the generic and disease-specific QoL measured by the 36-Item Short Form Health Survey (SF-36) and Pulmonary Embolism Quality of Life questionnaire.

Results: We included 251 patients from 26 centers in eight countries, of which 129 (51%) had been assigned to edoxaban and 122 (49%) to warfarin. Patient- and thrombus-specific characteristics were similar in both groups. Mean time since randomization in the Hokusai-VTE trial was 7.0 years (standard deviation, 1.0). No relevant or statistical differences were observed in the QoL for patients treated with edoxaban compared to patients treated with warfarin. The mean difference between patients treated with edoxaban and patients with PE treated with warfarin was 0.8 (95% confidence interval [CI]. -1.6 to 3.2) for the SF-36 summary mental score and 1.6 (95% CI, -0.9 to 4.1) for summary physical score.

Conclusion: Our findings indicate that patients with an index PE treated with edoxaban or warfarin have a similar long-term QoL. Since our study was a follow-up study from a well-controlled clinical trial setting, future studies should be designed in a daily clinical practice setting. We suggest a longitudinal design for investigation of changes in QoL over time.
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http://dx.doi.org/10.1002/rth2.12566DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8279124PMC
July 2021

Perioperative pharmacokinetic-guided factor VIII concentrate dosing in haemophilia (OPTI-CLOT trial): an open-label, multicentre, randomised, controlled trial.

Lancet Haematol 2021 Jul;8(7):e492-e502

Department of Pediatric Hematology, Erasmus MC Sophia Children's Hospital, Rotterdam, Netherlands. Electronic address:

Background: Dosing of replacement therapy with factor VIII concentrate in patients with haemophilia A in the perioperative setting is challenging. Underdosing and overdosing of factor VIII concentrate should be avoided to minimise risk of perioperative bleeding and treatment costs. We hypothesised that dosing of factor VIII concentrate on the basis of a patient's pharmacokinetic profile instead of bodyweight, which is standard treatment, would reduce factor VIII consumption and improve the accuracy of attained factor VIII levels.

Methods: In this open-label, multicentre, randomised, controlled trial (OPTI-CLOT), patients were recruited from nine centres in Rotterdam, Groningen, Utrecht, Nijmegen, The Hague, Leiden, Amsterdam, Eindhoven, and Maastricht in The Netherlands. Eligible patients were aged 12 years or older with severe or moderate haemophilia A (severe haemophilia was defined as factor VIII concentrations of <0·01 IU/mL, and moderate haemophilia as 0·01-0·05 IU/mL), without factor VIII inhibitors, and planned for elective low or medium risk surgery as defined by surgical risk score. Patients were randomly assigned (1:1) using a web-based randomisation system and treatment minimisation, stratified by method of administration of factor VIII concentrate (continuous infusion vs bolus administration) and risk level of surgery (low and medium risk surgery), to the pharmacokinetic-guided or standard treatment group. The primary endpoint was total amount of infused factor VIII concentrate (IU per kg bodyweight) during perioperative period (from day of surgery up to 14 days after surgery). Analysis was by intention to treat and the safety analysis population comprised all participants who underwent surgery with factor VIII concentrate. This study is registered with the Netherlands Trial Registry, NL3955, and is now closed to accrual.

Findings: Between May 1, 2014, and March 1, 2020, 98 patients were assessed for eligibility and 66 were enrolled in the trial and randomly assigned to the pharmacokinetic-guided treatment group (34 [52%]) or the standard treatment group (32 [48%]). Median age was 49·1 years (IQR 35·0 to 62·1) and all participants were male. No difference was seen in consumption of factor VIII concentrate during the perioperative period between groups (mean consumption of 365 IU/kg [SD 202] in pharmacokinetic-guided treatment group vs 379 IU/kg [202] in standard treatment group; adjusted difference -6 IU/kg [95% CI -88 to 100]). Postoperative bleeding occurred in six (18%) of 34 patients in the pharmacokinetic-guided treatment group and three (9%) of 32 in the standard treatment group. One grade 4 postoperative bleeding event occurred, which was in one (3%) patient in the standard treatment group. No treatment-related deaths occurred.

Interpretation: Although perioperative pharmacokinetic-guided dosing is safe, it leads to similar perioperative factor VIII consumption when compared with standard treatment. However, pharmacokinetic-guided dosing showed an improvement in obtaining factor VIII concentrations within the desired perioperative factor VIII range. These findings provide support to further investigation of pharmacokinetic-guided dosing in perioperative haemophilia care.

Funding: Dutch Research Council (NWO)-ZonMw and Takeda.
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http://dx.doi.org/10.1016/S2352-3026(21)00135-6DOI Listing
July 2021

A meta-analysis of andexanet alfa and prothrombin complex concentrate in the treatment of factor Xa inhibitor-related major bleeding.

Res Pract Thromb Haemost 2021 May 24;5(4):e12518. Epub 2021 May 24.

Department of Hospital Pharmacy OLVG Amsterdam The Netherlands.

Background: Andexanet alfa (andexanet) and prothrombin complex concentrate (PCC) are both reversal agents for major bleeding in patients using factor Xa inhibitors (FXaIs). Our aim was to evaluate the current evidence for the effectiveness and safety of andexanet and PCC in a systematic review and meta-analysis.

Objectives: Primary objective was hemostatic effectiveness. Secondary objectives were thromboembolic event rate and mortality.

Methods: A systematic review was performed in PubMed and Embase. Studies describing the effectiveness and/or safety of PCC or andexanet in patients with major bleeding using FXaIs were included. Meta-analysis was performed using a random-effects model.

Results: Seventeen PCC studies, 3 andexanet studies, and 1 study describing PCC and andexanet were included, comprising 1428 PCC-treated and 396 andexanet-treated patients. None of the included studies had control groups, hampering a pooled meta-analysis to compare the two reversal agents. Separate analyses for andexanet and PCC were performed. In subgroup analysis, the pooled proportion of patients with effective hemostasis in studies that used Annexa-4 criteria demonstrated a hemostatic effectiveness of 0.85 (95% confidence interval [CI], 0.80-0.90) in PCC and 0.82 (95% CI, 0.78-0.87) in andexanet studies. The pooled proportion of patients with thromboembolic events was 0.03 (95% CI, 0.02-0.04) in PCC and 0.11 (95% CI, 0.04-0.18) in andexanet studies.

Conclusion: Based on the available evidence with low certainty from observational studies, PCC and andexanet demonstrated a similar, effective hemostasis in the treatment of major bleeding in patients using FXaIs. Compared to PCC, the thromboembolic event rate appeared higher in andexanet-treated patients.
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http://dx.doi.org/10.1002/rth2.12518DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8143276PMC
May 2021

Risk of recurrent venous thromboembolism in patients with autoimmune diseases: data from the Registro Informatizado de Enfermedad TromboEmbólica (RIETE) registry.

Br J Haematol 2021 Jul 2;194(1):195-199. Epub 2021 Jun 2.

Department of Internal Medicine, Hospital Germans Trias i Pujol, Universidad Autonoma de Barcelona, Barcelona, Spain.

Autoimmune disease is a risk factor for first incident venous thromboembolism (VTE). However, data on the risk of recurrent VTE in people with autoimmune disease is sparse. We explored the risk of recurrent VTE using the RIETE registry, comparing people with autoimmune disease (n = 1305) to those without (n = 50608). Overall rates were 6.5 and 5.1 recurrent VTE/100 years for patients with autoimmune disease vs controls, respectively. After adjustment for sex and unprovoked/provoked VTE yielded an adjusted hazard ratio of 1.29 (95%CI 1.03-1.62). The analysis was limited by short median follow up time (161 days overall), precluding definitive conclusions on recurrent VTE risks.
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http://dx.doi.org/10.1111/bjh.17549DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8362114PMC
July 2021

Factor V Leiden Does Not Modify the Phenotype of Acute Coronary Syndrome or the Extent of Myocardial Necrosis.

J Am Heart Assoc 2021 06 17;10(11):e020025. Epub 2021 May 17.

Department of Cardiology St. Antonius Hospital Nieuwegein the Netherlands.

Background The prothrombotic defect factor V Leiden (FVL) may confer higher risk of ST-segment-elevation myocardial infarction (STEMI), compared with non-ST-segment-elevation acute coronary syndrome, and may be associated with more myocardial necrosis caused by higher thrombotic burden. Methods and Results Patients without history of cardiovascular disease were selected from 2 clinical trials conducted in patients with acute coronary syndrome. FVL was defined as G-to-A substitution at nucleotide 1691 in the factor V (factor V R506Q) gene. Odds ratios were calculated for the association of FVL with STEMI adjusted for age and sex in the overall population and in the subgroups including sex, age (≥70 versus <70 years), and traditional cardiovascular risk factors. The peak biomarker levels (ie, creatine kinase-myocardial band and high-sensitivity troponin I or T) after STEMI were contrasted between FVL carriers and noncarriers. Because of differences in troponin assays, peak high-sensitivity troponin levels were converted to a ratio scale. The prevalence of FVL mutation was comparable in patients with STEMI (6.0%) and non-ST-segment-elevation acute coronary syndrome (5.8%). The corresponding sex- and age-adjusted odds ratio was 1.06 (95% CI, 0.86-1.30; =0.59) for the association of FVL with STEMI. Subgroup analysis did not show any differences. In patients with STEMI, neither the median peak creatine kinase-myocardial band nor the peak high-sensitivity troponin ratio showed any differences between wild-type and FVL carriers ( for difference: creatine kinase-myocardial band=0.33; high sensitivity troponin ratio=0.54). Conclusions In a general population with acute coronary syndrome, FVL did not discriminate between a STEMI or non-ST-segment-elevation acute coronary syndrome presentation and was unrelated to peak cardiac necrosis markers in patients with STEMI. Registration URL: https://www.clinicaltrials.gov; Unique identifiers: NCT00391872 and NCT01761786.
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http://dx.doi.org/10.1161/JAHA.120.020025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8483522PMC
June 2021

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

Br J Clin Pharmacol 2021 Nov 4;87(11):4408-4420. Epub 2021 May 4.

Department of Pediatric Hematology, Erasmus University Medical Center, Sophia Children's Hospital Rotterdam, Rotterdam, the Netherlands.

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 . 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  68 kg , 2930 mL 68 kg , 1810 mL 68 kg , and 172 mL h  68 kg , respectively. This model adequately described all collected FVIII levels, with a slight median overprediction of 0.02 IU mL .

Conclusions: This study emphasizes the importance of external validation of population PK models using real-life data.
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http://dx.doi.org/10.1111/bcp.14864DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8596686PMC
November 2021

Confirmed long-term safety and efficacy of prophylactic treatment with BAY 94-9027 in severe haemophilia A: final results of the PROTECT VIII extension study.

Haemophilia 2021 May 5;27(3):e347-e356. Epub 2021 Apr 5.

National Haemophilia Centre, Chaim Sheba Medical Centre, Tel Aviv University, Tel Hashomer, Israel.

Introduction: The phase 2/3 PROTECT VIII main study demonstrated efficacy and safety of BAY 94-9027 (damoctocog alfa pegol; Jivi ), a B-domain-deleted recombinant factor VIII (FVIII), site-specifically PEGylated to extend its half-life.

Aim: To report the final efficacy and safety data for BAY 94-9027 from the PROTECT VIII extension.

Methods: Previously treated males aged 12-65 years with severe haemophilia A (FVIII <1%) who completed the multicentre, open-label PROTECT VIII main study were eligible for the extension. Patients received either on demand or prophylaxis treatments (30-40 IU/kg twice weekly [2 × W], 45-60 IU/kg every 5 days [E5D], or 60 IU/kg every 7 days [E7D]) and could switch to any prophylaxis regimen (variable frequency) as needed. Annualised bleeding rates (ABR), zero bleeds and safety outcomes were included in this final analysis.

Results: At extension completion, patients (n = 121) received BAY 94-9027 for a median (range) total time of 3.9 (0.8-7.0) years. Median (Q1; Q3) total ABR was 1.49 (0.36; 4.80) for prophylaxis patients (n = 107), compared with 34.09 (20.3; 36.6) for on-demand patients (n = 14). Median total ABRs for 2 × W (n = 23), E5D (n = 33), E7D (n = 23) and variable frequency (n = 28) groups were 1.57, 1.17, 0.65 and 3.10, respectively. Of prophylaxis patients, 20.6% were bleed-free during the entire extension (median time, 3.2 years) and 50.0% were bleed-free during the last 6 months. No patient developed FVIII inhibitors. No deaths or thrombotic events were reported.

Conclusions: Efficacy and safety of BAY 94-9027 was confirmed, with extension data supporting its use as a long-term treatment option for patients with haemophilia A.
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http://dx.doi.org/10.1111/hae.14297DOI Listing
May 2021

[Tranexamic acid: widely applicable, few risks].

Ned Tijdschr Geneeskd 2021 03 25;165. Epub 2021 Mar 25.

UMCG, afd. Hematologie, Groningen.

Tranexamic acid is a cheap and easy to use drug for the treatment and prevention of bleeding. In the past, its use was mainly empiric and primarily in patients with coagulation disorders. More recently, large scale randomized controlled trials have shown that tranexamic acid reduces mortality in women with postpartum hemorrhage and in victims of trauma. In a number of surgical settings, including cardiothoracic and orthopedic, tranexamic acid reduces bleeding complications. In these studies, there was no signal of increased risk of thrombosis. Tranexamic acid is also effective in reducing heavy menstrual bleeding, the prevention of bleeding after dental interventions and a number of other high-prevalence conditions. There are no data that support an increased risk of thrombosis when patients without haemostatic disorders use tranexamic acid for a longer period, but addition studies would be helpful. Finally, the topical administration of the drug for mucocutaneous nuisance bleeds deserves more attention.
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March 2021

Definition of haemostatic effectiveness in interventions used to treat major bleeding: Communication from the ISTH SSC Subcommittee on Control of Anticoagulation.

J Thromb Haemost 2021 04;19(4):1112-1115

Department of Hematology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

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http://dx.doi.org/10.1111/jth.15222DOI Listing
April 2021

Population pharmacokinetics of the von Willebrand factor-factor VIII interaction in patients with von Willebrand disease.

Blood Adv 2021 03;5(5):1513-1522

Hospital Pharmacy-Clinical Pharmacology, Amsterdam University Medical Center (UMC), University of Amsterdam, Amsterdam, The Netherlands.

Recent studies have reported that patients with von Willebrand disease treated perioperatively with a von Willebrand factor (VWF)/factor VIII (FVIII) concentrate with a ratio of 2.4:1 (Humate P/Haemate P) often present with VWF and/or FVIII levels outside of prespecified target levels necessary to prevent bleeding. Pharmacokinetic (PK)-guided dosing may resolve this problem. As clinical guidelines increasingly recommend aiming for certain target levels of both VWF and FVIII, application of an integrated population PK model describing both VWF activity (VWF:Act) and FVIII levels may improve dosing and quality of care. In total, 695 VWF:Act and 894 FVIII level measurements from 118 patients (174 surgeries) who were treated perioperatively with the VWF/FVIII concentrate were used to develop this population PK model using nonlinear mixed-effects modeling. VWF:Act and FVIII levels were analyzed simultaneously using a turnover model. The protective effect of VWF:Act on FVIII clearance was described with an inhibitory maximum effect function. An average perioperative VWF:Act level of 1.23 IU/mL decreased FVIII clearance from 460 mL/h to 264 mL/h, and increased FVIII half-life from 6.6 to 11.4 hours. Clearly, in the presence of VWF, FVIII clearance decreased with a concomitant increase of FVIII half-life, clarifying the higher FVIII levels observed after repetitive dosing with this concentrate. VWF:Act and FVIII levels during perioperative treatment were described adequately by this newly developed integrated population PK model. Clinical application of this model may facilitate more accurate targeting of VWF:Act and FVIII levels during perioperative treatment with this specific VWF/FVIII concentrate (Humate P/Haemate P).
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http://dx.doi.org/10.1182/bloodadvances.2020003891DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948283PMC
March 2021

Von Willebrand Factor Multimer Densitometric Analysis: Validation of the Clinical Accuracy and Clinical Implications in Von Willebrand Disease.

Hemasphere 2021 Mar 17;5(3):e542. Epub 2021 Feb 17.

Department of Hematology, Erasmus MC, University Medical Center Rotterdam, The Netherlands.

Von Willebrand factor (VWF) multimer analysis is important in the classification of von Willebrand disease (VWD). Current visual VWF multimer analysis is time consuming and inaccurate in detecting subtle changes in multimer patterns. Although VWF multimer densitometric analysis may be useful, the accuracy needs further investigation before it can be widely applied. In this study we aimed to validate VWF multimer densitometric analysis in a large cohort of VWD patients and to identify patient characteristics associated with densitometric outcomes. Patients were included from the Willebrand in the Netherlands (WiN) study, in which a bleeding score (BS) was obtained, and blood was drawn. For multimer analysis, citrated blood was separated on an agarose gel and visualized by Western blotting. IMAGEJ was used to generate densitometric images and medium-large VWF multimer index was calculated. We included 560 VWD patients: 328 type 1, 211 type 2, and 21 type 3 patients. Medium-large VWF multimer index performed excellent in distinguishing visually classified normal VWF multimers from reduced high-molecular-weight (HMW) multimers (area under the curve [AUC]: 0.96 [0.94-0.98], < 0.001), normal multimers from absence of HMW multimers (AUC 1.00 [1.00-1.00], < 0.001), and type 2A and 2B from type 2M and 2N (AUC: 0.96 [0.94-0.99], < 0.001). Additionally, higher medium-large VWF multimer index was associated with lower BS in type 1 VWD: β = -7.6 (-13.0 to -2.1), = 0.007, adjusted for confounders. Densitometric analysis of VWF multimers had an excellent accuracy compared with visual multimer analysis and may contribute to a better understanding of the clinical features such as the bleeding phenotype of VWD patients.
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http://dx.doi.org/10.1097/HS9.0000000000000542DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892298PMC
March 2021

Incidence, prognostic factors, and outcomes of venous thromboembolism in critically ill patients: data from two prospective cohort studies.

Crit Care 2021 01 12;25(1):27. Epub 2021 Jan 12.

Department of Critical Care, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

Background: The objective of this study was to describe the prevalence, incidence, prognostic factors, and outcomes of venous thromboembolism in critically ill patients receiving contemporary thrombosis prophylaxis.

Methods: We conducted a pooled analysis of two prospective cohort studies. The outcomes of interest were in-hospital pulmonary embolism or lower extremity deep vein thrombosis (PE-LDVT), in-hospital nonleg deep vein thrombosis (NLDVT), and 90-day mortality. Multivariable logistic regression analysis was used to evaluate the association between predefined baseline prognostic factors and PE-LDVT or NLDVT. Cox regression analysis was used to evaluate the association between PE-LDVT or NLDVT and 90-day mortality.

Results: A total of 2208 patients were included. The prevalence of any venous thromboembolism during 3 months before ICU admission was 3.6% (95% CI 2.8-4.4%). Out of 2166 patients, 47 (2.2%; 95% CI 1.6-2.9%) developed PE-LDVT and 38 patients (1.8%; 95% CI 1.2-2.4%) developed NLDVT. Renal replacement therapy (OR 3.5 95% CI 1.4-8.6), respiratory failure (OR 2.0; 95% CI 1.1-3.8), and previous VTE (OR 3.6; 95% CI 1.7-7.7) were associated with PE-LDVT. Central venous catheters (OR 5.4; 95% CI 1.7-17.8) and infection (OR 2.2; 95% CI 1.1-4.3) were associated with NLDVT. Occurrence of PE-LDVT but not NLDVT was associated with increased 90-day mortality (HR 2.7; 95% CI 1.6-4.6, respectively, 0.92; 95% CI 0.41-2.1).

Conclusion: Thrombotic events are common in critically ill patients, both before and after ICU admittance. Development of PE-LDVT but not NLDVT was associated with increased mortality. Prognostic factors for developing PE-LDVT or NLDVT despite prophylaxis can be identified at ICU admission and may be used to select patients at higher risk in future randomized clinical trials.

Trial Registration: NCT03773939.
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http://dx.doi.org/10.1186/s13054-021-03457-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7801861PMC
January 2021

Association of periodontitis with markers of immunologic and haemostatic state in people living with HIV.

J Infect 2021 03 19;82(3):e17-e19. Epub 2020 Dec 19.

Department of Internal Medicine, Division of Infectious Diseases, University of Groningen and University Medical Center Groningen, P.O. Box 30.001, 9700 RB Groningen, the Netherlands. Electronic address:

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http://dx.doi.org/10.1016/j.jinf.2020.12.011DOI Listing
March 2021

ADAMTS-13 and bleeding phenotype in von Willebrand disease.

Res Pract Thromb Haemost 2020 Nov 31;4(8):1331-1339. Epub 2020 Oct 31.

Department of Hematology Erasmus MC, University Medical Center Rotterdam Rotterdam The Netherlands.

Background: The bleeding phenotype of von Willebrand disease (VWD) varies highly between patients and can only partly be explained by von Willebrand factor (VWF) parameters. By cleaving large VWF multimers into smaller, less active multimers, ADAMTS-13 is an important regulator of VWF activity. However, it is unknown what the role of ADAMTS-13 is in individuals with VWD.

Objectives: We therefore studied how ADAMTS-13 activity is associated with the laboratory and bleeding phenotype in individuals with VWD.

Methods: We measured ADAMTS-13 activity using the fluorescence resonance energy transfer substrate VWF 73 assay in 638 individuals with VWD in the nationwide cross-sectional Willebrand in the Netherlands study and in 36 healthy controls. The bleeding phenotype was assessed using the Tosetto bleeding score.

Results: ADAMTS-13 activity was similar in individuals with VWD (109% ± 20.6%) and controls (110% ± 19.7%). ADAMTS-13 activity was higher in individuals with VWD with type 3 than those with type 1 (mean difference, 11.8%; 95% confidence interval [CI], 2.9%-20.8%) or type 2 (mean difference, 16.1%; 95% CI, 7.1%-25.1%). ADAMTS-13 activity was not associated with the Tosetto bleeding score (0.1 Tosetto bleeding score increase per 10% ADAMTS-13 increase, 95% CI, -0.2 to 0.3). Furthermore, ADAMTS-13 activity did not differ between individuals with and without a bleeding event during the year preceding blood sampling (mean difference, 1.4%; 95% CI, -2.1% to 4.9%).

Conclusion: ADAMTS-13 activity was highest in individuals with type 3 VWD, but it had only minor associations with VWF parameters. ADAMTS-13 activity does not influence the bleeding phenotype in individuals with VWD.
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http://dx.doi.org/10.1002/rth2.12442DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7695560PMC
November 2020

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

Br J Clin Pharmacol 2021 06 16;87(6):2602-2613. Epub 2020 Dec 16.

Department of Pediatric Hematology, Erasmus University Medical Center - Sophia Children's Hospital Rotterdam, The Netherlands.

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 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 ), overweight (BMI 25-30 kg m ) and obese haemophilia A patients (BMI > 30 kg m ).

Results: In total, 57 haemophilia A patients (FVIII≤0.05 IU mL ) 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.
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http://dx.doi.org/10.1111/bcp.14670DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8246536PMC
June 2021

Genetic testing of hereditary antithrombin deficiency in a large US pedigree using saliva samples.

Int J Lab Hematol 2021 06 21;43(3):e101-e103. Epub 2020 Nov 21.

Department of Laboratory Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

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http://dx.doi.org/10.1111/ijlh.13390DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8246558PMC
June 2021

Carotid plaque composition in persons with hemophilia: An explorative study with multi-contrast MRI.

Thromb Res 2021 01 6;197:138-140. Epub 2020 Nov 6.

Department of Internal Medicine, University Medical Center Groningen, University of Groningen, the Netherlands; Department of Internal Medicine, Tergooi Hospital, location Hilversum, the Netherlands.

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http://dx.doi.org/10.1016/j.thromres.2020.10.036DOI Listing
January 2021

Bleeding severity in patients with rare bleeding disorders: real-life data from the RBiN study.

Blood Adv 2020 10;4(20):5025-5034

Department of Hematology, Radboud University Medical Center, Nijmegen, The Netherlands.

Patients with hereditary rare bleeding disorders (RBDs) present with diverse hemorrhagic symptoms. Correlation between factor activity levels and clinical bleeding severity is poor for most RBDs. Threshold factor activity levels have been previously described in relation to bleeding severity but have not yet been validated. The Rare Bleeding Disorders in the Netherlands (RBiN) study is a nationwide cross-sectional study of patients registered in all 6 Dutch Haemophilia Treatment Centers with a known RBD and who are age 1 to 99 years. Bleeding scores were determined, and laboratory and clinical data were extracted from patient files. In all, 263 patients were included, of whom 202 (77%) attended the scheduled study visit. The median International Society of Thrombosis and Haemostasis (ISTH) bleeding assessment tool (BAT) score was 9. Correlations between baseline factor activity levels and ISTH BAT scores were strong for deficiencies in factor II (FII) (r = -0.792) and FX (r = -0.838) and were moderate for deficiencies of fibrinogen (r = -0.683), FV (r = -0.623), FVII (r = -0.516), FXIII (r = -0.516), and α2-antiplasmin (r = -0.594). There was no correlation for FXI deficiency (r = -0.218). The RBD BAT identified more women (94% vs 83%) and children (100% vs 71%) with an RBD than the ISTH BAT did. Importantly, 48% of patients had more severe bleeding than predicted for their baseline factor activity level. In addition, 34% of patients were predicted to be asymptomatic, but they actually had grade 2 (31%) or 3 (3%) bleeding. Bleeding severity in patients with RBDs is more pronounced than previously anticipated. The previously determined threshold factor activity levels to ensure no (spontaneous) bleeding in patients with an RBD are inaccurate. This trial was registered at www.clinicaltrials.gov as #NCT03347591.
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http://dx.doi.org/10.1182/bloodadvances.2020002740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7594388PMC
October 2020

Outcome of intracranial bleeding managed with prothrombin complex concentrate in patients on direct factor Xa inhibitors or vitamin K antagonists.

Thromb Res 2020 12 21;196:404-409. Epub 2020 Sep 21.

Amsterdam UMC, University of Amsterdam, Department of Vascular Medicine, Amsterdam Cardiovascular Sciences, Amsterdam, the Netherlands. Electronic address:

Intracranial hemorrhage (ICH) is the most feared complication of anticoagulation with a high mortality and morbidity. Before registration of a specific reversal agent for factor Xa inhibitors (FXa-I), international guidelines recommended prothrombin complex concentrate (PCC), which also is the specific reversal agent for vitamin K antagonists (VKA). In two contemporary cohorts, we compared clinical outcomes between patients with FXa-I and VKA related ICH treated with PCC between 2014 and 2018. Primary outcome was effective hemostasis after 24 h, according to the International Society of Thrombosis and Hemostasis definition. Safety outcomes were defined as venous and arterial thromboembolic complications and death within 30 days. Thirty-six patients with FXa-I-ICH and 39 patients with VKA-ICH were available for analysis. Baseline characteristics were comparable between both groups, except for time from start of symptoms to presentation at the hospital. In the FXa-I-ICH cohort, 24 (73%) patients achieved effective hemostasis compared to 23 (62%) patients in the VKA-ICH cohort (crude odds ratio [OR] 1.62 [95%CI 0.59-4.48], adjusted OR 1.45 [95%CI 0.44-4.83]). Eight (24%) patients with FXa-I-ICH deceased compared to 17 (45%) patients with VKA-ICH (crude OR 0.38 [95%CI 0.14-1.24], adjusted OR 0.41 [95%CI 0.12-1.24]). In this observational cohort study, the outcome of ICH managed with PCC was similar in patients with FXa-I-ICH and in patients with VKA-ICH.
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http://dx.doi.org/10.1016/j.thromres.2020.09.028DOI Listing
December 2020

Rotational thromboelastometry to assess hypercoagulability in COVID-19 patients.

Thromb Res 2020 12 1;196:379-381. Epub 2020 Sep 1.

Department of Critical Care, University Medical Center Groningen, P.O. Box 30.001, 9700 RB Groningen, the Netherlands. Electronic address:

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http://dx.doi.org/10.1016/j.thromres.2020.08.046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7462575PMC
December 2020

Treatment of acquired hemophilia A, a balancing act: results from a 27-year Dutch cohort study.

Am J Hematol 2021 01 10;96(1):51-59. Epub 2020 Oct 10.

Van Creveldkliniek, University Medical Center Utrecht, University Utrecht, Utrecht, The Netherlands.

Acquired hemophilia A (AHA) is a severe auto-immune bleeding disorder. Treatment of AHA is burdensome and optimal management is still unresolved. Therefore a retrospective nationwide multi-center cohort study (1992-2018) was performed to evaluate clinical presentation and treatment efficacy and safety of AHA in the Netherlands. Multivariate logistic and Cox regression analysis was used to study independent associations between patient characteristics and clinical outcomes. A total of 143 patients (median age 73 years; 52.4% male) were included with a median follow-up of 16.8 months (IQR 3.6-41.5 months). First-line immunosuppressive treatment was mostly steroid monotherapy (67.6%), steroids/cyclophosphamide (11.9%) and steroids/rituximab (11.9%), with success rates of 35.2%, 80.0% and 66.7% respectively, P < .05. Eventually 75% of patients achieved complete remission (CR). A high anti-FVIII antibody titer, severe bleeding and steroid monotherapy were associated with lower CR rates. Infections, the most important adverse event, occurred significantly more often with steroid combination therapy compared to steroids alone (38.7% vs 10.6%; P = .001). Overall mortality was 38.2%, mostly due to infections (19.2%) compared to 7.7% fatal bleeds. Advanced age, underlying malignancy and ICU admission were predictors for mortality. This study showed that AHA is characterized by significant disease-related and treatment-related morbidity and mortality. A high anti-FVIII titer, severe bleeding and steroid monotherapy were associated with a lower CR rate. The efficacy of steroid combination therapies however, was overshadowed by higher infection rates and infections represented the most important cause of death. The challenging and delicate balance between treatment effectivity and safety requires ongoing monitoring of AHA and further identification of prognostic markers.
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http://dx.doi.org/10.1002/ajh.26009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756759PMC
January 2021

Direct Oral Anticoagulants in Antithrombin Deficiency: Initial Experience in a Single Center.

Thromb Haemost 2021 02 30;121(2):242-245. Epub 2020 Aug 30.

Department of Haematology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands.

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http://dx.doi.org/10.1055/s-0040-1715647DOI Listing
February 2021

Effect of switching from acenocoumarol to phenprocoumon on time in therapeutic range and INR variability: A cohort study.

PLoS One 2020 10;15(7):e0235639. Epub 2020 Jul 10.

Department of Hematology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

Background: Treatment with vitamin K antagonists (VKA) requires a high proportion of time in the therapeutic range (TTR) and a low international normalised ratio (INR) variability to be maximally safe and effective. Switching from short-acting acenocoumarol to long-acting phenprocoumon could improve VKA control.

Aims: We assessed whether switching from acenocoumarol to phenprocoumon improves the time in the therapeutic range (TTR) and INR variability.

Methods And Results: In a retrospective cohort with data on 236,957 patients-years of VKA management from two first-line anticoagulation clinics in the Netherlands, we identified 124 patients in target range 2-3, 269 patients in target range 2-3.5 and 98 patients in target range 2.5-3.5 who switched from acenocoumarol to phenprocoumon. They were matched in a 1:2 ratio to non-switching controls using propensity score matching. Over the first 180 days after a switch, switchers' TTR declined 5 (95% CI 1 to 10), 10 (95% CI 7 to 13) and 5 (95% CI 0 to 11) percentage points relative to non-switchers, in target ranges 2-3, 2-3.5 and 2.5-3.5. Anticoagulation was more often supra-therapeutic in switchers, and switchers had a higher INR variability. In the following 180 days, TTR in switchers became 1 (95% CI -4 to 6), 4 (95% CI 0 to 7) and 6 (95% CI 1 to 12) percentage points better than in non-switchers. Switchers' INRs were much more stable than non-switchers'.

Conclusion: Eventually, a switch from acenocoumarol to phenprocoumon leads to a higher TTR and a lower INR variability. However, this is preceded by a transition period with opposite effects. An improved conversion algorithm could possibly shorten the transition period. Until then, physicians and patients should decide whether switching is worth the increased risk during the transition phase.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0235639PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7351201PMC
September 2020
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