Anne-Sophie Larock

Appropriateness of Prescribing Dabigatran Etexilate and Rivaroxaban in Patients With Nonvalvular Atrial Fibrillation A Prospective Study

Background: Direct oral anticoagulants have been developed to address some of the drawbacks of vitamin-K antagonists. However, special attention should be given when using these drugs, especially in patients with renal insufficiency, questionable compliance, and those at high risk of bleeding. Objective: To evaluate the appropriateness of prescribing dabigatran etexilate (DE) and rivaroxaban in patients with nonvalvular atrial fibrillation (NVAF) in real-life clinical practice. Methods: This was a prospective study that included patients presenting to a teaching hospital from April to mid-October 2013, who were taking rivaroxaban or DE for NVAF. Appropriateness of prescribing was evaluated using 9 of the 10 criteria of the Medication Appropriateness Index. The primary outcome measure was the prevalence of inappropriate prescribing. Secondary outcome measures included (a) categories of inappropriateness, (b) prevalence of adverse drug events, and (c) interventions made by a clinical pharmacist to optimize prescribing. Results: A total of 69 patients were evaluated; 16 patients (23%) had 1 inappropriate criterion, and an additional 18 (26%) had more than 1 inappropriate criterion. The most frequent inappropriate criteria were inappropriate choice (28% of patients), wrong dosage (26%), and impractical modalities of administration (26%). An adverse event (AE) was found in 51% of patients (including 8 patients with transient ischemic attack/stroke). The clinical pharmacists performed 48 interventions, and 94% were accepted by the physician. Conclusions: Inappropriate use of DE and rivaroxaban in patients with NVAF is frequent and possibly leads to AEs. Reinforcing education of health care professionals and patients is needed. Collaboration with clinical pharmacists can contribute to better use.

Estimation of Rivaroxaban Plasma Concentrations in the Perioperative Setting in Patients With or Without Heparin Bridging

Introduction: Estimation of residual rivaroxaban plasma concentrations may be requested before invasive procedures and some patients at high thromboembolic risk will have a bridging therapy with heparins when rivaroxaban is interrupted. Objective: The objective of this study was to assess the performance of the STA-Liquid Anti-Xa assay (STA LAX) and the low and normal procedures of the Biophen Direct Factor Xa Inhibitors (DiXaI) assay, in patients with and without bridging with low-molecular-weight heparins (LMWHs). Materials and Methods: Seventy-nine blood samples were collected from 77 patients on rivaroxaban at CTROUGH or before an invasive procedure. Rivaroxaban plasma concentrations were estimated using Biophen DiXaI, Biophen DiXaI LOW, and STA LAX and compared to liquid chromatography coupled with mass spectrometry (LC-MS/MS) measurements. Stratifications were performed according to heparin bridging. Results: The Biophen DiXaI LOW and STA LAX showed better correlation with LC-MS/MS measurements than Biophen DiXaI in patients not bridged with LMWH (R: 0.97, 0.96, and 0.91, respectively). However, the performance of Biophen DiXaI LOW and STA LAX decreased when residual LMWH activity was present (R: 0.18 and 0.19 respectively) demonstrating that these tests are not specific to rivaroxaban. Conclusion: In patients not bridged with LMWH, we suggest to use the Biophen DiXaI LOW and STA LAX for the estimation of rivaroxaban concentrations <50 ng/mL. These results should be confirmed on a larger cohort of patients. Patients bridged with LMWH have inaccurate estimates of low levels of rivaroxaban and the 3 assays studied should not be used to estimate if it is safe to perform a procedure.

An optimized dRVVT-based assay to estimate the intensity of anticoagulation in patients treated with direct oral anticoagulants

BACKGROUND The dilute Russells viper venom time (dRVVT) has been suggested for the assessment of the intensity of anticoagulation of all direct oral anticoagulants (DOACs). This study aimed to compare the performance of an optimized liquid-stable dRVVT-based DOAC assay (DRVV-DOAC) on clinical samples before and after mixing these with normal pooled plasma (NPP). METHODS Forty-one apixaban, 25 dabigatran, 56 rivaroxaban and 49 vitamin K antagonists (VKAs) plasma samples were included for retrospective analysis. Plasma DOAC concentrations were determined by liquid chromatography coupled with tandem mass-spectrometry. INR was determined for all VKA samples. DRVV-DOAC was performed with an original ready-to-use reagent (Haematex Research™) where plasma samples were tested neat and in a 1:1 mix with NPP. RESULTS Plasma concentrations ranged from 1 to 406ng/ml for apixaban, 0 to 386ng/ml for dabigatran and 0 to 719ng/ml for rivaroxaban. INR ranged from 2.2 to 6.1. DRVV-DOAC correlated well with plasma concentrations (r2=0.70, 0.94, 0.63 (non-mixed procedure) and 0.77, 0.97, 0.86 (mixed procedure) for apixaban, dabigatran and rivaroxaban, respectively). DRVV-DOAC measurements in the normal range ruled out dabigatran and rivaroxaban concentrations above 30 and 50ng/ml, but performance was lower for apixaban. DRVV-DOAC was sensitive to VKA samples but poorly reflected INR values. When VKA samples were mixed with NPP, DRVV-DOAC measurements decreased to values close to baseline clotting time. CONCLUSIONS DRVV-DOAC is a quick method which showed increased sensitivity compared with other phospholipid-rich dRVVT reagents already investigated. Mixing samples with NPP improved the specificity but reduced sensitivity, especially for apixaban.

Idarucizumab for the treatment of hemorrhage and dabigatran reversal in patients requiring urgent surgery or procedures

ABSTRACT Introduction: Idarucizumab is a specific antagonist for dabigatran etexilate (DE). The recent market authorization of idarucizumab in Europe and the USA may reassure prescribers of DE, as it can increase the safety of the emergency management of patients taking this anticoagulant. However, idarucizumab use should be limited to specific indications to avoid unnecessary risks to patients and costs to healthcare systems. Areas covered: The authors provide an overview of idarucizumab development and its pharmacokinetic and pharmacodynamic properties. The results of the clinical phase III trial RE-VERSE AD and a review of recent case reports of idarucizumab use in emergency contexts are also discussed. Expert opinion: Although idarucizumab has shown clear efficacy in reversing dabigatran-induced coagulopathy, its overall effects on patient outcome have not been proven. Information regarding the clinical context in which patients on DE are admitted for emergency treatment, and accurate laboratory tests of dabigatran plasma level during reversal may inform selection and help with the follow-up of patients who may benefit from idarucizumab. Idarucizumab should be integrated into protocol for the emergency management of patients on DE. Furthermore, the benefit of idarucizumab in specific indications such as acute ischemic stroke should be investigated.

Preventability of serious thromboembolic and bleeding events related to the use of oral anticoagulants: a prospective study

To determine the preventability of serious adverse drug reactions (ADRs) related to the use of direct oral anticoagulants (DOACs), and to explore contributing factors to preventable ADRs. Results were compared with vitamin K antagonists (VKAs).

Partial economic evaluation of clinical pharmacy interventions on the prescription of direct oral anticoagulants in a teaching hospital

Background Potential inappropriate use of direct oral anticoagulants (DOACs) increases the risk of thromboembolic and haemorrhagic events. Purpose To determine the net cost benefit of clinical pharmacy interventions on the prescription of DOACs. Method We constructed a decision tree model using a public payer perspective. The appropriateness of the prescription was assessed using the Medication Appropriateness Index. The theoretical risks were collected from the literature and the individual potential risks were calculated using the Nesbit risk assignment conducted by two independent clinical pharmacists. Different costs were included based on diagnosis-related group coding and data in the literature. A univariate sensitivity analysis was performed. Results Thirty-six of 75 patients had an inappropriate prescription of DOACs. The saved difference between avoided costs (7954€) and annualised medication costs and pharmacist cost (4323€) was 3631€ for 75 patients. Conclusions In addition to the enhancement of the quality of the prescription, our results indicate that pharmacist interventions provide a positive net cost benefit.

4CPS-230 Prospective study to explore the impact of a clinical pharmacist in a cardiac surgical population or after acute coronary syndrome

Background Patients in the intensive care unit (ICU) are at risk of medication errors (polypharmacy, critical nature of their illnesses and use of high-risk drugs). Collaboration with a clinical pharmacist can be helpful in minimising these risks. In order to develop and sustain clinical pharmacy activity in the ICU at our hospital, formal evaluation of the potential benefit was required. Purpose To describe the characteristics of interventions performed by an ICU clinical pharmacist, including their clinical relevance and likelihood of preventing adverse drug events (ADEs), as well as carrying out a cost analysis on a subgroup of critical interventions. Material and methods A prospective interventional study was conducted in the cardiac and cardio-surgical ICU of a university teaching hospital. The clinical pharmacist provided pharmaceutical care to cardiovascular surgical and acute coronary syndrome ICU patients over a 9 week period. All clinical pharmacy interventions (CPIs) were recorded and evaluated by two independent evaluators for clinical relevance and likelihood of preventing ADEs. The CPIs were categorised in a risk classification system adapted from the Society of Hospital Pharmacists of Australia. For the cost analysis, we relied on German adverse drug events micro-costing data by Rottenkolber et al. Results A total of 230 CPIs were performed in 58 patients. The acceptance rate was 85.5%. The medication classes most frequently involved were: blood and coagulation (16.9%), cardiovascular system (14.8%), pain and fever drugs (14.8%). Sixty-six (33.8%) interventions were considered high/extreme risk, and anticoagulants and antiplatelet agents alone accounted for 25.8% of those. The cut-off to cover the salary of the clinical pharmacist could be reached, if 24 severe adverse events on anticoagulants and antiplatelet agents were avoided per 7 weeks. Two-thirds of all CPIs required the presence of the pharmacist in the unit. Analysis of the medical record (45.1%) and contact with a primary care provider (46.7%) were proportionally the sources of information most often used in the case of high/extreme CPIs. Conclusion This study provides data that supports the expansion of clinical pharmacy services to cardiovascular surgical patients in the ICU. Reference and/or Acknowledgements 1. Rottenkolber D, et al. Costs of adverse drug events in German hospitals – a microcosting study. Value Health2012Sep–Oct;15(6):868–875. No conflict of interest

Matrix effect of commercially available direct oral anticoagulant standards: a look through the limits and the need for standardization of current calibrators

Abstracts Supported bys Supported by ABSTRACTS OF THE 62ND ANNUAL MEETING OF THE SCIENTIFIC AND STANDARDIZATION COMMITTEE OF THE INTERNATIONAL SOCIETY ON THROMBOSIS AND HAEMOSTASIS MAY 25–28, 2016S OF THE 62ND ANNUAL MEETING OF THE SCIENTIFIC AND STANDARDIZATION COMMITTEE OF THE INTERNATIONAL SOCIETY ON THROMBOSIS AND HAEMOSTASIS MAY 25–28, 2016 Animal, Cellular and Molecular Models AMC01 Endothelial injury and hypoxia enhances neutrophil recruitment, extravasation, and apoptosis during thrombus formation Nishimura S, Seo K and Sakata A Jichi Med Univ, and the Univ of Tokyo, Tochigi, Japan; Jichi Med Univ, Tochigi, Japan Background: Primary trigger of cardiovascular events remains unclear due to the absence of direct analysis tools of in vivo thrombus formation. Aims: To elucidate blood cell behavior and vascular responses, we improved in vivo imaging technique based on multi-photon microscopy, and analyzed new three animal thrombus formation models. Methods:We combined multi-photon microscope technique, and lightmanipulations system, which enabled us to evaluate platelet aggregations by photochemical reactions. Results: First, we induced rapidly developing thrombi composed of discoid platelets, which was triggered by ROS production without endothelial damage. Discoid platelet activations and aggregations were induced without leukocyte recruitment in this system. Second, thrombus formation was also induced by direct endothelial cell disruption by femto-second laser irradiations. With the rapid recruitment of inflammatory neutrophils into damaged area, following fibrin net formation and tissue regenerative changes were observed, indicating tight association between endothelial damage and inflammatory reactions, Spontaneous apoptotic neutrophil death, and endothelial-neutrophilinteractions were induced after platelet aggregations. Last, platelet aggregations, and inflammatory neutrophil recruitment were also observed after transient ischemia and reperfusion. Combination of hypoxia and endothelial injury enhanced thrombus formation, and extravasation steps were remarkably enhanced. Leukocyte escaped from specific and limited “holes” in endothelial junctions. Conclusions: Intravital visualization of thrombus formation elucidated association of inflammation of endothelium, leukocyte recruitment, and platelet aggregations in vivo. Neutrophils were selectively recruited in early phase, which was enhanced by endothelial damages and hypoxic conditions. Our real-time imaging system can evaluate multicellular thrombotic processes and therapeutic strategies against them. AMC02 TMEM16F-mediated platelet pro-coagulant activity contributes to infarct progression after ischemic stroke Baig AA, Haining EJ, Geuss E, Beck S, Stegner D, Kleinschnitz C, Braun A and Nieswandt B University of W€ urzburg, Rudolf Virchow Center for Experimental Biomedicine, Wuerzburg, Germany; University Hospital of W€ urzburg, Department of Experimental Biomedicine, Wuerzburg, Germany; University Hospital of W€ urzburg, Department of Neurology, Wuerzburg, Germany Background: Transmembrane protein TMEM16F, mutated in patients with the bleeding disorder Scott syndrome, is important for the scrambling of phosphatidylserine (PS) to the platelet surface upon platelet activation. Thus, it plays an essential role in the platelet pro-coagulant response. However, the contribution of TMEM16F and the pro-coagulant activity of platelets to thrombo-inflammation after ischemic stroke is unknown. Aims: To investigate the pathophysiological role of TMEM16Fmediated platelet pro-coagulant activity in the setting of ischemic stroke. Methods: A platelet and megakaryocyte specific TMEM16F knockout (KO) mouse was generated by targeted deletion of exon 3 in the Anoctamin6 gene. The mice were assessed in the transient middle cerebral artery occlusion (tMCAO)model of ischemic stroke in addition tomodels of thrombosis and hemostasis, as well as in vitro platelet analyses. Results: TMEM16F KO platelets exposed significantly less PS and also failed to acquire a ballooned morphology after stimulation with ionomycin, indicating a reduced pro-coagulant potential. Likewise, thrombinoscope measurements showed that time to peak thrombin concentration was significantly delayed in KO platelet rich plasma (PRP), as compared to WT PRP. KO mice displayed significantly prolonged tail bleeding times, and were protected in a model of ferric chloride induced thrombosis in the carotid artery, confirming previous reports. These results highlighted the TMEM16F KO as a suitable model with which to investigate the pathophysiological significance of pro-coagulant platelets in cerebral infarct progression following tMCAO. Initial experiments indicate that female TMEM16F KO mice are protected from infarct growth after tMCAO. Further experiments are underway to test if this is also the case in male mice and to understand how pro-coagulant platelets contribute to thrombo-inflammation during ischemic-reperfusion injury. Figure 1

Impact of apixaban on the Dilute Russell’s viper venom time: an ex-vivo study

Abstracts Supported bys Supported by ABSTRACTS OF THE 62ND ANNUAL MEETING OF THE SCIENTIFIC AND STANDARDIZATION COMMITTEE OF THE INTERNATIONAL SOCIETY ON THROMBOSIS AND HAEMOSTASIS MAY 25–28, 2016S OF THE 62ND ANNUAL MEETING OF THE SCIENTIFIC AND STANDARDIZATION COMMITTEE OF THE INTERNATIONAL SOCIETY ON THROMBOSIS AND HAEMOSTASIS MAY 25–28, 2016 Animal, Cellular and Molecular Models AMC01 Endothelial injury and hypoxia enhances neutrophil recruitment, extravasation, and apoptosis during thrombus formation Nishimura S, Seo K and Sakata A Jichi Med Univ, and the Univ of Tokyo, Tochigi, Japan; Jichi Med Univ, Tochigi, Japan Background: Primary trigger of cardiovascular events remains unclear due to the absence of direct analysis tools of in vivo thrombus formation. Aims: To elucidate blood cell behavior and vascular responses, we improved in vivo imaging technique based on multi-photon microscopy, and analyzed new three animal thrombus formation models. Methods:We combined multi-photon microscope technique, and lightmanipulations system, which enabled us to evaluate platelet aggregations by photochemical reactions. Results: First, we induced rapidly developing thrombi composed of discoid platelets, which was triggered by ROS production without endothelial damage. Discoid platelet activations and aggregations were induced without leukocyte recruitment in this system. Second, thrombus formation was also induced by direct endothelial cell disruption by femto-second laser irradiations. With the rapid recruitment of inflammatory neutrophils into damaged area, following fibrin net formation and tissue regenerative changes were observed, indicating tight association between endothelial damage and inflammatory reactions, Spontaneous apoptotic neutrophil death, and endothelial-neutrophilinteractions were induced after platelet aggregations. Last, platelet aggregations, and inflammatory neutrophil recruitment were also observed after transient ischemia and reperfusion. Combination of hypoxia and endothelial injury enhanced thrombus formation, and extravasation steps were remarkably enhanced. Leukocyte escaped from specific and limited “holes” in endothelial junctions. Conclusions: Intravital visualization of thrombus formation elucidated association of inflammation of endothelium, leukocyte recruitment, and platelet aggregations in vivo. Neutrophils were selectively recruited in early phase, which was enhanced by endothelial damages and hypoxic conditions. Our real-time imaging system can evaluate multicellular thrombotic processes and therapeutic strategies against them. AMC02 TMEM16F-mediated platelet pro-coagulant activity contributes to infarct progression after ischemic stroke Baig AA, Haining EJ, Geuss E, Beck S, Stegner D, Kleinschnitz C, Braun A and Nieswandt B University of W€ urzburg, Rudolf Virchow Center for Experimental Biomedicine, Wuerzburg, Germany; University Hospital of W€ urzburg, Department of Experimental Biomedicine, Wuerzburg, Germany; University Hospital of W€ urzburg, Department of Neurology, Wuerzburg, Germany Background: Transmembrane protein TMEM16F, mutated in patients with the bleeding disorder Scott syndrome, is important for the scrambling of phosphatidylserine (PS) to the platelet surface upon platelet activation. Thus, it plays an essential role in the platelet pro-coagulant response. However, the contribution of TMEM16F and the pro-coagulant activity of platelets to thrombo-inflammation after ischemic stroke is unknown. Aims: To investigate the pathophysiological role of TMEM16Fmediated platelet pro-coagulant activity in the setting of ischemic stroke. Methods: A platelet and megakaryocyte specific TMEM16F knockout (KO) mouse was generated by targeted deletion of exon 3 in the Anoctamin6 gene. The mice were assessed in the transient middle cerebral artery occlusion (tMCAO)model of ischemic stroke in addition tomodels of thrombosis and hemostasis, as well as in vitro platelet analyses. Results: TMEM16F KO platelets exposed significantly less PS and also failed to acquire a ballooned morphology after stimulation with ionomycin, indicating a reduced pro-coagulant potential. Likewise, thrombinoscope measurements showed that time to peak thrombin concentration was significantly delayed in KO platelet rich plasma (PRP), as compared to WT PRP. KO mice displayed significantly prolonged tail bleeding times, and were protected in a model of ferric chloride induced thrombosis in the carotid artery, confirming previous reports. These results highlighted the TMEM16F KO as a suitable model with which to investigate the pathophysiological significance of pro-coagulant platelets in cerebral infarct progression following tMCAO. Initial experiments indicate that female TMEM16F KO mice are protected from infarct growth after tMCAO. Further experiments are underway to test if this is also the case in male mice and to understand how pro-coagulant platelets contribute to thrombo-inflammation during ischemic-reperfusion injury. Figure 1

CP-057 Partial economic evaluation of pharmaceutical interventions on the prescription of direct oral anticoagulants in a teaching hospital

Background Direct oral anticoagulants (DOAC) are widely used in patients with atrial fibrillation. However, inappropriate use is prevalent, and this potentially increases the risk of thromboembolic and haemorrhagic events. These events also imply an important economic burden. In our institution, a clinical pharmacist is dedicated to performing medication review for all DOAC patients. Purpose To determine the net cost avoidance of pharmaceutical interventions on the DOAC prescription. Material and methods We constructed a decision tree model, using a public payer perspective. We included hospitalised medical patients taking a DOAC. The appropriateness of the prescription was assessed using nine items of the Medication Appropriatenes Index1. The theoretical thromboembolic and haemorrhagic risks of patients under DOAC were collected from the literature. Evaluation of the individual potential risks was based on the Nesbit risk assignment conducted by two independent clinical pharmacists2. Based on diagnosis related group coding and literature data, different costs were included: institutional disease costs of complications, annualised ambulatory stroke costs, drugs costs and pharmacist costs. In the reference case we did not add consultancy fees for the pharmacist. A univariate sensitivity analysis was performed to evaluate the robustness of our results and key assumptions. Results 75 patients met the inclusion criteria. 36 (48%) had an inappropriate DOAC prescription. The net cost benefit analysis showed that the saved difference between avoided costs (7954€) and annualised medication costs and pharmacist costs (4 323€) was 3631€ for 75 patients. The univariate sensitivity analysis enlightened a net cost benefit if the prevalence of inappropriate prescribing and disease costs decreased to 28% and 45%, respectively. Conclusion Besides enhancement of the prescription’s quality by the clinical pharmacist, our results provide evidence that this intervention brings positive economic benefits. A complete economic analysis should be considered to demonstrate the cost effectiveness of a clinical pharmacist. References and/or Acknowledgements Larock AS, et al. Appropriateness of prescribing dabigatran etexilate and rivaroxaban in patients with nonvalvular atrial fibrillation: a prospective study, Ann Pharmacother 2014;48:1258 Nesbit, et al. Implementation and pharmacoeconomic analysis of a clinical staff pharmacist practice model, Am J Health Syst Pharm 2001;58:784 No conflict of interest.