Antithrombotic Questionnaire Tool for Evaluation of Combined Antithrombotic Therapy in Community Pharmacies.

OBJECTIVE: The objective of this paper is to assess the diagnostic value of an antithrombotic questionnaire tool compared with the hospital's medical record information tool. The hypothesis of this study was that the antithrombotic questionnaire tool could identify patients with potentially incorrect antithrombotic therapy. METHODS: This cross-sectional study was conducted in eight community pharmacies in the Netherlands. A standardized questionnaire was developed as antithrombotic questionnaire tool. The pharmacist assessed whether the antithrombotic therapy was correct or potentially incorrect based on answers given by patients and based on the medical record. The primary outcome of the study was the sensitivity and specificity of the antithrombotic questionnaire tool to identify patients with potentially incorrect antithrombotic therapy. RESULTS: For 95 patients, the pharmacist assessed that in 81 (85%) the antithrombotic therapy was correct and in 14 (15%) potentially incorrect. Based on the medical record, 86 patients (91%) were assessed as correct and 9 (9%) as potentially incorrect. The sensitivity of the tool was 100% and the specificity 94%. CONCLUSIONS: This study demonstrated that the antithrombotic questionnaire tool is a suitable tool to assess whether the patient's antithrombotic therapy is potentially incorrect. It can be applied to identify patients with potentially incorrect antithrombotic therapy.

Adoption of antithrombotic stewardship and utilization of clinical decision support systems-A questionnaire-based survey in Dutch hospitals.

Antithrombotics require careful monitoring to prevent adverse events. Safe use can be promoted through so-called antithrombotic stewardship. Clinical decision support systems (CDSSs) can be used to monitor safe use of antithrombotics, supporting antithrombotic stewardship efforts. Yet, previous research shows that despite these interventions, antithrombotics continue to cause harm. Insufficient adoption of antithrombotic stewardship and suboptimal use of CDSSs may provide and explanation. However, it is currently unknown to what extent hospitals adopted antithrombotic stewardship and utilize CDSSs to support safe use of antithrombotics. A semi-structured questionnaire-based survey was disseminated to 12 hospital pharmacists from different hospital types and regions in the Netherlands. The primary outcome was the degree of antithrombotic stewardship adoption, expressed as the number of tasks adopted per hospital and the degree of adoption per task. Secondary outcomes included characteristics of CDSS alerts used to monitor safe use of antithrombotics. All 12 hospital pharmacists completed the survey and report to have adopted antithrombotic stewardship in their hospital to a certain degree. The median adoption of tasks was two of five tasks (range 1-3). The tasks with the highest uptake were: drafting and maintenance of protocols (100%) and professional's education (58%), while care transition optimization (25%), medication reviews (8%) and patient counseling (8%) had the lowest uptake. All hospitals used a CDSS to monitor safe use of antithrombotics, mainly via basic alerts and less frequently via advanced alerts. The most frequently employed alerts were: identification of patients using a direct oral anticoagulant (DOAC) or a vitamin K antagonist (VKA) with one or more other antithrombotics (n = 6) and patients using a VKA to evaluate correct use (n = 6), both reflecting basic CDSS. All participating hospitals adopted antithrombotic stewardship, but the adopted tasks vary. CDSS alerts used are mainly basic in their logic.

Anticoagulation for stroke prevention in atrial fibrillation and treatment of venous thromboembolism and portal vein thrombosis in cirrhosis: guidance from the SSC of the ISTH.

While advanced liver disease was previously considered to be an acquired bleeding disorder, there is increasing recognition of an associated prothrombotic state with patients being at higher risk of atrial fibrillation (AF) and stroke and venous thromboembolism (VTE) including portal vein thrombosis (PVT). We review the available literature on epidemiology, pathophysiology, and risk factors and provide guidance on anticoagulant management of these conditions in adults with cirrhosis. In patients with Child-Pugh A or B cirrhosis and AF, we recommend anticoagulation with standard-dose direct oral anticoagulants (DOACs) in accordance with cardiology guideline recommendations for patients without liver disease. In those with Child-Pugh C cirrhosis, there is inadequate evidence with respect to the benefit and risk of anticoagulation for stroke prevention in AF. In patients with cirrhosis and acute deep vein thrombosis or pulmonary embolism, we recommend anticoagulation and suggest use of either a DOAC or low-molecular-weight heparin (LMWH)/vitamin K antagonist (VKA) in Child-Pugh A or B cirrhosis and LMWH alone (or as a bridge to VKA in patients with a normal baseline international normalized ratio) in Child-Pugh C cirrhosis. We recommend anticoagulation for patients with cirrhosis and symptomatic PVT. We suggest anticoagulation for those with asymptomatic, progressing PVT and recommend continuing extended anticoagulation for liver transplant candidates with PVT.

The effect of current antithrombotic therapy on mortality in nursing home residents with COVID-19: a multicentre retrospective cohort study.

BACKGROUND: The first wave of COVID led to an alarmingly high mortality rate among nursing home residents (NHRs). In hospitalised patients, the use of anticoagulants may be associated with a favourable prognosis. However, it is unknown whether the use of antithrombotic medication also protected NHRs from COVID-19-related mortality. OBJECTIVES: To investigate the effect of current antithrombotic therapy in NHRs with COVID-19 on 30-day all-cause mortality during the first COVID-19 wave. METHODS: We performed a retrospective cohort study linking electronic health records and pharmacy data in NHRs with COVID-19. A propensity score was used to match NHRs with current use of therapeutic dose anticoagulants to NHRs not using anticoagulant medication. The primary outcome was 30-day all-cause mortality, which was evaluated using a logistic regression model. In a secondary analysis, multivariable logistic regression was performed in the complete study group to compare NHRs with current use of therapeutic dose anticoagulants and those with current use of antiplatelet therapy to those without such medication. RESULTS: We included 3521 NHRs with COVID-19 based on a positive RT-PCR for SARS-CoV-2 or with a well-defined clinical suspicion of COVID-19. In the matched propensity score analysis, NHRs with current use of therapeutic dose anticoagulants had a significantly lower all-cause mortality (OR = 0.73; 95% CI: 0.58-0.92) compared to NHRs who did not use therapeutic anticoagulants. In the secondary analysis, current use of therapeutic dose anticoagulants (OR: 0.62; 95% CI: 0.48-0.82) and current use of antiplatelet therapy (OR 0.80; 95% CI: 0.64-0.99) were both associated with decreased mortality. CONCLUSIONS: During the first COVID-19 wave, therapeutic anticoagulation and antiplatelet use were associated with a reduced risk of all-cause mortality in NHRs. Whether these potentially protective effects are maintained in vaccinated patients or patients with other COVID-19 variants, remains unknown.

Predictive performance of pharmacokinetic-guided prophylactic dosing of factor concentrates in hemophilia A and B.

Background: Pharmacokinetic (PK)-guided dosing is used to individualize factor (F)VIII and FIX replacement therapy. Objectives: This study investigates the reliability and feasibility of PK-guided prophylactic dosing of factor concentrates in hemophilia A and B. Methods: In this multicenter, prospective cohort study, people of all ages with hemophilia received prophylactic treatment with factor concentrates based on individual PK parameters. During follow-up, at least 4 measured FVIII/FIX levels per patient were compared with corresponding predicted levels obtained by Bayesian forecasting. Predictive performance was defined as adequate when ≥80% of measured FVIII/FIX levels were within ±25% of prediction (relative error). Additionally, mean absolute error and mean error were calculated. In post hoc analyses, predictive performance was assessed allowing maximum absolute errors of 1 (trough), 5 (mid), and 15 (peak) IU/dL. Five-point scale questionnaires addressed feasibility of PK guidance. Results: We included 50 patients (median age, 19 years; range: 2-72 years). Median follow-up was 36 weeks. Seventy-one percent of levels (58% trough, 83% mid, and 80% peak) were within ±25% of prediction. Mean absolute errors were 0.8 (trough), 2.0 (mid), and 8.6 (peak) IU/dL. In post hoc analyses, 81% (trough), 96% (mid), and 82% (peak) of levels were within set limits. Patients reported low burden and high satisfaction. Conclusion: PK-guided dosing was reliable according to post hoc analyses, based on low absolute errors that were regarded as clinically irrelevant in most cases. The predefined predictive performance was achieved in mid and peak factor levels but not in trough factor levels due to measurement inaccuracy. PK guidance also seemed feasible.

Tailored anticoagulant treatment after a first venous thromboembolism: protocol of the Leiden Thrombosis Recurrence Risk Prevention (L-TRRiP) study - cohort-based randomised controlled trial.

INTRODUCTION: Patients with a first venous thromboembolism (VTE) are at risk of recurrence. Recurrent VTE (rVTE) can be prevented by extended anticoagulant therapy, but this comes at the cost of an increased risk of bleeding. It is still uncertain whether patients with an intermediate recurrence risk or with a high recurrence and high bleeding risk will benefit from extended anticoagulant treatment, and whether a strategy where anticoagulant duration is tailored on the predicted risks of rVTE and bleeding can improve outcomes. The aim of the Leiden Thrombosis Recurrence Risk Prevention (L-TRRiP) study is to evaluate the outcomes of tailored duration of long-term anticoagulant treatment based on individualised assessment of rVTE and major bleeding risks. METHODS AND ANALYSIS: The L-TRRiP study is a multicentre, open-label, cohort-based, randomised controlled trial, including patients with a first VTE. We classify the risk of rVTE and major bleeding using the L-TRRiP and VTE-BLEED scores, respectively. After 3 months of anticoagulant therapy, patients with a low rVTE risk will discontinue anticoagulant treatment, patients with a high rVTE and low bleeding risk will continue anticoagulant treatment, whereas all other patients will be randomised to continue or discontinue anticoagulant treatment. All patients will be followed up for at least 2 years. Inclusion will continue until the randomised group consists of 608 patients; we estimate to include 1600 patients in total. The primary outcome is the combined incidence of rVTE and major bleeding in the randomised group after 2 years of follow-up. Secondary outcomes include the incidence of rVTE and major bleeding, functional outcomes, quality of life and cost-effectiveness in all patients. ETHICS AND DISSEMINATION: The protocol was approved by the Medical Research Ethics Committee Leiden-Den Haag-Delft. Results are expected in 2028 and will be disseminated through peer-reviewed journals and during (inter)national conferences. TRIAL REGISTRATION NUMBER: NCT06087952.

Peri-operative desmopressin combined with pharmacokinetic-guided factor VIII concentrate in non-severe haemophilia A patients.

INTRODUCTION: Non-severe haemophilia A patient can be treated with desmopressin or factor VIII (FVIII) concentrate. Combining both may reduce factor consumption, but its feasibility and safety has never been investigated. AIM: We assessed the feasibility and safety of combination treatment in nonsevere haemophilia A patients. METHODS: Non-severe, desmopressin responsive, haemophilia A patients were included in one of two studies investigating peri-operative combination treatment. In the single-arm DAVID study intravenous desmopressin (0.3 µg/kg) once-a-day was, after sampling, immediately followed by PK-guided FVIII concentrate, for maximally three consecutive days. The Little DAVID study was a randomized trial in patients undergoing a minor medical procedure, whom received either PK-guided combination treatment (intervention arm) or PK-guided FVIII concentrate only (standard arm) up to 2 days. Dose predictions were considered accurate if the absolute difference between predicted and measured FVIII:C was ≤0.2 IU/mL. RESULTS: In total 32 patients (33 procedures) were included. In the DAVID study (n = 21), of the FVIII:C trough levels 73.7% (14/19) were predicted accurately on day 1 (D1), 76.5% (13/17) on D2. On D0, 61.9% (13/21) of peak FVIII:C levels predictions were accurate. In the Little DAVID study (n = 12), on D0 83.3% (5/6) FVIII:C peak levels for both study arms were predicted accurately. Combination treatment reduced preoperative FVIII concentrate use by 47% versus FVIII monotherapy. Desmopressin side effects were mild and transient. Two bleeds occurred, both despite FVIII:C > 1.00 IU/mL. CONCLUSION: Peri-operative combination treatment with desmopressin and PK-guided FVIII concentrate dosing in nonsevere haemophilia A is feasible, safe and reduces FVIII consumption.

Smaller nadroparin dose reductions required for patients with renal impairment: A multicenter cohort study.

BACKGROUND: Guidelines advise 50 % and 25 % dose reduction of the therapeutic nadroparin dose (86 IU/kg) in patients with eGFR 15-29 and 30-60 ml/min respectively. For monitoring, peak anti-Xa levels are suggested. Data lack whether this results in therapeutic anti-Xa levels or in anti-Xa levels that are comparable to those of patients without renal impairment. AIMS: To determine dose ranges in patients with renal impairment that result in therapeutic anti-Xa levels and to determine the percentage of the 86 IU/kg dose that results in anti-Xa levels normally occurring in patients without renal impairment. METHODS: A retrospective cohort study was conducted in five hospitals. Patients ≥18 years of age, with an eGFR ≥ 15 ml/min were included. The first correctly sampled peak (i.e. 3-5 h after ≥ third administration, regardless of dose per patient) was included. Simulated prediction models were developed using multiple linear regression. RESULTS: 770 patients were included. eGFR and hospital affected the association between dose and anti-Xa level. The doses for peak anti-Xa levels of 0.75 IU/ml differed substantially between hospitals and ranged from 55 to 91, 65-359 and 68-168 IU/kg in eGFR 15-29, 30-60 and > 60 ml/min/1.73m2, respectively. In eGFR 15-29 and 30-60 ml/min/1.73m2, doses of 75 % and 91 % of 86 IU/kg respectively, were needed for anti-Xa levels normally occurring in patients with eGFR > 60 ml/min. CONCLUSION: We advise against anti-Xa based dose-adjustments as long as anti-Xa assays between laboratories are not harmonized and an anti-Xa target range is not validated. A better approach might be to target levels similar to eGFR > 60 ml/min/1.73m2, which are achieved by smaller dose reductions.

Interim analyses of the multinational real-world prospective cohort HEM-POWR study evaluating the effectiveness and safety of damoctocog alfa pegol in patients with hemophilia A.

OBJECTIVES: To assess effectiveness and safety of damoctocog alfa pegol in interim analyses of the ongoing real-world hemophilia A HEM-POWR study. METHODS: HEM-POWR (NCT03932201) is a multinational Phase 4 prospective observational study. The primary objective was annualized bleeding rate (ABR) in previously treated patients (PTPs) with hemophilia A. Secondary objectives included adverse events and number of affected joints. RESULTS: At data cut-off (August 17, 2022), the safety analysis set included 268 patients and the full analysis set (FAS) included 161 patients. The most common dosing regimen during observation period was prophylaxis (FAS = 158/161, 98.1%) every 3-4 days (twice weekly; FAS = 78/158, 49.4%) and a median (min, max) infusion dose of 37.5 (10, 72) IU/kg. PTPs receiving prophylactic damoctocog alfa pegol have fewer infusions compared with prior treatment. Median total ABR (Q1, Q3) was 0.0 (0.0, 1.8) and mean total ABR (SD) was 2.4 (8.2). The proportion of patients with no affected joints increased between initial visit and follow-up. No FVIII inhibitors, treatment-related adverse events, or deaths were reported. CONCLUSIONS: Damoctocog alfa pegol shows effectiveness and acceptable safety, as well as consistent utilization, in real-world PTPs with hemophilia A, including in patients with non-severe hemophilia and those with a history of inhibitors. Please see video for a summary of this study.

Type 1 VWD classification revisited: novel insights from combined analysis of the LoVIC and WiN studies.

ABSTRACT: There is significant ongoing debate regarding type 1 von Willebrand disease (VWD) defintion. Previous guidelines recommended patients with von Willebrand factor (VWF) levels <30 IU/dL be diagnosed type 1 VWD, whereas patients with significant bleeding and VWF levels from 30 to 50 IU/dL be diagnosed with low VWF. To elucidate the relationship between type 1 VWD and low VWF in the context of age-induced increases in VWF levels, we combined data sets from 2 national cohort studies: 162 patients with low VWF from the Low VWF in Ireland Cohort (LoVIC) and 403 patients with type 1 VWD from the Willebrand in The Netherlands (WiN) studies. In 47% of type 1 VWD participants, VWF levels remained <30 IU/dL despite increasing age. Conversely, VWF levels increased to the low VWF range (30-50 IU/dL) in 30% and normalized (>50 IU/dL) in 23% of type 1 VWD cases. Crucially, absolute VWF antigen (VWF:Ag) levels and increase of VWF:Ag per year overlapped between low VWF and normalized type 1 VWD participants. Moreover, multiple regression analysis demonstrated that VWF:Ag levels in low VWF and normalized type 1 VWD patients would not have been different had they been diagnosed at the same age (ß = 0.00; 95% confidence interval, -0.03 to 0.04). Consistently, no difference was found in the prevalence of VWF sequence variants; factor VIII activity/VWF:Ag or VWF propeptide/VWF:Ag ratios; or desmopressin responses between low VWF and normalized type 1 VWD patients. In conclusion, our findings demonstrate that low VWF does not constitute a discrete clinical or pathological entity. Rather, it is part of an age-dependent type 1 VWD evolving phenotype. Collectively, these data have important implications for future VWD classification criteria.

Ethical aspects of hemophilia gene therapy: a qualitative interview study with stakeholders.

Background: There are great expectations for the potential role of gene therapy in the treatment of hemophilia. At the same time, developments in the field of hemophilia gene therapy have always raised ethical issues. It remains unknown how these ethical issues are perceived by stakeholders, particularly regarding the most recent developments in the field. Objectives: To obtain insight into stakeholders' morally reasoned opinions on gene therapy for hemophilia. Methods: We conducted qualitative research with Dutch people with hemophilia (n = 13), parents of children with hemophilia (n = 5), physicians (n = 4), nurses (n = 3), a regulator (n = 1), and a representative from a pharmaceutical company (n = 1). We conducted semistructured interviews based on a topic list and reported the results according to the Consolidated Criteria for Reporting Qualitative Research guidelines. Results: We identified 3 main themes. The theme freedom and independence describes the hope people with hemophilia have of increasing their freedom through gene therapy, as well as concerns that gene therapy increases their dependence on their treatment center. The theme trust and altruism describes how people with hemophilia have a high level of trust in their physician and treatment center as well as in scientific research. As a result of this trust, they are willing to participate in research to help other people with hemophilia. The theme incremental benefits describes doubts respondents have about the added value of gene therapy compared to standard treatment. Conclusion: Stakeholders embrace the theoretical potential of gene therapy, while several people with hemophilia question the added value of the current gene transfer products for themselves.

Effect of Previous INR Control during VKA Therapy on Subsequent DOAC Adherence and Persistence, in Patients Switched from VKA to DOAC.

INTRODUCTION: Current guideline suggests a switch from vitamin K antagonist (VKA) to direct oral anticoagulant (DOAC) in patients with low time in therapeutic range (TTR < 70%). Poor international normalized ratio (INR) control may be the result of poor compliance, and might therefore be associated with subsequent DOAC intake. Therefore, this study evaluates the effect of previous TTR and other measures of INR control on DOAC nonadherence and nonpersistence, in patients who switched from VKA to DOAC. METHODS: A total of 437 patients who switched from VKA to DOAC between 2012 and 2019 were included using data from Certe Thrombosis Service, IADB.nl pharmacy community database University Groningen, and Statistics Netherlands. DOAC prescriptions were used to determine nonadherence and nonpersistence. INR control (i.e., TTR, time under therapeutic range [TUR], and INR variability) was assessed during the last 180 days of VKA use. Multivariable regression models were applied to determine the association between INR control and DOAC nonpersistence/nonadherence. RESULTS: On VKA, 67.7% of the patients had a TTR below 70%. DOAC nonpersistence was 39.8% (95% confidence interval [CI]: 33.4-45.5%) during a median follow-up of 34.4 months (interquartile range: 19.1-49.2). Approximately 80% of persistent patients were DOAC-adherent. Low TTR was not associated with DOAC nonpersistence (hazard ratio: 1.14, 95% CI: 0.69-1.87) and DOAC nonadherence (odds ratio: 1.38, 95% CI: 0.67-2.84), nor were TUR and INR variability. CONCLUSION: Previous INR control during VKA therapy is not associated with subsequent DOAC nonadherence and nonpersistence. This study suggests that INR control on VKA cannot, and therefore should not, be used for predicting DOAC adherence or persistence.

Exploring heterogeneity in reported venous thromboembolism risk in COVID-19 and comparison to other viral pneumonias: a systematic review and meta-regression.

Background: Sources of heterogeneity in venous thromboembolism (VTE) risk in COVID-19 are unclear and comparisons to other viruses are lacking. Objectives: To describe VTE risk in patients with COVID-19, explore sources of heterogeneity, and make comparisons with other viral pneumonia. Methods: PubMed and Embase data were searched on March 14, 2021, for studies on VTE in adults hospitalized with viral pneumonia. VTE risk estimates were pooled in a random effects meta-analysis stratified by virus type. Heterogeneity in COVID-19 was explored in multivariable meta-regression. Results: Seventy studies in COVID-19 (intensive care [ICU] [47] vs ward [23]), 4 studies in seasonal influenza (ICU [3] vs ward [1]), 2 ICU studies in H1N1 and 1 ICU study in SARS-CoV-1 were included. For COVID-19 ICU, pooled VTE risk was 19.6% (95% confidence interval [CI], 16.2%-23.5; I2 = 92.8%) for nonscreening studies and 30.0% (95% CI, 17.9%-45.7%; I2 = 81.9%) for screening studies. For COVID-19 ward, pooled VTE risk was 3.4% (95% CI, 2.4%-4.7%; I2 = 91.3%) and 22.5% (95% CI, 10.2%-42.7%; I2 = 91.6%) for nonscreening and screening studies, respectively. Higher sample size was associated with lower VTE risk. Pooled VTE risk in seasonal influenza and H1N1 at ICU were 9.0% (95% CI, 5.6%-14.2%; I2 = 39.7%) and 29.2% (95% CI, 8.7%-64.2%; I2 = 77.9%), respectively. At ward, VTE risk of seasonal influenza was 2.4% (95% CI, 2.1%-2.7%). In SARS-CoV-1, VTE risk was 47.8% (95% CI, 34.0-62.0). Conclusion: Pooled risk estimates in COVID-19 should be interpreted cautiously as a high degree of heterogeneity is present, which hinders comparison to other viral pneumonia. The association of VTE risk in COVID-19 to sample size suggests publication bias.

High prevalence of heavy menstrual bleeding in women with rare bleeding disorders in the Netherlands: retrospective data from the RBiN study.

BACKGROUND: Heavy menstrual bleeding (HMB) is associated with a reduced quality of life and limitations in social and physical functioning. Data on HMB in women with rare bleeding disorders (RBDs), including coagulation factor deficiencies and fibrinolytic disorders, are scarce. OBJECTIVES: To analyze the prevalence, severity, and treatment of HMB in Dutch women with an RBD. METHODS: The Rare Bleeding Disorders in the Netherlands (RBiN) study included 263 patients with an RBD from all 6 hemophilia treatment centers (October 2017-November 2019). In this analysis, data of 111 women aged ≥16 years were studied. According to the International Society on Thrombosis and Haemostasis bleeding assessment tool, HMB symptoms were scored from 0 (no/trivial) to 4 (severe symptoms requiring medical intervention). HMB was defined as a score ≥1. Age at RBD diagnosis was extracted from patient files. RESULTS: HMB was reported by 80% of women (89/111) and was more prevalent in women with a fibrinolytic disorder (33/35; 94%) than in women with a coagulation factor deficiency (56/76; 74%) (P = .011). Of the 89 women with HMB, 82% (n = 73) ever required treatment. Multiple treatment modalities were frequently used, both in severe and mild deficiencies. Hormonal treatment was mostly used (n = 64; 88%), while antifibrinolytics were prescribed less frequently (n = 18; 25%). In women with HMB since menarche (n = 61; 69%), median age at RBD diagnosis was 28 years (IQR, 14-41). CONCLUSION: HMB is common in women with RBDs. Women with mild deficiencies also frequently reported HMB. Only a minority of women were treated with hemostatic agents. A significant diagnostic delay was observed after the onset of HMB symptoms.

Implementation of a Patient Questionnaire in Community Pharmacies to Improve Care for Patients Using Combined Antithrombotic Therapy: A Qualitative Study.

For several indications or combinations of indications the use of more than one antithrombotic agent is required. The duration of combined antithrombotic therapy depends on indication and patient characteristics. This study investigated the use of an antithrombotic questionnaire tool that had been developed for pharmacists to detect patients with possible incorrect combined antithrombotic therapy. The objective of this study was to identify potential barriers and facilitators that could influence the implementation of the developed antithrombotic questionnaire tool in daily community pharmacy practice. A qualitative study was conducted at 10 Dutch community pharmacies in which the antithrombotic questionnaire tool had been used with 82 patients. Semi-structured interviews were conducted with pharmacy staff who used the antithrombotic questionnaire tool. The interview questions to identify barriers and facilitators were based on the Consolidated Framework for Implementation Research. The interview data were analysed using a deductive thematic analysis. Ten staff members from nine different pharmacies were interviewed. Facilitators for implementation were that the questionnaire was easily adaptable and easy to use, as well as the relative short duration to administer the questionnaire. A possible barrier for using the questionnaire was a lower priority for using the questionnaire at moments when the workload was high. The pharmacists estimated that the questionnaire could be used for 70-80% of the patient population and they thought that it was a useful addition to regular medication surveillance. The antithrombotic questionnaire tool can be easily implemented in pharmacy practice. To implement the tool, the focus should be on integrating its use into daily activities. Pharmacists can use this tool in addition to regular medication surveillance to improve medication safety in patients who use combined antithrombotic therapy.

Adherence to protocols for the use of reversal agents in patients treated with direct oral anticoagulants.

OBJECTIVES: This study aimed to evaluate the adherence to protocols for the use of reversal agents in direct oral anticoagulant (DOAC) users in Dutch hospitals. METHODS: A retrospective cohort study was conducted in seven hospitals in the Netherlands. Treatment protocols for bleeding and (urgent) procedures in patients on DOAC were collected from each hospital. All patient data on the use of reversal agents were retrospectively collected from September 2021 to April 2022 and compared to the protocols. The degree of per-protocol adherence (compliance score) was categorized into four levels as follows: poor (<45%), moderate (45-79%), high (80-89%), and full (> 90%) adherence rates. RESULTS: A total of 290 patients were included in our study. In patients with bleeding under DOAC, the protocol adherence for prothrombin complex concentrate (PCC) was "moderate" (61%). In the remaining cases (39%), non-adherence was mainly caused by underdosing (68%), overdosing (12%), and a lack of indication (14%). Furthermore, idarucizumab was administered for bleeding with "full" adherence (96%). For andexanet alfa, adherence to the hospital bleeding protocol was "moderate" (67%), with a lack of indication being the only reason for non-adherence. In case of reversal for an urgent procedure, the protocol adherence for PCC was "low" (45%), with underdosing, a lack of indication, and missing lab data being the main reasons for non-adherence. Missing lab data on dabigatran plasma concentration before reversal was the main reason for "low" adherence (26%) in idarucizumab. The adherence for andexanet alfa was also "low" (0%). CONCLUSION: In case of reversal for bleeding under DOAC, overall adherence to the protocol was "moderate"; however, in patients needing an urgent procedure, it was "low." The major reasons for non-adherence were underdosing, off-label use, and a lack of specific lab testing. The results of this study can assist in improving the implementation of hospital protocols.

Occurrence of FVIII Inhibitors in Hemophilia A Patients Following an Institutional Switch to a Third Generation B-Domain-Deleted FVIII.

In 2018, Refacto AFR, a B-domain-deleted third-generation FVIII concentrate, became our preferential product. After the introduction, the development of inhibitors was prospectively monitored; retrospectively, we sought for risk factors in the patients who developed a de-novo inhibitor. Over a period of 15 months, 4/19 adult patients with non-severe haemophilia who were treated on demand for surgery, developed high titer antibodies to FVIII after administration of Refacto AFR; 5/52 mostly severe patients on prophylaxis, developed an inhibitor (3 ≥ 0.1 BU; 1 > 0.6 BU, 1 high titre) after they switched to Refacto AFR; all were children <14 years of age and with >100 exposure days, none related to surgery or intensive treatment; all received KovaltryR before. In conclusion: inhibitors were encountered in on demand patients and previously treated prophylaxis patients; this observation might be a coincidental finding, but also risk factors like genotype and surgery and/or that Refacto AFR is more immunogenic should be considered. For the patients on prophylaxis we hypothesize that loss of tolerance by preceding KovaltryR might have contributed to inhibitor development.