Oral anticoagulants are used to

Size: px
Start display at page:

Download "Oral anticoagulants are used to"

Transcription

1 special feature Management of bleeding and reversal strategies for oral anticoagulants: Clinical practice considerations Edith A. Nutescu, William E. Dager, James S. Kalus, John J. Lewin III, and Mark D. Cipolle Oral anticoagulants are used to manage a variety of common age-related conditions (e.g., atrial fibrillation), and the frequency of their use will likely rise significantly in the United States as the population ages. The number of elderly Americans 65 years of age or older is expected to increase markedly over the next two decades, from 39.6 million in 2009 to 72.1 million by Nearly one in five Americans will be elderly in Warfarin has been widely used since it was introduced more than 50 years ago, but it is a less-than-ideal anticoagulant because of its narrow therapeutic range, interactions with numerous drugs and foods, and need for routine laboratory monitoring. 2 Warfarin is a common cause of emergency hospitalization in elderly patients and of serious, disabling, or fatal injury from bleeding in patients of all ages. 3,4 The recent introduction of the oral direct thrombin (factor IIa) Purpose. Currently available clinical data and optimal strategies for reversing oral anticoagulants in patients who are bleeding or need an urgent invasive procedure or operation are reviewed. Summary. Bleeding from oral anticoagulants, including new target-specific oral agents (TSOAs), is a common cause of morbidity and mortality, especially in elderly patients. Limited clinical data are available to guide the reversal of warfarin or TSOAs in patients who are bleeding or need an urgent invasive procedure or operation. A panel of five experts with diverse backgrounds in anticoagulation therapy, cardiology, critical care, and emergency medicine and with experience in managing complications of anticoagulation therapy was convened to develop practical strategies for managing patients receiving oral anticoagulants who are bleeding or have an urgent need for an invasive procedure. The strategies were designed to guide inhibitor dabigatran and the direct factor Xa inhibitors rivaroxaban and apixaban was eagerly anticipated clinicians in the acute care setting by providing efficient and potentially effective management concepts to avoid delays in initiating treatment that could adversely affect patient outcomes. The consensus of this expert panel is summarized herein. Recommendations are based on currently available evidence from a comprehensive review of the literature and other pertinent data, along with the experience and expert opinion of the panelists. Conclusion. Bleeding is a serious complication of the use of oral anticoagulants, and limited information is available to guide the reversal of warfarin or TSOAs in patients who are bleeding or are in need of an urgent invasive procedure. Use of a systematic approach to assessing and treating these patients based on available evidence and expert opinion can help avoid delays that could adversely affect patient outcomes. Am J Health-Syst Pharm. 2013; 70:e82-97 because these agents do not require routine coagulation monitoring and are associated with a lower number Edith A. Nutescu, Pharm.D., FCCP, is Clinical Professor, Department of Pharmacy Practice, Center for Pharmacoepidemiology and Pharmacoeconomic Research, College of Pharmacy, University of Illinois at Chicago, and Director, Antithrombosis Center, and Co-Director, Pharmacogenetics Service, University of Illinois Hospital and Health Sciences System, Chicago. William E. Dager, Pharm.D., BCPS (AQ- Cardiology), FCSHP, FCCP, FCCM, FASHP, is Pharmacist Specialist, University of California (UC) Davis Medical Center, Sacramento, and Clinical Professor of Medicine, School of Medicine, UC Davis. James S. Kalus, Pharm.D., BCPS (AQ-Cardiology), is Senior Manager, Patient Care Services, Department of Pharmacy Services, Henry Ford Hospital, Detroit, MI, and Adjunct Assistant Professor of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit. John J. Lewin III, Pharm.D., M.B.A., FASHP, is Division Director, Critical Care and Surgery Pharmacy Services, Johns Hopkins Hospital, Baltimore, MD, and Clinical Professor, University of Maryland School of Pharmacy, Baltimore. Mark D. Cipolle, M.D., Ph.D., FACS, FCCM, is Medical Director, Trauma Program, Christiana Care Health System, Wilmington, DE. Address correspondence to Dr. Nutescu at the Department of Pharmacy Practice, Center for Pharmacoepidemiology and Pharmacoeconomic Research, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, MC 886, Chicago, IL e82 Am J Health-Syst Pharm Vol 70, 2013

2 of clinically significant drug interactions. Also, unlike warfarin, which inhibits hepatic production of the vitamin-k-dependent clotting factors II, VII, IX, and X, these new oral anticoagulants act on specific components in the coagulation cascade. In separate clinical trials comparing dabigatran, rivaroxaban, or apixaban with warfarin for stroke prevention in patients with atrial fibrillation, the risk for major bleeding was significantly lower with apixaban compared with warfarin, and there was no significant difference in the risk of major bleeding between dabigatran (the larger of two dosages evaluated) or rivaroxaban when compared with warfarin. 5-7 The rate of intracranial hemorrhage was significantly lower with all three target-specific oral anticoagulants (TSOAs) when compared with warfarin. However, the rate of major gastrointestinal bleeding was significantly higher with dabigatran (the larger of two dosages evaluated) and rivaroxaban compared with warfarin, though there was no significant difference in gastrointestinal bleeding between apixaban and warfarin. Whether the safety profile of the TSOAs in clinical practice will mirror event rates reported in large clinical trials remains to be determined. It is also unclear if outcomes may be different between agents once major bleeding occurs. Observational studies and postmarketing surveillance will assist in further clarifying the real-world safety profile of these agents. Elderly patients with renal impairment are particularly vulnerable to bleeding during treatment with dabigatran. 8 During 2011, the FDA MedWatch adverse-eventreporting program received more reports of dabigatran-associated serious, disabling, or fatal injury due to bleeding compared with warfarin. 4 For the second quarter of 2012, reports to the MedWatch program indicated that dabigatran was associated with a fivefold higher risk of death than warfarin after adjusting for age, sex, and the type and source of the report. 9 However, in a subsequent FDA analysis of insurance claims and administrative data, gastrointestinal and intracranial bleeding rates associated with newly initiated dabigatran did not appear to be higher than bleeding rates associated with newly initiated warfarin Therefore, the differences between dabigatran and warfarin in the MedWatch data may reflect reporting biases, such as a greater tendency to report problems with the newer drug. 10 Interestingly, in the second quarter of 2012, rivaroxaban was also associated with a larger number of serious injury reports to the FDA MedWatch program and a nearly twofold higher risk of death in cases of bleeding compared with warfarin. 9 Data on apixaban were not collected because the drug did not have FDAapproved labeling at that time. Regardless, the use of any anticoagulant carries a risk of bleeding, so it is vital to have a strategy to manage or prevent bleeding complications. Guidelines developed by the American College of Chest Physicians (ACCP) address options for reversing the anticoagulant effects of warfarin and mitigating the risk of warfarin-associated bleeding. 12 These guidelines involve withholding warfarin and, because of the time needed for the depletion of vitamin K-dependent clotting factors, administration of exogenous vitamin K (phytonadione) and clotting factor concentrates when urgent reversal is needed. Because clinical trials exploring the emergent reversal of war-farin and TSOAs in patients who are bleeding or need an urgent invasive procedure are limited or nonexistent, there is a certain degree of subjectivity involved in the available guidelines, leaving knowledge gaps in how to best manage these patients. In light of these knowledge and management gaps, a panel of five experts (the authors of this article) with diverse backgrounds in anticoagulation therapy, cardiology, critical care, and emergency medicine and with experience in managing complications of anticoagulation therapy was convened during the ASHP Midyear Clinical Meeting in Las Vegas, Nevada, on December 5, 2012, for the purpose of developing practical strategies for managing patients receiving oral anticoagulants who are bleeding or have an urgent need for an invasive procedure. The strategies were designed to guide clinicians in the acute care setting by providing efficient and potentially effective management concepts to avoid delays in initiating treatment that could adversely affect patient outcomes. This article summarizes the consensus of this expert panel. Recommendations are based on currently available evidence from a comprehensive review of the literature and other pertinent data, along with the experience and expert opinion of The assistance of Carla J. Brink, M.S., B.S.Pharm., and Susan R. Dombrowski, M.S., B.S.Pharm., in manuscript development is acknowledged. Based on the proceedings of an expert panel meeting on December 5, 2012, during the ASHP Midyear Clinical Meeting and Exhibition in Las Vegas, NV. The expert panel comprised the authors of this article. Supported by an educational grant from CSL Behring. All authors received an honorarium for participating in the expert panel and preparing this article. Dr. Nutescu has served as a consultant for Daiichi-Sankyo and has received a research grant from and served as a consultant for Janssen Pharmaceuticals. Dr. Cipolle has served as a consultant for CSL Behring. This article will appear in the November 1, 2013, issue of AJHP. Copyright 2013, American Society of Health-System Pharmacists, Inc. All rights reserved /13/0000-0e82$ DOI /ajhp Am J Health-Syst Pharm Vol 70, 2013 e83

3 the panelists. Tools and strategies for patient assessment are provided for use with a user-friendly algorithm and tables for patient assessment and treatment as part of paper-based or electronic systems. These materials can be readily updated to reflect emerging data and adapted to meet the unique needs of individual institutions and the patient populations they serve. The lists, algorithm, and tables can be hyperlinked as part of a clinical decision-support system. These materials provide only a framework for clinical decisionmaking; applying them to the care of individual patients requires clinical judgment. This article does not represent consensus guidelines of the American Society of Health-System Pharmacists or any other organization, and the recommendations are not graded on level of evidence. Pharmacokinetics and pharmacodynamics of oral anticoagulants The pharmacokinetics and pharmacodynamics of warfarin are well characterized and described elsewhere. 13 The pharmacokinetics of TSOAs are summarized in Table 1. The kidneys play a more important role in the elimination of dabigatran compared with rivaroxaban and apixaban. Therefore, the potential for drug accumulation and bleeding in patients with impaired renal function, a common condition in elderly patients, is of greater concern with the direct thrombin inhibitor dabigatran than the other two TSOAs. The plasma protein binding of dabigatran is low, enabling removal by hemodialysis (e.g., at least half of the dabigatran in plasma was removed over a four-hour hemodialysis session in experimental models). 14,19 By contrast, rivaroxaban and apixaban are highly protein bound and unlikely to be dialyzable. 15,16 Dabigatran is a substrate for the efflux transporter P-glycoprotein and can interact with P-glycoprotein inhibitors and inducers. Concomitant use with potent P-glycoprotein inhibitors can increase the bioavailability of dabigatran and the risk of bleeding. 14 In renally impaired patients who are receiving dabigatran and a P-glycoprotein inhibitor, the enhanced dabigatran bioavailability and reduced clearance are likely to lead to even greater systemic exposure and risk of bleeding. Rivaroxaban and apixaban are substrates for P-glycoprotein and cytochrome P-450 (CYP) isoenzyme 3A4 and can interact with inhibitors and inducers of P-glycoprotein and CYP3A4. Concomitant use of these TSOAs with potent inhibitors of P-glycoprotein or CYP3A4 can increase the risk of bleeding, especially when doses are given closely together or at the same time. 15,16 Additional details about drug interactions involving TSOAs are available in the product labeling and published literature. 2,20 As with warfarin, the anticoagulant effects of TSOAs are highly influenced by their pharmacokinetics. The pharmacodynamic effects of these drugs, however, also reflect their effects on the clotting cascade, resulting in changes in coagulability not predicted by pharmacokinetics alone. For example, there is evidence to suggest that discontinuation of rivaroxaban could be followed by a rebound increase in coagulation (i.e., a procoagulable state) mediated by prothrombin and clotting factors V and X. 21 The clinical significance of this phenomenon is unclear. Table 1. Pharmacokinetics of Target-Specific Oral Anticoagulants 14-18,a Characteristic Dabigatran Rivaroxaban Apixaban Renal elimination of unchanged drug, % Half-life by age, hr Young, healthy adults Elderly Half-life by renal function, hr >80 ml/min ml/min ml/min <30 ml/min Protein binding, % Dialyzable? Key drug interactions a = creatinine clearance, CYP = cytochrome P-450 isoenzyme. b Data not available Yes Potent inhibitors and inducers of P-glycoprotein Unlikely Potent inhibitors and inducers of P-glycoprotein or CYP3A b Unlikely Potent inhibitors and inducers of P-glycoprotein or CYP3A4 e84 Am J Health-Syst Pharm Vol 70, 2013

4 Laboratory assessment of anticoagulation effects The prothrombin time (PT) and International Normalized Ratio (INR) are common assays used to assess the anticoagulation effects of warfarin therapy. Although routine anticoagulant monitoring is not required during treatment with TSOAs, laboratory assessment could provide valuable insight into the level of anticoagulation during treatment with these agents or after interruption of therapy in patients with bleeding. Laboratory assays may be used to assist in decisions about when it is safe for a patient to undergo surgery or restart anticoagulant therapy. The response to therapeutic interventions to reverse anticoagulation (e.g., hemodialysis) also may be monitored using laboratory tests, though most tests are of limited value, and care must be taken in interpreting these results. The usefulness of laboratory tests varies with the anticoagulant being used (Table 2). The availability of certain tests in clinical practice is limited. For example, the ecarin clotting time (ECT) test is the most useful for assessing dabigatran anticoagulation because it is sensitive to the drug at all concentrations, but the ECT test is not widely available. 22 The commercially available nondiluted thrombin time (TT) test is very sensitive to the level of dabigatran, making the test useful at low concentrations but not higher concentrations of dabigatran. 24 The activated partial thromboplastin time (aptt) and PT tests are widely available but are not ideal for quantifying the amount of dabigatran present. 24 The PT test is less sensitive than the aptt test at usual concentrations of dabigatran. 22 Limited data are available for laboratory assessment of coagulation during treatment with the factor Xa inhibitors rivaroxaban and apixaban. Chromogenic antifactor Xa assays are useful for monitoring coagulation during therapy with these agents. However, the need to calibrate the assay for the specific factor Xa inhibitor and the contribution of variables that can influence results present notable challenges in using these assays. 27 Given that such calibrators are becoming available, 28 some laboratories are now bringing this test onsite. As with any test, it is important to know the reliability of the assay and assess the clinical presentation when incorporating results into management decisions. Several newer coagulation assays have been developed and may be used in certain specialized situations, though data are not currently available to determine the clinical usefulness of these tests. These newer tests include thromboelastography, thrombin generation curve, plasmadiluted TT, chromogenic ECT, and diluted PT. 22 Thromboelastography has been used as a tool to guide transfusions in the presence of bleeding, and it may be used during surgery or in trauma centers to provide insight into the possible causes of and ways to mitigate bleeding. The usefulness of thromboelastography in the presence of TSOAs, however, has not been established. As noted, interpretation of laboratory coagulation test values and therapeutic decision-making require consideration of each patient s specific scenario and clinical status. For example, administration of hemostatic agents may stem bleeding without affecting laboratory coagulation test results in a patient needing an urgent invasive procedure. 29 In addition, the timing of the last anticoagulant dose should be considered when scheduling and interpreting coagulation test values. Turnaround time is also a critical point in the practical applicability of these assays, particularly in the hemorrhaging patient. Frequent reassessment of the patient s clinical status and laboratory tests may be needed to accommodate acute changes in unstable patients. Reversal agents Various interventions may be used to reverse the effects of warfarin, including oral and i.v. phytonadione, fresh frozen plasma (FFP), and clotting factor concentrates. Concentrated clotting factor products, FFP, activated charcoal, and hemodialysis also have been considered for reversing the effects of TSOAs. Various antidotes for reversal of TSOAs are in development, but they are not yet available FFP is obtained from human blood and contains all of the vitamin K-dependent clotting factors in plasma. The large volume of fluid administered is a potential disadvantage of using FFP. 33 The limited data from FFP use for reversing TSOAs to date have not been encouraging. 34 Concentrated clotting factor products include three- and four-factor prothrombin complex concentrate (PCC) products, recombinant factor VIIa (rfviia), and activated PCC (apcc, also known as antiinhibitor factor complex, factor VIII inhibitor bypassing activity, or FEIBA). The PCC products vary in their clotting factor content, but all three-factor PCC (PCC3) products contain inactivated clotting factors II, IX, and X and only small amounts of factor VII in an inactivated form. Four-factor PCC (PCC4) products contain a larger amount of inactivated clotting factor VII than PCC3 products as well as clotting factors II, IX, and X in an inactivated form. Activated PCC contains clotting factor VII in an activated form and clotting factors II, IX, and X primarily in an inactivated form. The risk for thrombosis is a concern with clotting factor concentrates, especially activated products. This risk must be weighed against the potential benefit of using these products for anticoagulant reversal. Some PCC4 products and apcc contain the natural regulatory anticoagulant protein C, protein S, or both. 22,35,36 Some PCC3 and PCC4 products (but not apcc or rfviia) contain heparin, which is a concern Am J Health-Syst Pharm Vol 70, 2013 e85

5 Table 2. Various Laboratory Tests To Consider When Concerned About Bleeding With Warfarin and Target-Specific Oral Anticoagulants (TSOAs) 22-26,a Laboratory Test Warfarin Dabigatran Rivaroxaban Apixaban Comments SCr and CBC with platelets INR or PT aptt TT ECT Diluted TT Chromogenic antifactor Xa assay Potentially useful increased somewhat increased Clinical use limited Clinical use limited Clinical use limited Inadequate measure Potentially useful increased; use central laboratory because pointof-care test can give much higher values increased, but aptt response flattens at higher serum drug concentration Potentially useful; very sensitive at low concentration but not useful at higher concentration Potentially useful if available; potential ability to quantify amount of drug present Potentially useful if available; potential ability to quantify amount of drug present Inadequate measure Potentially useful increased increased Inadequate measure Inadequate measure Inadequate measure increased Potentially useful increased increased Inadequate measure Inadequate measure Inadequate measure increased Monitor serum calcium concentration if transfusing blood PT may be considered because INR may not be calibrated for the TSOAs; PT more responsive to factor Xa inhibitors than to dabigatran; limited ability to quantify amount of drug aptt more responsive to dabigatran than to factor Xa inhibitors; limited ability to quantify amount of drug Limited ability to quantify amount of dabigatran Limited availability; potential quantitative test Lack of standardization and potential differences in measured results among laboratories; may have limitations at low dabigatran concentration Limited availability; nonstandardized; results may vary among laboratories where available a SCr = serum creatinine, CBC = complete blood count, INR = International Normalized Ratio, PT = prothrombin time, aptt = activated partial thromboplastin time, TT = thrombin time, ECT = ecarin clotting time. e86 Am J Health-Syst Pharm Vol 70, 2013

6 in patients with recent heparininduced thrombocytopenia. Information about the composition of concentrated clotting factor products is available in the product labeling and additional sources. 22,36-38 Limited data are available regarding the benefits of concentrated clotting factor products for reversing TSOAs in humans. In addition, the dosages of these reversal agents used experimentally to date may not reflect the dosages used in clinical practice (Table 3). Data from animal testing have been summarized elsewhere. 18,33,53-56 Dosages of PCC are expressed as units of the factor IX component, and apcc dosages are expressed as FEIBA units. The composition of clotting factors and other regulators of coagulation in PCC products varies among manufacturers. The effects of a PCC4 product (Cofact, Sanquin Blood Supply, Amsterdam, Netherlands) on the anticoagulant effects of dabigatran and rivaroxaban were evaluated in a randomized, double-blind, placebocontrolled, crossover study of 12 healthy male volunteers. 46 Dabigatran etexilate 150 mg twice daily or rivaroxaban 20 mg twice daily was given for 2.5 days followed by 50 units of the PCC4 product per kilogram of body weight or a placebo (0.9% sodium chloride injection). After an 11-day washout period, volunteers received 2.5 days of treatment with the other anticoagulant followed by the PCC4 product or placebo. The PCC4 product had no effect on aptt, ECT, or TT in dabigatran-treated volunteers. The PCC4 product normalized the PT and endogenous thrombin potential (a measure of thrombin generation) within 15 minutes in rivaroxabantreated participants. The effects of a PCC4 product (Cofact) on the anticoagulant effects of rivaroxaban were also evaluated in an in vitro study. 47 Plasma and whole blood samples from healthy volunteers were spiked with rivaroxaban Table 3. Recommended Dosing of Concentrated Clotting Factor Products for Oral Anticoagulant Reversal 29,33,34,39-52,a,b Dose(s) for Reversal of Specific Anticoagulant Reversal Agent Clotting Factor(s) Replaced Warfarin Dabigatran Rivaroxaban 50 units/kg units/kg 42, mg/kg 45,d,e Up to 25 units/kg initially; no data available in patients with active bleeding; 80 units/kg 45,g No data available; possibly extrapolate doses from warfarin reversal... c units/kg 45, mg/kg 45,d,e Up to 25 units/kg initially f with subsequent doses based on response 29 ; 80 units/kg 45,g No data available; possibly extrapolate doses from warfarin reversal units/kg 33,34,40, units/kg 36,43, mg/kg 48-50,d 500 units for INR of <5 and 1000 units for INR of 5 51 II, IX, and X (inactivated) II, VII, IX, and X (inactivated) VII (activated) II, IX, X (inactivated) and VII (activated) PCC3 PCC4 rfviia apcc PCC3 50 units/kg (or a fixed dose of 4000 units for an 80-kg patient) + rfviia 1 mg 52 ; if rfviia is not available, the addition of a small dose of FFP (1 2 units) to PCC3 could be considered PCC3: II, IX, and X (inactivated); rfviia: VII (activated) Building of PCC4 a PCC3 = three-factor prothrombin complex concentrate, PCC4 = four-factor prothrombin complex concentrate, rfviia = recombinant factor VIIa, apcc = activated prothrombin complex concentrate, INR = International Normalized Ratio, FFP = fresh frozen plasma. b Experience with the doses listed in this table for reversal of oral anticoagulants is limited. Aside from one abstract at the time of writing, 39 there are insufficient data to make specific dosing recommendations for apixaban. Current references and the product labeling should be consulted for the most recent information about appropriate dosing of concentrated clotting factor products. Depending on the urgency of bleeding and estimated anticoagulant effect, lower doses can be used initially and increased as necessary to achieve the desired effect. Doses of PCC and apcc products are expressed as units of the factor IX component and FEIBA units, respectively. The composition of PCC products varies, so doses of different products may not be equivalent. c Data are not available on PCC3 use for target-specific oral anticoagulant reversal. Doses of units/kg can be considered if a PCC4 product or apcc is not available. d Higher doses of rfviia have been associated with increased thrombosis risk. If this option is selected, a lower dose of approximately 20 mg/kg is suggested. e Limited effects noted in vitro or ex vivo even at higher doses; usefulness unclear. f Based on limited case reports. g Larger apcc doses corresponding to 80 units/kg were evaluated in an ex vivo study of dabigatran and rivaroxaban. 45 The initial apcc dose should be based on the severity of bleeding, keeping in mind that additional doses can be given. Lower doses (e.g., 1 vial or ~5 10 units/kg) can be considered initially for emergent procedures, such as vascular line placement; however, limited supportive evidence is currently available. Am J Health-Syst Pharm Vol 70, 2013 e87

7 (up to 800 mg/l), and PCC4 was added to these samples in concentrations used clinically to reverse the effects of vitamin K antagonists. PT (Innovin, Dade Behring, Liederbach, Germany), endogenous thrombin potential, and calibrated automated thrombography assays were performed with varying tissue factor concentrations. The PCC4 product did not neutralize the increase in PT and lag time of rivaroxaban-anticoagulated blood in vitro, suggesting that the Innovin PT may not be applicable for the in vitro assessment of rivaroxaban reversal by PCC4. However, the total thrombin potential was normalized, and the response of the different thrombin generation tests was found to be dependent on assay conditions. In contrast to these findings, the ex vivo study by Eerenberg et al. 46 found that the PT of healthy human volunteers receiving rivaroxaban could be normalized using PCC4. Another in vitro study evaluated the impact of different clotting factor concentrates in reversing the actions of apixaban. 39 Whole-blood samples from healthy volunteers were mixed with apixaban (200 ng/ml), and various clotting factor concentrates were added to these samples. The clotting factor concentrates PCC4 (50 units/ kg; Beriplex, CSL Behring, Marburg, Germany), apcc (75 units/kg; Feiba, Baxter, Westlake Village, CA), and rfviia (270 mg/kg; NovoSeven, Novo Nordisk, Bagsvaerd, Denmark) compensated for or reversed apixaban s anticoagulant action with varying degrees of efficacy. Thrombin generation improved most with the administration of PCC4, followed by apcc and then rfviia. Correction of clotting time responded best to rfviia, followed by apcc and then PCC4. The effects of another PCC4 product (Kanokad, LFB-Biomedicaments, Paris, France), rfviia, and apcc on the anticoagulant effects of dabigatran and rivaroxaban were evaluated by Marlu and colleagues 45 in an ex vivo, crossover study of 10 healthy male volunteers. Venous blood samples were obtained immediately before and two hours after single 150-mg doses of dabigatran etexilate or 20-mg doses of rivaroxaban and exposed to several concentrations of PCC4 (0.25, 0.5, and 1 unit/ml, with the intermediate concentration corresponding to a dose of 25 units per kilogram of body weight), rfviia (0.5, 1.5, and 3 mg/ml, with the highest concentration corresponding to a dose of 120 mg/kg), and apcc (0.25, 0.5, 1, and 2 units/ ml, with the 1-unit/mL concentration corresponding to a dose of 80 units per kilogram of body weight). After a two-week washout period, blood samples were obtained immediately before and two hours after the volunteers received the other anticoagulant. The PCC4 product and rfviia had inconsistent effects on laboratory values of thrombin generation in dabigatran- and rivaroxaban-treated blood samples. However, apcc had a consistent impact on thrombin generation in rivaroxaban-treated blood. The impact of apcc on thrombin generation in dabigatran-treated blood was less consistent than the effect on rivaroxaban-treated blood, though the impact of apcc on dabigatrantreated blood was greater than that of PCC4 and rfviia. These findings suggest that apcc may play a role in reversing the anticoagulant effects of rivaroxaban and perhaps dabigatran. Levi et al. 42 evaluated the effects of PCC4 (Beriplex) and PCC3 (Profilnine, Grifols Biologicals, Los Angeles, CA) products on PT and thrombin generation in an open-label, parallelgroup study in 35 healthy adult volunteers treated with rivaroxaban 20 mg twice daily for four days to attain steady-state concentrations. On day 5, four hours after rivaroxaban administration, participants were randomized to receive a single bolus dose of PCC3 50 units/kg, PCC4 50 units/kg, or 100 ml of 0.9% sodium chloride injection (control). The PT and endogenous thrombin potential were measured before and serially after the administration of PCC or the control. While PCC4 reduced the mean PT by seconds, PCC3 resulted in a mean reduction of only second. In contrast to its effect on the PT, PCC3 more effectively reversed rivaroxabaninduced changes in endogenous thrombin generation (area under the concentration time curve, peak, and time-to-peak values) than did PCC4. Changes in lag time values did not differ greatly. The discrepancy in these results on PT and thrombin generation may reflect the absence of factor VII in PCC3 (Profilnine) and the presence of heparin in PCC4 (Beriplex). Additional studies are needed to further clarify these issues. The administration of the PCC products in this study was deemed safe and well tolerated, with no signs of prothrombotic response reported. The limited availability of data in humans requiring reversal of the anticoagulant effects of TSOAs using the reversal agents listed in Table 3 leaves large gaps in knowledge about the best approach to use in clinical practice. Further research is underway to fill these gaps. Examples include the REVNEWANTICO study, a randomized, open-label, controlled, crossover, Phase IV study examining the use of PCC, rfviia, and apcc after the administration of single 150- mg dabigatran etexilate doses and the use of a specific rivaroxaban decoy (Gla-domainless activated factor X) after the administration of a single 20-mg rivaroxaban dose in 10 young, healthy, male volunteers. 57 The antifibrinolytic agents aminocaproic acid and tranexamic acid have been used to minimize blood loss during surgery. 58 However, data are not available to characterize the role of these agents in managing serious bleeding in patients receiving oral anticoagulants. e88 Am J Health-Syst Pharm Vol 70, 2013

8 Clinical management of bleeding The management of patients receiving oral anticoagulants who are bleeding or need an urgent invasive procedure requires weighing the risks for thrombosis and bleeding and consideration of short- and longterm treatment goals. Individualization of therapy is needed, taking into consideration these goals, age, renal function, clinical status, and laboratory test results. If a patient has bleeding or needs an urgent invasive procedure, a medication history should be obtained (Figure 1). If the medication history reveals the use of an anticoagulant, therapy should immediately be discontinued and the patient s risk for thrombosis should be assessed (Table 4). The time since the last anticoagulant dose should be determined. Institutional or published tools (e.g., CHADS 2 or CHA 2 DS 2 -Vasc risk scoring system for atrial fibrillation) should be used to determine the risk for thrombosis. 59,60 The reasons for anticoagulation therapy (e.g., atrial fibrillation, venous thromboembolism prophylaxis or treatment, cardiac valve) and the use of antiplatelet therapy or other medications that contribute to bleeding or excessive anticoagulation effects (e.g., drug interactions) should be taken into consideration. If the patient is bleeding, the considerations listed in Table 5 should be used to further evaluate the patient. The bleeding location, bleeding severity (i.e., volume of blood loss), and accessibility of the bleeding site should be assessed. The feasibility of surgical intervention, including mechanical procedures and the ability to drain or remove blood, can affect patient outcomes. Bleeding in enclosed spaces, especially the central nervous system (e.g., intracranial hemorrhage), eyes, and pericardium, can have devastating consequences. Imaging and other diagnostic test results (e.g., endoscopy), physical examination findings, overt evidence of bleeding, and vital signs provide insight about the bleeding location and its severity. Laboratory test results, including a complete blood count, and the patient s clinical status also must be considered when evalu- Figure 1. Management of patients with bleeding or needing an urgent invasive procedure. Is the patient on an oral anticoagulant? Yes No Exit algorithm Is the patient bleeding? (See Tables 2 and 5) Yes No Does the patient need an invasive procedure? Yes No Exit algorithm Urgent reversal (See Table 4) Yes (See Table 6) Urgent? Warfarin (See Tables 3 and 7) Dabigatran (See Tables 3 and 7) Rivaroxaban or apixaban (See Tables 3 and 7) No (See Tables 4, 6, and 8) Am J Health-Syst Pharm Vol 70, 2013 e89

9 Table 4. Considerations in Assessing Risk of Thrombosis in Patients Receiving Oral Anticoagulants a Oral anticoagulant therapy Drug and dosing regimen Time since last dose History of or current hypercoagulable condition Nonvalvular atrial fibrillation (use CHADS 2 or CHA 2 DS 2 -Vasc risk scoring system b ) Presence of cardiac thrombus on recent echocardiogram VTE prophylaxis (use institutional or published guidelines for risk assessment) Positive history of recent VTE (within past 6 12 mo) (assess time since last event and number of events) Negative history of VTE but at high risk for VTE Cardiac valve Type (mechanical valve has higher thrombotic risk compared with tissue valve) Position (mitral valve has higher thrombotic risk compared with aortic valve) Other Mechanical device or vascular hardware, arterial thromboembolic disease (individualize risk assessment) Recent administration of concentrated clotting factors Use of medications that contribute to thrombosis Indication for use Type of therapy Risk associated with withholding therapy a VTE = venous thromboembolism. b CHADS 2 score estimates stroke risk based on the following factors: congestive heart failure, hypertension, age of 75 years, diabetes mellitus, and history of embolic stroke or transient ischemic attack. CHA 2 DS 2 -Vasc score is a modification of the CHADS 2 score that aims to improve stroke risk prediction in patients with atrial fibrillation by adding three risk factors: age of years, female sex, and history of vascular disease. Table 5. Considerations in Assessing Bleeding in Patients Receiving Oral Anticoagulants a Vital signs Physical examination for external evidence of hemorrhage (e.g., epistaxis, open fracture, scalp laceration) Diagnosis of internal hemorrhage (e.g., endoscopy, CT scan, ultrasound) Access to bleeding site and feasibility of intervention Bleeding severity (i.e., assessment of significance of blood loss) Laboratory test results (see Table 2) Level of anticoagulation Markers for blood loss (e.g., CBC, serum lactate concentration, arterial blood gas and basic metabolic panel to evaluate for presence of acidosis) Organ function (e.g., LFT values, SCr) Additional test considerations (e.g., serum calcium concentration if transfusing with blood products, fibrinogen, thromboelastrogram) Clinical status Need for emergent procedures Rebound anticoagulant effect after administering concentrated clotting factors Allergies and any recent concern for heparin-induced thrombocytopenia a Because the clinical and laboratory status of patients with bleeding is subject to change, frequent monitoring is needed. CT = computed tomography, CBC = complete blood count, LFT = liver function test, SCr = serum creatinine. ating and managing a patient with bleeding. If the anticoagulated patient is not bleeding and requires an invasive procedure, the considerations and strategies listed in Table 6 should be used to further evaluate the patient. The risk for bleeding and thrombosis from the procedure must be balanced with the risk of thrombosis from the interruption of anticoagulant therapy, taking into consideration the indication for the anticoagulant before an invasive procedure is planned. Institutional or published guidelines (e.g., ACCP guidelines) can be consulted to guide the risk assessment The urgency and timing of the planned procedure in relation to the last dose of anticoagulant, the pharmacokinetics and pharmacodynamics of the anticoagulant therapy in use, concurrent drug interactions, and laboratory test results (e.g., level of anticoagulation, renal impairment) should be considered. 61 The actions taken after completing the assessments in Tables 4 6 depend on the type of oral anticoagulant and the urgency of the need for intervention (Table 7). Patients may be stratified based on the urgency of the need for intervention in one of three categories: (1) patients for whom no action is needed within 24 hours (i.e., when there is no rush to make a decision), (2) patients for whom an expedited decision is needed within 1 24 hours, and (3) patients with an emergent need for intervention within 1 hour (i.e., patients with life-threatening bleeding or an urgent need for a procedure). The clinical status and laboratory test values of anticoagulated patients with or at risk for bleeding are subject to change, so these classifications are not fixed. For example, a patient with an expedited need for intervention may need to be reclassified as having an emergent need for intervention if his or her condition deteriorates and becomes life threatening. The choice of therapeutic options e90 Am J Health-Syst Pharm Vol 70, 2013

10 may be limited by the resources and agents available at each institution. Follow-up clinical decision-making should address whether and when to reinitiate oral anticoagulant therapy to reduce the risk of thrombosis and the use of alternative shorter-acting agents. Warfarin. In all patients who are bleeding or need an urgent invasive procedure, warfarin should be withheld and laboratory test values (i.e., INR or PT) should be used to assess the level of anticoagulation (Table 7). In patients for whom an intervention is not needed for more than 24 hours, oral phytonadione should be Table 6. Considerations in Assessing Nonbleeding Patients Receiving Oral Anticoagulants Who Require Invasive Procedures 61,a Indication for oral anticoagulant use Risk for thromboembolic events associated with interruption of oral anticoagulant therapy for invasive procedure Need for bridging with alternative anticoagulant Planned procedure or surgery Urgency (e.g., emergent, elective) Risk for bleeding and thrombosis from intervention (use published or institutional guidelines for risk assessment) Laboratory test results Level of anticoagulation Organ function (e.g., LFT values, SCr) a Because the clinical and laboratory status and risk for bleeding and thrombosis in patients with indications for oral anticoagulant therapy who undergo invasive procedures are subject to change, frequent clinical and laboratory monitoring and risk assessment are needed. LFT = liver function test, SCr = serum creatinine. Table 7. Therapeutic Interventions for Reversal of Oral Anticoagulants Based on Urgency 12,15,16,18,19,45,46,66-69 Level of Urgency Warfarin Dabigatran Rivaroxaban or Apixaban No rush (>24 hr) a Expedited (1 24 hr) a Emergent (<1 hr) Withhold warfarin and consider oral phytonadione, with dose based on INR Withhold drug and give oral phytonadione (1 5 mg) or lowdose i.v. phytonadione ( mg), with dose based on initial INR and postreversal INR (checked 24 hr after dose) Withhold drug, consider high-dose i.v. phytonadione c (depending on anticipated need to restart warfarin), and consider clotting factor supplement (listed in order of preference): PCC4 Build PCC4 with PCC3 plus rfviia d apcc PCC3 rfviia FFP e Withhold drug and monitor clinical status and pertinent laboratory tests Withhold drug, give activated charcoal b if last dose was taken within past 2 hr, and use prolonged hemodialysis (>2 hr) Withhold drug, give activated charcoal b if last dose was taken within past 2 hr, use prolonged hemodialysis (>2 hr), and consider clotting factor supplement (listed in order of preference): apcc PCC4 Build PCC4 with PCC3 plus rfviia d Withhold drug and monitor clinical status and pertinent laboratory tests Withhold drug and give activated charcoal b if last dose was taken within past 2 hr and repeat 6 hr after the last dose Withhold drug, give activated charcoal b if last dose was taken within past 2 hr and repeat 6 hr after the last dose, and consider clotting factor supplement (listed in order of preference): PCC4 apcc Build PCC4 with PCC3 plus rfviia d PCC3 f a The intervention may need to be modified based on changes in the patient s clinical status (e.g., if status worsens, expedited or emergent treatment options should be considered). INR = International Normalized Ratio, PCC4 = four-factor prothrombin complex concentrate, PCC3 = three-factor prothrombin complex concentrate, rfviia = recombinant factor VIIa, apcc = activated prothrombin complex concentrate, FFP = fresh frozen plasma. b Contraindicated in the setting of gastrointestinal bleeding. c I.V. phytonadione doses exceeding 2 mg may not increase the rate or extent of INR reversal after hours compared with 2-mg doses. Large doses (i.e., 5 10 mg) could be considered if there is no plan to restart warfarin in the near future. d In some health systems, rfviia is used in combination with PCC3 to enhance the factor VII effects of the reversal strategy. If rfviia is not available, the addition of a small dose of FFP (1 2 units) to PCC3 could be considered. e While FFP is currently the most widely used option for warfarin reversal in the United States, the expert panel ranked the other options higher than FFP based on current evidence and existing guidelines. 12 f The order of PCC3 in this listing was based on the availability of a single abstract at the time of writing. 42 Pending release of the full study data, clinician preference for these listed options may change. Am J Health-Syst Pharm Vol 70, 2013 e91

11 considered, with the dose based on the initial INR and postreversal target INR. 12 In patients for whom an intervention is needed within 1 24 hours, oral or low-dose i.v. phytonadione should be administered, with the dose depending on the INR. Warfarin-treated patients with an emergent need for intervention (e.g., life-threatening bleeding) or no plans to subsequently restart warfarin can receive high-dose (5 10 mg) i.v. phytonadione along with concentrated clotting factor products or FFP. Phytonadione 5 10 mg by slow i.v. injection plus PCC4 is recommended for emergent warfarin reversal by ACCP. 12 There is increasing evidence suggesting that i.v. phytonadione doses exceeding 2 3 mg are no more effective for reversing the INR in acutely ill patients treated with warfarin, and higher doses may increase the need for and duration of bridging therapy (i.e., dual anticoagulation with another anticoagulant plus warfarin to prevent thrombosis once bleeding has resolved) compared with smaller doses. 27,68-70 These phenomena may reflect the fat-soluble nature of vitamin K (i.e., storage of excess vitamin K in adipose tissues) and warfarin refractoriness (i.e., resistance to the effects of warfarin when the drug is restarted). The lowerdose phytonadione strategy may be attractive in situations without lifethreatening bleeding and where warfarin may be reinitiated within one to two weeks. Given the paucity of comparative trials, a definitive strategy for reversal of the INR in warfarin-treated patients is not clear, and the expert panel s suggested therapeutic interventions are based on the available evidence and clinical experience (Table 7). The expert panelists first choice for reversal of the INR in a warfarin-treated patient with serious bleeding or an emergent need for intervention is PCC4, which has been shown to promptly but only partially reverse the INR. 44,52,71,72 PCC3 doses of units/kg may also be considered for INR reversal in warfarin-treated patients, though complete correction of the INR may not occur, even when doses at the upper end of this range are used. 40,41,72-74 If premade PCC4 is not available, the expert panelists suggest that a better option than using PCC3 alone is building a PCC4 product by using low-dose rfviia in combination with PCC3 to enhance the factor VII effects of the reversal strategy. Using FFP with PCC3 may also be considered as an alternative method Table 8. Interruption of Target-Specific Oral Anticoagulant Therapy for Invasive Procedures and Surgery 14-16,77-79,a Drug (Renal Function) Dabigatran >50 ml/min ml/min 30 ml/min Rivaroxaban or apixaban >50 ml/min ml/min 30 ml/min Time of Last Dose Before Minor Procedure 1 day (24 hr) 2 days 4 days 1 day (24 hr) 1 2 days 2 days Time of Last Dose Before Major Surgery 2 days 4 days 6 days 2 days 3 4 days 4 days a Therapy should generally be resumed hours after a minor procedure and hours after major surgery. If unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) is used as bridging therapy in patients with atrial fibrillation or with venous thromboembolism who are at high risk for thromboembolism, oral anticoagulant therapy with a target-specific agent should be resumed when the UFH infusion is discontinued and when the next scheduled dose of LMWH would have been given. = creatinine clearance. for providing factor VII. Use of PCC3 plus FFP appears more effective for reducing the INR than PCC3 alone or FFP alone. 34,75 There is evidence that PCC3 plus rfviia is more effective for reducing the INR than PCC3 plus FFP, though it may carry an increased risk of thromboembolism if the dose of factor VIIa is high. 52 The use of apcc is an alternative to building a PCC4 product, with evidence suggesting that apcc appears to be more effective for INR reversal than FFP alone. 51 In addition, use of small doses (11 25 mg/kg) of rfviia has been shown to completely reverse the INR, though the impact of this intervention on bleeding outcomes is unclear. 48,52,76 Dabigatran. The approach to reversing dabigatran in a patient with bleeding or the need for an invasive procedure depends on the urgency of the need for intervention. Guidance is available for how much time should elapse between the last dose of dabigatran and an invasive procedure based on renal function and the risk of bleeding, which varies by surgery type (Table 8) In patients for whom no intervention is needed within 24 hours (i.e., when there is no rush to make a decision), withholding dabigatran and monitoring clinical status and laboratory coagulation test values may suffice, especially in the setting of normal renal function (Table 7). TT, aptt, and INR/PT are commonly available tests for detection of the presence of dabigatran, but the results are not quantitative (Table 2). Diluted TT and ECT may be more useful for quantifying the amount of dabigatran present, but these tests are not commonly available in practice. Thromboelastography and activated clotting time may be considered, depending on the availability of the test and the clinical situation. However, one trauma group reported that the only abnormal thromboelastographic value in a patient who died from a dabigatran-related e92 Am J Health-Syst Pharm Vol 70, 2013

12 massive subdural hemorrhage was a prolonged activated clotting time. The remainder of the values, which measured clot kinetics, clot strength, and clot stability, were within the normal ranges. 81 In patients who need an expedited intervention within 1 24 hours, dabigatran should be withheld. If the last dose was taken within the past 2 hours, activated charcoal should be given to reduce drug absorption unless contraindicated (e.g., gastrointestinal source of bleeding). 18 Hemodialysis should be initiated and continued until sufficient dabigatran removal occurs. The mode and duration of dialysis and blood flow rates may depend on the level of anticoagulation and follow-up laboratory coagulation test results. Case reports suggest that prolonged dialysis (more than 2 hours) is needed to remove substantial amounts of the drug. In addition, a rebound in plasma drug concentrations after stopping dialysis has been observed. 19,66,67,82,83 The actual duration of dialysis will depend on the assessed anticoagulation state using available tests to guide decision-making (Table 2). Laboratory coagulation tests should be repeated 1 hour after the completion of dialysis because of the risk of a rebound increase in plasma dabigatran concentration due to redistribution of the drug from tissues into the plasma. 67 If the clinical situation is such that waiting for dialysis to reverse the effects of dabigatran is not an option, the reversal strategies listed for emergent reversal in Table 7 should be considered. The expert panelists first choice for reversal of dabigatran in a patient with serious bleeding or an emergent need for intervention is apcc (in addition to withholding dabigatran and using activated charcoal and prolonged hemodialysis). 8 This suggestion is based on limited available evidence (ex vivo studies in healthy volunteers) and case reports. 29,45,46 The optimal apcc dose is unclear and may be lower than that explored by Marlu et al. 45 or used in the management of hemophilia. Although the evidence is very limited, low doses of apcc (i.e., 25 units/kg) may suffice. 29 Since additional apcc doses can be given and the onset of effect is rapid, therapy can be initiated with a low dose, and additional doses can be given based on an assessment of bleeding. The initial and any subsequent doses may depend in part on the vial size to avoid unnecessary wastage. An additional vial may need to be readily available for use if bleeding persists. 29 The expert panelists suggest PCC4 as the next option for the reversal of dabigatran. An alternative would be using PCC3 plus rfviia to build a PCC4 product or using PCC3 plus FFP, though currently available data are limited and do not support the use of these combinations for dabigatran reversal. While acknowledging the lack of supporting data, the expert panelists prefer a combination of PCC3 plus rfviia over PCC3 plus FFP in a life-threatening bleeding event based on limited clinical experience. Since no studies have evaluated the impact of PCC3 plus rfviia for dabigatran reversal, dose selection is difficult. It may be reasonable to consider doses that have been used with relative safety for warfarin reversal (Table 3). 52 If rfviia is the only therapeutic option available, it may be considered, but case reports and an animal model suggest that rfviia has a limited ability to reverse the effects of dabigatran. 8,53,84 If rfviia is used, the panelists recommend an initial dose of approximately 20 mg/kg, extrapolated from lower doses shown effective with warfarin. 48 Currently, no data are available to support the use of a PCC3 product alone for the reversal of dabigatran. It is important to be aware of the potential for a rebound anticoagulation effect after an attempt at dabigatran reversal because of the relatively short half-life of the clotting factors used for reversal compared with the half-life of dabigatran. A rebound increase in the INR has been observed with the use of rfviia in patients taking warfarin who have traumatic hemorrhage. 85 Follow-up laboratory coagulation tests should be considered minutes after completing the infusion of concentrated clotting factor products to monitor for the desired reversal effect. However, clinical judgment about whether the bleeding has stopped or improved may be more useful, especially given the limited availability of assays as well as their limitations in measuring the effects of dabigatran. Clinicians could consider administering small doses of apcc (e.g., 8 10 units/kg) immediately before the insertion of dialysis catheters or other invasive procedures in patients receiving dabigatran, as lifethreatening bleeding could develop. This suggestion is based on two case reports in which hemostasis was rapidly achieved with apcc at these doses in patients receiving dabigatran who developed bleeding while undergoing cardiac ablation or the placement of a dialysis catheter for emergent hemodialysis. 29,67 Minimally invasive procedures (e.g., use of the right femoral vein to establish dialysis access) are preferred to reduce the risk of bleeding in patients receiving dabigatran. Rivaroxaban and apixaban. In patients receiving factor Xa inhibitors for whom there is no need to reverse the anticoagulant effects within 24 hours, withholding the drug and monitoring laboratory coagulation test values should suffice (Table 7). Guidance is available for how much time should elapse between the last dose of rivaroxaban or apixaban and an invasive procedure based on the risk of bleeding, which varies with the type of procedure being performed (Table 8). 77,78,80 In patients receiving factor Xa inhibitors with an emergent need for Am J Health-Syst Pharm Vol 70, 2013 e93

13 intervention, most of the anticoagulant effects should be absent ideally within 24 hours after discontinuation of the drug. If the last dose of the factor Xa inhibitor was taken within 2 hours, activated charcoal may be administered unless contraindicated (e.g., gastrointestinal source of bleeding) and repeated approximately 6 hours after the last dose of factor Xa inhibitor, though it should be noted that this recommendation is extrapolated from existing data for apixaban; data supporting the effectiveness of this intervention are lacking for rivaroxaban. 15,16 Hemodialysis probably does not have a role in removing factor Xa inhibitors because they are highly protein bound (Table 1). In patients with an emergent need for intervention, PCC4 is preferred by the expert panel based on currently available, albeit very limited, data and clinical experience. 39,42,45-47 Limited data suggest that apcc might be an alternative to PCC4, but the expert panelists prefer PCC4 because of the potential for thrombosis with apcc. 45,51 Alternatively, a combination of PCC3 plus rfviia could be used to build a PCC4. If rfviia is not available, using FFP in combination with PCC3 may be considered as an alternative option for providing factor VII. While no data are available in the literature to support the approach of combining clotting factor products to build a PCC4 for reversal of factor Xa antagonists, this approach may be considered because it has been studied in the setting of warfarin reversal. If building a PCC4 is considered for reversal of factor Xa antagonists, extrapolation of doses used safely for reversing the effects of warfarin may be considered (Table 3). 52 If PCC4 is not available, PCC3 may also be considered as a potential reversal option. 42 Systematic approach A plan for managing patients receiving oral anticoagulants who are bleeding or need an urgent invasive procedure should be developed using a systematic approach to ensure that appropriate laboratory tests and therapeutic interventions for anticoagulant reversal are promptly ordered when needed. The anticoagulant reversal plan must be readily accessible so that it can be promptly implemented in emergent situations at any time of day. Implementation of such a plan should be facilitated by information technology (e.g., clinical decision-support system). A pragmatic approach is needed to ensure that the plan is user-friendly. The plan should be sufficiently flexible to address other patient care needs. The anticoagulant reversal plan should contain provisions to gain access to reversal agents and other therapeutic interventions that are not available in the institution (e.g., small or rural health care facilities lacking hemodialysis services). Clinicians need timely access to these therapies in emergent situations to avoid compromising patient outcomes. The plan should ensure that policies and procedures are established to avoid delays in obtaining reversal therapies or transferring the patient to another institution where the necessary therapy is available. The plan should address transporting the patient and communicating about the patient s status (e.g., time since last oral anticoagulant dose, laboratory results, use of activated charcoal and reversal agents) with health care providers at the facility receiving the patient. Patient transfer agreements should be established before an emergent need arises. Such provisions will ensure a smooth transition of care. The anticoagulant reversal plan may be communicated with local emergency medical services personnel (especially first responders) so that they are aware of institutional capabilities to manage bleeding from oral anticoagulants. Valuable time can be saved in addressing life-threatening bleeding events if patients are taken to a health care facility where the necessary interventions are available. In devising the anticoagulant reversal plan, interprofessional input should be obtained from key clinical decision-makers and stakeholders involved in the use of reversal agents in the institution. These include emergency and trauma physicians, hematologists, nephrologists, pharmacists, intensivists (including neurointensivists), neurosurgeons and other surgeons, nurses, clinical laboratory personnel, blood bank representatives, risk managers, and health informatics professionals. This input could be obtained in conjunction with the formulary decision-making process for reversal agents or through the formation of institutional committees responsible for issues related to anticoagulation. The cost of these agents is a consideration in formulary decisions and the anticoagulant reversal plan. Volume discounts and manufacturer rebates vary widely among institutions and can have a substantial effect on product acquisition cost. The acquisition cost may also reflect local practice and physician preference. For example, the acquisition cost may be higher when PCC3 plus rfviia is used to build a PCC4 product instead of using apcc. 33 The clinical situation and therapeutic goals (e.g., need for multiple doses instead of a single dose to achieve management goals) can also affect the cost of treatment. Reversal agents placed on the formulary may be subject to prescribing restrictions or requirements for approval by key individuals who are knowledgeable about anticoagulant reversal due to safety and economic concerns. Although prescribing restrictions can ensure that reversal agents are used only by personnel who are aware of their risks and benefits and prevent inappropriate use, restrictions have the potential to delay treatment. Provisions should be made to ensure that prescribing restrictions do not cause an undue e94 Am J Health-Syst Pharm Vol 70, 2013

14 delay in treatment. Ideally, persons charged with approving the use of reversal agents should be available at any hour. In addition, a method for some flexibility in reversal agent use beyond what is formally outlined in institutional protocols should be devised because of the uncertainty about the optimal approach for using reversal agents. Many clinicians may be unfamiliar with and ill equipped to handle questions that arise regarding the use of anticoagulant reversal agents, as many of these agents are new, the use of these agents is infrequent, and guidelines and supporting literature are limited. Many tertiary references for concentrated clotting factor products provide information on dosing and monitoring recommendations that are appropriate for treating hematology issues (e.g., hemophilia), not for reversing anticoagulation. Confusion may arise among staff about which department or location in the institution stores and dispenses reversal agents (e.g., blood bank, pharmacy department), because it varies among health care facilities. Knowledgeable individuals in the institution who can respond to questions about the use of anticoagulant reversal agents should be identified. Policies and procedures for promptly referring questions to these individuals should be established as part of the anticoagulant reversal plan to expedite the resolution of questions. Emergency department or intensive care unit clinicians, neurointensivists, hematologists, or designated pharmacists often have this expertise and can serve in this capacity. To minimize delays in providing treatment in emergent situations, contact information (e.g., pager number) for these individuals should be made available to personnel who may have questions and concerns. Education of pharmacists and other clinicians is needed to increase their knowledge of the oral anticoagulants and available reversal strategies. Although reversal agents are not often used, their use is accompanied by a high risk of harm if used inappropriately. In education departments at some health care systems, case studies with simulated clinical scenarios involving reversal agents have been developed to train emergency medicine residents, and these simulations would be helpful for pharmacists, nurses, and other staff. Continuing education about anticoagulant reversal is needed to maintain competence due to the continually evolving and limited information currently available to guide the use of reversal agents and the rapid emergence of new data. The anticoagulant reversal plan should be periodically revised to accommodate institutional needs. A mechanism should be established to update the plan as new reversal agents are introduced and new information about the use of established reversal agents becomes available. In revising the anticoagulant reversal plan, an assessment of past patient cases should be performed. This assessment can provide valuable insight into pitfalls encountered in managing bleeding associated with oral anticoagulants and strategies to avoid these pitfalls in the future. In addition, clinical scenario simulations with key stakeholders may be useful for understanding the clinical process and preparing staff to respond to the need for an emergency anticoagulant reversal around-the-clock. Conclusion Bleeding is a serious complication of the use of oral anticoagulants. Limited information is available to guide the reversal of warfarin or TSOAs in patients who are bleeding or are in need of an urgent invasive procedure. Use of a systematic approach to assessing and treating these patients based on available evidence and expert opinion can help avoid delays that could adversely affect patient outcomes. References 1. U.S. Department of Health and Human Services. Aging statistics. AoARoot/Aging_Statistics/index.aspx (accessed 2013 Jun 28). 2. Nutescu E, Chuatrisorn I, Hellenbart E. Drug and dietary interactions of warfarin and novel oral anticoagulants: an update. J Thromb Thrombolysis. 2011; 31: Budnitz DS, Lovegrove MC, Shehab N et al. Emergency hospitalizations for adverse drug events in older Americans. N Engl J Med. 2011; 365: Institute for Safe Medication Practices. QuarterWatch monitoring FDA Med- Watch reports: anticoagulants the leading reported drug risk in QuarterWatch/pdfs/2011Q4.pdf (accessed 2013 Jun 28). 5. Connolly SJ, Ezekowitz MD, Yusuf S et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009; 361: Patel MR, Mahaffey KW, Garg J et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011; 365: Granger CB, Alexander JH, McMurray JJ et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011; 365: Harinstein LM, Morgan JW, Russo N. Treatment of dabigatran-associated bleeding: case report and review of the literature. J Pharm Pract. 2013; 26: Food and Drug Administration. FDA drug safety communication: update on the risk for serious bleeding events with the anticoagulant Pradaxa (dabigatran). ucm htm#data (accessed 2013 Jun 28). 10. Southworth MR, Reichman ME, Unger EF. Dabigatran and postmarketing reports of bleeding. N Engl J Med. 2013; 368: Institute for Safe Medication Practices. QuarterWatch monitoring FDA MedWatch reports: update on anticoagulants. pdfs/2012q2.pdf (accessed 2013 Jun 28). 12. Holbrook A, Schulman S, Witt DM et al. Evidence-based management of anticoagulant therapy: antithrombotic therapy and prevention of thrombosis, 9th ed. American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012; 141(suppl 2):e152S- 184S. 13. Neel S. Essential warfarin knowledge. In: Gulseth M, ed. Managing anticoagulation patients in the hospital. Bethesda, MD: American Society of Health-System Pharmacists; 2007: Pradaxa (dabigatran etexilate mesylate) prescribing information. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals; 2013 Apr. Am J Health-Syst Pharm Vol 70, 2013 e95

15 15. Xarelto (rivaroxaban) prescribing information. Titusville, NJ: Janssen Pharmaceuticals; 2013 Mar. 16. Eliquis (apixaban) prescribing information. New York, NY: Pfizer; 2012 Dec. 17. Eriksson BI, Quinlan DJ, Weitz JI. Comparative pharmacodynamics and pharmacokinetics of oral direct thrombin and factor Xa inhibitors in development. Clin Pharmacokinet. 2009; 48: Kaatz S, Kouides PA, Garcia DA et al. Guidance on the emergent reversal of oral thrombin and factor Xa inhibitors. Am J Hematol. 2012; 87(suppl 1):S Stangier J, Rathgen K, Stähle H et al. Influence of renal impairment on the pharmacokinetics and pharmacodynamics of oral dabigatran etexilate: an open-label, parallel-group, single-centre study. Clin Pharmacokinet. 2010; 49: Ufer M. Comparative efficacy and safety of the novel oral anticoagulants dabigatran, rivaroxaban and apixaban in preclinical and clinical development. Thromb Haemost. 2010; 103: Haynes LM, Orfeo T, Mann KG. Rivaroxaban delivery and reversal at a venous flow rate. Arterioscler Thromb Vasc Biol. 2012; 32: Miyares MA, Davis K. Newer oral anticoagulants: a review of laboratory monitoring options and reversal agents in the hemorrhagic patient. Am J Health-Syst Pharm. 2012; 69: Palladino M, Thomson L, Swift B et al. Implementing the new oral anticoagulants into the hospital formulary. Am J Hematol. 2012; 87(suppl 1):S Dager WE, Gosselin RC, Kitchen S et al. Dabigatran effects on the international normalized ratio, activated partial thromboplastin time, thrombin time, and fibrinogen: a multicenter, in vitro study. Ann Pharmacother. 2012; 46: Avecilla ST, Ferrell C, Chandler WL et al. Plasma-diluted thrombin time to measure dabigatran concentrations during dabigatran etexilate therapy. Am J Clin Pathol. 2012; 137: Stangier J, Feuring M. Using the HEMO- CLOT direct thrombin inhibitor assay to determine plasma concentrations of dabigatran. Blood Coagul Fibrinolysis. 2012; 23: Dager WE. Developing a management plan for oral anticoagulant reversal. Am J Health-Syst Pharm. 2013; 70(suppl 1):S Aniara. Biophen rivaroxaban plasma calibrator (12 1 ml). PROD/A html (accessed 2013 Jun 28). 29. Dager WE, Gosselin RC, Roberts AJ. Reversing dabigatran in life-threatening bleeding occurring during cardiac ablation with factor eight inhibitor bypassing activity. Crit Care Med. 2013; 41(5):e Van Ryn J, Litzenburger T, Waterman A et al. An antibody selective to dabigatran safely neutralizes both dabigatran- induced and anticoagulant and bleeding activity in in vitro and in vivo models. J Thromb Haemost. 2011; 9(suppl 2): P-MO-166. Abstract. 31. Lu G, DeGuzman FR, Hollenbach SJ et al. A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa. Nat Med. 2013; 19: Laulicht B, Bakhru S, Lee C et al. Small molecule antidote for anticoagulants. Circulation. 2012; 126:A Abstract. 33. Kalus JS. Pharmacologic interventions for reversing the effects of oral anticoagulants. Am J Health-Syst Pharm. 2013; 70(suppl 1):S Holland L, Warkentin TE, Refaai M et al. Suboptimal effect of a threefactor prothrombin complex concentrate (Profilnine-SD) in correcting supratherapeutic international normalized ratio due to warfarin overdose. Transfusion. 2009; 49: FEIBA NF (anti-inhibitor coagulant complex) product monograph. Baxter Corporation: Mississauga, Ontario, Canada; 2011 Jul. 36. Kcentra (prothrombin complex concentrate, human) prescribing information. Kankakee, IL: CSL Behring LLC; 2013 Apr. 37. Peacock WF, Gearhart MM, Mills RM. Emergency management of bleeding associated with old and new oral anticoagulants. Clin Cardiol. 2012; 35: Sørensen B, Spahn DR, Innerhofer P et al. Clinical review: prothrombin complex concentrates evaluation of safety and thrombogenicity. Crit Care. 2011; 15: Escolar Albaladejo G. Reversal of apixaban induced alterations of hemostasis by different coagulation factor concentrates: studies in vitro with circulating human blood. ucm_ pdf (accessed 2013 Jun 28). 40. Imberti D, Barillari G, Biasioli C et al. Emergency reversal of anticoagulation with a three-factor prothrombin complex concentrate in patients with intracranial haemorrhage. Blood Transfus. 2011; 9: Baggs JH, Patanwala AE, Williams EM et al. Dosing of 3-factor prothrombin complex concentrate for international normalized ratio reversal. Ann Pharmacother. 2012; 46: Levi M, Moore T, Castillejos C et al. Effects of three-factor and four-factor prothrombin complex concentrates on the pharmacodynamics of rivaroxaban. publicabstractviewdo?id=217276& congressid=6839 (accessed 2013 Jun 28). 43. Pabinger I, Brenner B, Kalina U et al. Prothrombin complex concentrate (Beriplex P/N) for emergency anticoagulation reversal: a prospective multinational clinical trial. J Thromb Haemost. 2008; 6: Sarode R, Milling TJ, Refaai MA et al. Integrated safety analysis of a 4-factor prothrombin complex concentrate versus plasma in phase III clinical trials. cdn.f1000.com/posters/docs/ (accessed 2013 Jun 28). 45. Marlu R, Hodaj E, Paris A et al. Effect of non-specific reversal agents on anticoagulant activity of dabigatran and rivaroxaban: a randomised crossover ex vivo study in healthy volunteers. Thromb Haemost. 2012; 108: Eerenberg ES, Kamphuisen PW, Sijpkens MK et al. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebocontrolled, crossover study in healthy subjects. Circulation. 2011; 124: Dinkelaar J, Molenaar PJ, Ninivaggi M et al. In vitro assessment, using thrombin generation, of the applicability of prothrombin complex concentrate as an antidote for rivaroxaban. J Thromb Haemost. 2013; 11: Dager WE, King JH, Regalia RC et al. Reversal of elevated international normalized ratios and bleeding with lowdose recombinant activated factor VII in patients receiving warfarin. Pharmacotherapy. 2006; 26: Nishijima DK, Dager WE, Schrot RJ et al. The efficacy of factor VIIa in emergency department patients with warfarin use and traumatic intracranial hemorrhage. Acad Emerg Med. 2010; 17: Pinner NA, Hurdle AC, Oliphant C et al. Treatment of warfarin-related intracranial hemorrhage: a comparison of prothrombin complex concentrate and recombinant activated factor VII. World Neurosurg. 2010; 74: Wójcik C, Schymik ML, Cure EG. Activated prothrombin complex concentrate factor VIII inhibitor bypassing activity (FEIBA) for the reversal of warfarininduced coagulopathy. Int J Emerg Med. 2009; 2: Sarode R, Matevosyan K, Bhagat R et al. Rapid warfarin reversal: a 3-factor prothrombin complex concentrate and recombinant factor VIIa cocktail for intracerebral hemorrhage. J Neurosurg. 2012; 116: Zhou W, Schwarting S, Illanes S et al. Hemostatic therapy in experimental intracerebral hemorrhage associated with the direct thrombin inhibitor dabigatran. Stroke. 2011; 42: Godier A, Miclot A, Le Bonniec B et al. Evaluation of prothrombin complex concentrate and recombinant activated factor VII to reverse rivaroxaban in a rabbit model. Anesthesiology. 2012; 116: Van Ryn J, Ruehl D, Priepke H et al. Reversibility of the anticoagulant effect of high doses of the direct thrombin inhibitor dabigatran, by recombinant factor VIIa or activated prothrombin complex concentrate. online.haematologica.org/eha13/browsere cord.php?-action=browse&-recid=1923 (accessed 2013 Jun 28). e96 Am J Health-Syst Pharm Vol 70, 2013

16 56. Gruber A, Marzek UM, Buetehorn U et al. Potential of activated prothrombin complex concentrate and activated factor VII to reverse the anticoagulant effects of rivaroxaban in primates. abstracts.hematologylibrary.org/cgi/ content/abstract/112/11/3825? maxtoshow=&hits=10&result FORMAT=&fulltext=gruber&searchid =1&FIRSTINDEX=0&volume=112& issue=11&resourcetype=hwcit (accessed 2013 Jun 28) 57. Clinicaltrials.gov. Study in healthy volunteers of the reversion by haemostatic drugs of the anticoagulant effect of new anti-thrombotics (REVNEWANTICO) ?term=rivaroxaban+dabigatran+ reversal&rank=2 (accessed 2013 Jun 28). 58. Henry DA, Carless PA, Moxey AJ et al. Anti-fibrinolytic use for minimising perioperative allogeneic blood transfusion. Cochrane Database Syst Rev. 2011; 1:CD Gage BF, Waterman AD, Shannon W et al. Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA. 2001; 285: Lip GY, Nieuwlaat R, Pisters R et al. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the Euro Heart Survey on Atrial Fibrillation. Chest. 2010; 137: Douketis JD, Spyropoulos AC, Spencer FA et al. Perioperative management of antithrombotic therapy: antithrombotic therapy and prevention of thrombosis, 9th ed.: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012; 141(suppl 2):e326S-50S. 62. Falck-Ytter Y, Francis CW, Johanson NA et al. Prevention of VTE in orthopedic surgery patients: antithrombotic therapy and prevention of thrombosis, 9th ed.: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012; 141(suppl 2):e278S- 325S. 63. Gould MK, Garcia DA, Wren SM et al. Prevention of VTE in nonorthopedic surgical patients: antithrombotic therapy and prevention of thrombosis, 9th ed.: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012; 141(suppl 2):e227S- 77S. 64. Kearon C, Akl EA, Comerota AJ et al. Antithrombotic therapy for VTE disease: antithrombotic therapy and prevention of thrombosis, 9th ed.: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012; 141(suppl 2):e419S-994S. 65. Caprini JA. Identification of patient venous thromboembolism risk across the continuum of care. Clin Appl Thromb Hemost. 2011; 17: Wanek MR, Horn ET, Elapavaluru S et al. Safe use of hemodialysis for dabigatran removal before cardiac surgery. Ann Pharmacother. 2012; 46:e Chang DN, Dager WE, Chin AI. Removal of dabigatran by hemodialysis. Am J Kidney Dis. 2013; 61: Tsu LV, Dienes JE, Dager WE. Vitamin K dosing to reverse warfarin based on INR, route of administration, and home warfarin dose in the acute/critical care setting. Ann Pharmacother. 2012; 46: Meehan R, Tavares M, Sweeney J. Clinical experience with oral versus intravenous vitamin K for warfarin reversal (CME). Transfusion. 2013; 53: Burbury KL, Milner A, Snooks B et al. Short-term warfarin reversal for elective surgery using low-dose intravenous vitamin K: safe, reliable and convenient. Br J Haematol. 2011; 154: Song MM, Warne CP, Crowther MA. Prothrombin complex concentrate (PCC, Octaplex) in patients requiring immediate reversal of vitamin K antagonist anticoagulation. Thromb Res. 2012; 129: Switzer JA, Rocker J, Mohorn P et al. Clinical experience with three-factor prothrombin complex concentrate to reverse warfarin anticoagulation in intracranial hemorrhage. Stroke. 2012; 43: Leissinger CA, Blatt PM, Hoots WK et al. Role of prothrombin complex concentrates in reversing warfarin anticoagulation: a review of the literature. Am J Hematol. 2008; 83: Dager WE. Using prothrombin complex concentrates to rapidly reverse oral anticoagulant effects. Ann Pharmacother. 2011; 45: Chapman SA, Irwin ED, Beal AL et al. Prothrombin complex concentrate versus standard therapies for INR reversal in trauma patients receiving warfarin. Ann Pharmacother. 2011; 45: Ilyas C, Beyer GM, Dutton RP et al. Recombinant factor VIIa for warfarinassociated intracranial bleeding. J Clin Anesth. 2008; 20: Viles-Gonzalez JF, Fuster V, Halperin JL. New anticoagulants for prevention of stroke in patients with atrial fibrillation. J Cardiovasc Electrophysiol. 2011; 22: Schulman S, Crowther MA. How I treat with anticoagulants in 2012: new and old anticoagulants, and when and how to switch. Blood. 2012; 119: Van Ryn J, Stangier J, Haertter S et al. Dabigatran etexilate a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost. 2010; 103: Nutescu EA. Oral anticoagulant therapies: balancing the risks. Am J Health-Syst Pharm. 2013; 70(suppl 1):S Cotton B, McCarthy M, Holcomb J. Acutely injured patients on dabigatran. N Engl J Med. 2011; 365: Khadzhynov D, Wagner F, Formella S et al. Effective elimination of dabigatran by haemodialysis: a phase I single-centre study in patients with end-stage renal disease. Thromb Haemost. 2013; 109: Singh T, Maw TT, Henry BL et al. Extracorporeal therapy for dabigatran removal in the treatment of acute bleeding: a single center experience. Clin J Am Soc Nephrol. Epub ahead of print May 23 (DOI /CJN ). 84. Warkentin TE, Margetts P, Connolly SJ et al. Recombinant factor VIIa (rfviia) and hemodialysis to manage massive dabigatran-associated postcardiac surgery bleeding. Blood. 2012; 119: Harrison TD, Laskosky J, Jazaeri O et al. Low-dose recombinant activated factor VII results in less blood and blood product use in traumatic hemorrhage. J Trauma. 2005; 59: Am J Health-Syst Pharm Vol 70, 2013 e97

Speaker Disclosure. Outline. Pharmacist Objectives. Patient Case. Outline 9/4/2014

Speaker Disclosure. Outline. Pharmacist Objectives. Patient Case. Outline 9/4/2014 Speaker Disclosure Matthew K. Pitlick, Pharm.D., BCPS St. Louis College of Pharmacy/VA St. Louis HCS mpitlick@stlcop.edu Matthew K. Pitlick, Pharm.D., BCPS declares no conflicts of interest, real or apparent,

More information

DVT/PE Management with Rivaroxaban (Xarelto)

DVT/PE Management with Rivaroxaban (Xarelto) DVT/PE Management with Rivaroxaban (Xarelto) Rivaroxaban is FDA approved for the acute treatment of DVT and PE and reduction in risk of recurrence of DVT and PE. FDA approved indications: Non valvular

More information

To assist clinicians in the management of minor, major, and/or life-threatening bleeding in patients receiving new oral anticoagulants (NOACs).

To assist clinicians in the management of minor, major, and/or life-threatening bleeding in patients receiving new oral anticoagulants (NOACs). MANAGEMENT OF BLEEDING IN PATIENTS WHO ARE RECEIVING A NEW ORAL ANTICOAGULANT (DABIGATRAN, RIVAROXABAN, APIXABAN) TARGET AUDIENCE: All Canadian health care professionals. OBJECTIVE: To assist clinicians

More information

Stop the Bleeding: Management of Drug-induced Coagulopathy. Stacy A. Voils, PharmD, BCPS Critical Care Specialist, Neurosurgery

Stop the Bleeding: Management of Drug-induced Coagulopathy. Stacy A. Voils, PharmD, BCPS Critical Care Specialist, Neurosurgery Stop the Bleeding: Management of Drug-induced Coagulopathy Stacy A. Voils, PharmD, BCPS Critical Care Specialist, Neurosurgery Objectives Discuss contemporary management of warfarin reversal in patients

More information

LAMC Reversal Agent Guideline for Anticoagulants 2013. Time to resolution of hemostasis (hrs) Therapeutic Options

LAMC Reversal Agent Guideline for Anticoagulants 2013. Time to resolution of hemostasis (hrs) Therapeutic Options LAMC Reversal Agent Guideline for Anticoagulants 2013 Medication resolution of hemostasis (hrs) Intervention Administration Instructions Heparin 3-4 Protamine 1mg IV for every 100 units of heparin Slow

More information

Comparison between New Oral Anticoagulants and Warfarin

Comparison between New Oral Anticoagulants and Warfarin Comparison between New Oral Anticoagulants and Warfarin Warfarin was the mainstay of oral anticoagulant therapy until the recent discovery of more precise targets for therapy. In recent years, several

More information

The author has no disclosures

The author has no disclosures Mary Bradbury, PharmD, BCPS Clinical Pharmacy Specialist, Cardiac Surgery September 18, 2012 Mary.bradbury@inova.org This presentation will discuss unlabeled and investigational use of products The author

More information

Reversal of Anticoagulants at UCDMC

Reversal of Anticoagulants at UCDMC Reversal of Anticoagulants at UCDMC Introduction: Bleeding complications are a common concern with the use of anticoagulant agents. In selected situations, reversing or neutralizing the effects of an anticoagulant

More information

5/21/2012. Perioperative Use Issues. On admission: During hospitalization:

5/21/2012. Perioperative Use Issues. On admission: During hospitalization: Dabigatran and Rivaroxaban: Challenges in the Perioperative Setting Claudia Swenson, Pharm.D., CDE, BC-ADM, FASHP Central Washington Hospital Wenatchee, WA claudia.swenson@cwhs.com Dabigatran and Rivaroxaban:

More information

Dabigatran (Pradaxa) Guidelines

Dabigatran (Pradaxa) Guidelines Dabigatran (Pradaxa) Guidelines Dabigatran is a new anticoagulant for reducing the risk of stroke in patients with atrial fibrillation. Dabigatran is a direct thrombin inhibitor, similar to warfarin, without

More information

USE AND INTERPRETATION OF LABORATORY COAGULATION TESTS IN PATIENTS WHO ARE RECEIVING A NEW ORAL ANTICOAGULANT (DABIGATRAN, RIVAROXABAN, APIXABAN)

USE AND INTERPRETATION OF LABORATORY COAGULATION TESTS IN PATIENTS WHO ARE RECEIVING A NEW ORAL ANTICOAGULANT (DABIGATRAN, RIVAROXABAN, APIXABAN) USE AND INTERPRETATION OF LABORATORY COAGULATION TESTS IN PATIENTS WHO ARE RECEIVING A NEW ORAL ANTICOAGULANT (DABIGATRAN, RIVAROXABAN, APIXABAN) TARGET AUDIENCE: All Canadian health care professionals:

More information

Disclosure. Warfarin

Disclosure. Warfarin Disclosure No conflicts of interest to disclose Reversal Strategies for Novel Oral Anticoagulants Noelle de Leon, PharmD, BCPS Critical Care Pharmacist, Department of Pharmaceutical Services Assistant

More information

Novel Anticoagulation Agents DISCLOSURES. Objectives ATRIAL FIBRILLATION TRIALS. NOAC Comparison 6/12/2015

Novel Anticoagulation Agents DISCLOSURES. Objectives ATRIAL FIBRILLATION TRIALS. NOAC Comparison 6/12/2015 Novel Anticoagulation Agents DISCLOSURES James W. Haynes, MD Department of Family Medicine Univ of TN Health Science Center (Chattanooga) Objectives Understand mechanism of action behind the NOAC agents

More information

NnEeWw DdEeVvEeLlOoPpMmEeNnTtSs IiıNn OoRrAaLl AaNnTtIiıCcOoAaGgUuLlAaTtIiıOoNn AaNnDd RrEeVvEeRrSsAaLl

NnEeWw DdEeVvEeLlOoPpMmEeNnTtSs IiıNn OoRrAaLl AaNnTtIiıCcOoAaGgUuLlAaTtIiıOoNn AaNnDd RrEeVvEeRrSsAaLl NnEeWw DdEeVvEeLlOoPpMmEeNnTtSs IiıNn OoRrAaLl AaNnTtIiıCcOoAaGgUuLlAaTtIiıOoNn AaNnDd RrEeVvEeRrSsAaLl Mikele Wissing, RN June 2014 Introduction until recently, was the unrivaled medication for treatment

More information

Anticoagulation and Reversal

Anticoagulation and Reversal Anticoagulation and Reversal John Howard, PharmD, BCPS Clinical Pharmacist Internal Medicine Affiliate Associate Clinical Professor South Carolina College of Pharmacy Disclosures I have no Financial, Industry,

More information

Critical Bleeding Reversal Protocol

Critical Bleeding Reversal Protocol Critical Bleeding Reversal Protocol Coagulopathy, either drug related or multifactorial, is a major contributing factor to bleeding related mortality in a variety of clinical settings. Standard therapy

More information

48 th Annual Meeting. Non-VKA Oral Anticoagulants: Prevention & Treatment of Bleeding. Terminology. Disclosure. Public Health Impact.

48 th Annual Meeting. Non-VKA Oral Anticoagulants: Prevention & Treatment of Bleeding. Terminology. Disclosure. Public Health Impact. 48 th Annual Meeting Terminology Non-VKA Oral Anticoagulants: Prevention & Treatment of Bleeding Stacy A. Voils, PharmD, MS, BCPS Navigating the Oceans of Opportunity Target-specific oral anticoagulants

More information

The management of cerebral hemorrhagic complications during anticoagulant therapy

The management of cerebral hemorrhagic complications during anticoagulant therapy The management of cerebral hemorrhagic complications during anticoagulant therapy Maurizio Paciaroni Stroke Unit Division of Cardiovascular Medicine University of Perugia - Italy Perugia Stroke Registry

More information

Prescriber Guide. 20mg. 15mg. Simply Protecting More Patients. Simply Protecting More Patients

Prescriber Guide. 20mg. 15mg. Simply Protecting More Patients. Simply Protecting More Patients Prescriber Guide 20mg Simply Protecting More Patients 15mg Simply Protecting More Patients 1 Dear Doctor, This prescriber guide was produced by Bayer Israel in cooperation with the Ministry of Health as

More information

Session 3 Topics. Argatroban. Argatroban. Drug Use and Adverse Effects. Laboratory Monitoring of Anticoagulant Therapy

Session 3 Topics. Argatroban. Argatroban. Drug Use and Adverse Effects. Laboratory Monitoring of Anticoagulant Therapy ~~Marshfield Labs Presents~~ Laboratory Monitoring of Anticoagulant Therapy Session 3 of 4 Michael J. Sanfelippo, M.S. Technical Director, Coagulation Services Session 3 Topics Direct Thrombin Inhibitors:

More information

New Anticoagulation Options for Stroke Prevention in Atrial Fibrillation. Joy Wahawisan, Pharm.D., BCPS April 25, 2012

New Anticoagulation Options for Stroke Prevention in Atrial Fibrillation. Joy Wahawisan, Pharm.D., BCPS April 25, 2012 New Anticoagulation Options for Stroke Prevention in Atrial Fibrillation Joy Wahawisan, Pharm.D., BCPS April 25, 2012 Stroke in Atrial Fibrillation % Stroke 1991;22:983. Age Range (years) CHADS 2 Risk

More information

Anticoagulant therapy

Anticoagulant therapy Anticoagulation: The risks Anticoagulant therapy 1990 2002: 600 incidents reported 120 resulted in death of patient 92 deaths related to warfarin usage 28 reports related to heparin usage Incidents in

More information

Blood products and pharmaceutical emergencies

Blood products and pharmaceutical emergencies Blood products and pharmaceutical emergencies Kasey L. Bucher PharmD, BCPS Clinical Specialist, Emergency Medicine Mercy Health Saint Mary s September 12, 2013 Disclosures None significancemagazine.com

More information

Anticoagulants in Atrial Fibrillation

Anticoagulants in Atrial Fibrillation Anticoagulants in Atrial Fibrillation Starting and Stopping Them Safely Carmine D Amico, D.O. Overview Learning objectives Introduction Basic concepts Treatment strategy & options Summary 1 Learning objectives

More information

DABIGATRAN ETEXILATE TARGET Vitamin K epoxide reductase WARFARIN RIVAROXABAN APIXABAN

DABIGATRAN ETEXILATE TARGET Vitamin K epoxide reductase WARFARIN RIVAROXABAN APIXABAN TARGET SPECIFIC ORAL ANTICOAGULANTS (TSOACs) This document is intended as a guideline only and should not replace sound clinical judgment Please refer to UNMH formulary in Lexicomp for approved use(s)

More information

STROKE PREVENTION IN ATRIAL FIBRILLATION. TARGET AUDIENCE: All Canadian health care professionals. OBJECTIVE: ABBREVIATIONS: BACKGROUND:

STROKE PREVENTION IN ATRIAL FIBRILLATION. TARGET AUDIENCE: All Canadian health care professionals. OBJECTIVE: ABBREVIATIONS: BACKGROUND: STROKE PREVENTION IN ATRIAL FIBRILLATION TARGET AUDIENCE: All Canadian health care professionals. OBJECTIVE: To guide clinicians in the selection of antithrombotic therapy for the secondary prevention

More information

Xabans Good for What Ails Ya? Brian Tiffany, MD, PhD, FACEP Dept of Emergency Medicine Chandler Regional Medical Center Mercy Gilbert Medical Center

Xabans Good for What Ails Ya? Brian Tiffany, MD, PhD, FACEP Dept of Emergency Medicine Chandler Regional Medical Center Mercy Gilbert Medical Center Xabans Good for What Ails Ya? Brian Tiffany, MD, PhD, FACEP Dept of Emergency Medicine Chandler Regional Medical Center Mercy Gilbert Medical Center DISCLOSURES No relevant financial disclosures I will

More information

STROKE PREVENTION IN ATRIAL FIBRILLATION

STROKE PREVENTION IN ATRIAL FIBRILLATION STROKE PREVENTION IN ATRIAL FIBRILLATION OBJECTIVE: To guide clinicians in the selection of antithrombotic therapy for the secondary prevention of ischemic stroke and arterial thromboembolism in patients

More information

Reversal of Antiplatelet and Anticoagulant Therapy: What You Need To Know. Ronald Walsh, MD Chief Medical Officer Community Blood Services

Reversal of Antiplatelet and Anticoagulant Therapy: What You Need To Know. Ronald Walsh, MD Chief Medical Officer Community Blood Services Reversal of Antiplatelet and Anticoagulant Therapy: What You Need To Know Ronald Walsh, MD Chief Medical Officer Community Blood Services HEMOSTATIC PROCESS Initiation and formation of the platelet plug

More information

The Anticoagulated Patient A Hematologist s Perspective

The Anticoagulated Patient A Hematologist s Perspective The Anticoagulated Patient A Hematologist s Perspective Deborah M. Siegal MD MSc FRCPC Clinical Scholar Division of Hematology and Thromboembolism Thrombosis Canada Research Fellow McMaster University

More information

Reversing the New Anticoagulants

Reversing the New Anticoagulants Reversing the New Anticoagulants Disclosure Susan C. Lambe, MD Assistant Clinical Professor Department of Emergency Medicine University of California, San Francisco Roadmap for today 1 Roadmap for today

More information

New Anticoagulants: When and Why Should I Use Them? Disclosures

New Anticoagulants: When and Why Should I Use Them? Disclosures Winship Cancer Institute of Emory University New Anticoagulants: When and Why Should I Use Them? Christine L. Kempton, MD, MSc Associate Professor of Pediatrics and Hematology and Medical Oncology Hemophilia

More information

NHS FORTH VALLEY Rivaroxaban for Stroke Prevention in Atrial Fibrillation

NHS FORTH VALLEY Rivaroxaban for Stroke Prevention in Atrial Fibrillation NHS FORTH VALLEY Rivaroxaban for Stroke Prevention in Atrial Fibrillation Date of First Issue 06/06/2012 Approved 06/06/2012 Current Issue Date 29/10/2014 Review Date 29/10/2016 Version 1.4 EQIA Yes 01/06/2012

More information

Recommendation for the Reversal of Novel Anticoagulants in Emergent Situations

Recommendation for the Reversal of Novel Anticoagulants in Emergent Situations Lauren Edwards PharmD Candidate 2016 Truman Medical Center, Lakewood Preceptor: Dr. Melissa Gabriel June 11, 2015 Recommendation for the Reversal of Novel Anticoagulants in Emergent Situations Background

More information

Disclosures. Objective (NRHS) Self Assessment #2

Disclosures. Objective (NRHS) Self Assessment #2 Development and Implementation of a Protocol for Reversing the Effects of Anticoagulants for Use in a Community Hospital Samantha Sepulveda, Pharm.D. PGY1 Pharmacy Resident Norman Regional Health System

More information

Anticoagulation Dosing at UCDMC Indication Agent Standard Dose Comments and Dose Adjustments VTE Prophylaxis All Services UFH 5,000 units SC q 8 h

Anticoagulation Dosing at UCDMC Indication Agent Standard Dose Comments and Dose Adjustments VTE Prophylaxis All Services UFH 5,000 units SC q 8 h Indication Agent Standard Dose Comments and Dose Adjustments VTE Prophylaxis All Services UFH 5,000 units SC q 8 h See EMR adult VTE prophylaxis CI order set Enoxaparin See service specific dosing Assess

More information

Inpatient Anticoagulation Safety. To provide safe and effective anticoagulation therapy through a collaborative approach.

Inpatient Anticoagulation Safety. To provide safe and effective anticoagulation therapy through a collaborative approach. Inpatient Anticoagulation Safety Purpose: Policy: To provide safe and effective anticoagulation therapy through a collaborative approach. Upon the written order of a physician, Heparin, Low Molecular Weight

More information

AHA/ASA Scientific Statement Oral Antithrombotic Agents for the Prevention of Stroke in Atrial Fibrillation

AHA/ASA Scientific Statement Oral Antithrombotic Agents for the Prevention of Stroke in Atrial Fibrillation AHA/ASA Scientific Statement Oral Antithrombotic Agents for the Prevention of Stroke in Atrial Fibrillation A Statement for Healthcare Professionals from the American Heart Association/American Stroke

More information

What to do in case of hemorragia. L Camoin Jau Service d Hématologie APHM Marseille

What to do in case of hemorragia. L Camoin Jau Service d Hématologie APHM Marseille What to do in case of hemorragia with NOAC? L Camoin Jau Service d Hématologie APHM Marseille Disclosure Boehringer Bayer Daishi Sanofi BMS Pharmacodynamic and kinetic properties of new oral anticoagulants.

More information

NEWER ANTICOAGULANTS: FOCUS ON STROKE PREVENTION IN ATRIAL FIBRILLATION AND DEEP VEIN THROMBOSIS/PULMONARY EMBOLISM

NEWER ANTICOAGULANTS: FOCUS ON STROKE PREVENTION IN ATRIAL FIBRILLATION AND DEEP VEIN THROMBOSIS/PULMONARY EMBOLISM NEWER ANTICOAGULANTS: FOCUS ON STROKE PREVENTION IN ATRIAL FIBRILLATION AND DEEP VEIN THROMBOSIS/PULMONARY EMBOLISM Carol Lee, Pharm.D., Jessica C. Song, M.A., Pharm.D. INTRODUCTION For many years, warfarin

More information

PERI-OPERATIVE MANAGEMENT OF PATIENTS WHO ARE RECEIVING A NEW ORAL ANTICOAGULANT (DABIGATRAN, RIVAROXABAN,

PERI-OPERATIVE MANAGEMENT OF PATIENTS WHO ARE RECEIVING A NEW ORAL ANTICOAGULANT (DABIGATRAN, RIVAROXABAN, PERI-OPERATIVE MANAGEMENT OF PATIENTS WHO ARE RECEIVING A NEW ORAL ANTICOAGULANT (DABIGATRAN, RIVAROXABAN, APIXABAN) TARGET AUDIENCE: All Canadian health care professionals, including primary care physicians,

More information

Three new/novel oral anticoagulants (NOAC) have been licensed in Ireland since 2008:

Three new/novel oral anticoagulants (NOAC) have been licensed in Ireland since 2008: Key Points to consider when prescribing NOACs Introduction Three new/novel oral anticoagulants (NOAC) have been licensed in Ireland since 2008: Dabigatran Etexilate (Pradaxa ) 75mg, 110mg, 150mg. Rivaroxaban

More information

STARTING, SWITCHING OR STOPPING NEW ORAL ANTICOAGULANTS: A Practical Approach

STARTING, SWITCHING OR STOPPING NEW ORAL ANTICOAGULANTS: A Practical Approach STARTING, SWITCHING OR STOPPING NEW ORAL ANTICOAGULANTS: A Practical Approach Jeffrey I Weitz, MD, FRCP(C), FACP Professor of Medicine and Biochemistry McMaster University Canada Research Chair in Thrombosis

More information

Post-ISTH review: Thrombosis-I New Oral Anticoagulants 臺 大 醫 院 內 科 部 血 液 科 周 聖 傑 醫 師

Post-ISTH review: Thrombosis-I New Oral Anticoagulants 臺 大 醫 院 內 科 部 血 液 科 周 聖 傑 醫 師 Post-ISTH review: Thrombosis-I New Oral Anticoagulants 臺 大 醫 院 內 科 部 血 液 科 周 聖 傑 醫 師 The antithrombotic efficacy is limited but the risk of bleeding is indefinite Fuster V et al. Circulation 2011;123:e269-e367

More information

COMPARISON OF NEW ORAL ANTICOAGULANTS AND FREQUENTLY- ASKED QUESTIONS FROM PATIENTS. TARGET AUDIENCE: All Canadian health care professionals.

COMPARISON OF NEW ORAL ANTICOAGULANTS AND FREQUENTLY- ASKED QUESTIONS FROM PATIENTS. TARGET AUDIENCE: All Canadian health care professionals. COMPARISON OF NEW ORAL ANTICOAGULANTS AND FREQUENTLY- ASKED QUESTIONS FROM PATIENTS AND PHYSICIANS TARGET AUDIENCE: All Canadian health care professionals. OBJECTIVES: To provide a comparison of the new

More information

New Treatments for Stroke Prevention in Atrial Fibrillation. John C. Andrefsky, MD, FAHA NEOMED Internal Medicine Review course May 5 th, 2013

New Treatments for Stroke Prevention in Atrial Fibrillation. John C. Andrefsky, MD, FAHA NEOMED Internal Medicine Review course May 5 th, 2013 New Treatments for Stroke Prevention in Atrial Fibrillation John C. Andrefsky, MD, FAHA NEOMED Internal Medicine Review course May 5 th, 2013 Classification Paroxysmal atrial fibrillation (AF) Last < 7

More information

3/25/14. To Clot or Not What s New In Anticoagulation? Clotting Cascade. Anticoagulant drug targets. Anita Ralstin, MS CNS CNP. Heparin.

3/25/14. To Clot or Not What s New In Anticoagulation? Clotting Cascade. Anticoagulant drug targets. Anita Ralstin, MS CNS CNP. Heparin. To Clot or Not What s New In Anticoagulation? Anita Ralstin, MS CNS CNP 1 Clotting Cascade 2 Anticoagulant drug targets Heparin XI VIII IX V X VII LMWH II Warfarin Fibrin clot 1 Who Needs Anticoagulation

More information

Impact of new (direct) oral anticoagulants in patient blood management

Impact of new (direct) oral anticoagulants in patient blood management Impact of new (direct) oral anticoagulants in patient blood management Yulia Lin, MD, FRCPC, CTBS Transfusion Medicine & Hematology, Sunnybrook Health Sciences Centre Dept of Laboratory Medicine & Pathobiology,

More information

NON-VITAMIN K ORAL ANTICOAGULANT REVERSAL

NON-VITAMIN K ORAL ANTICOAGULANT REVERSAL DISCLAIMER: These guidelines were prepared by the Department of Surgical Education, Orlando Regional Medical Center. They are intended to serve as a general statement regarding appropriate patient care

More information

Cardiology Update 2014

Cardiology Update 2014 Cardiology Update 2014 Update on the Novel Oral Anticoagulants (NOACS) Raymond Kawasaki, MD AMG Cardiology December 6, 2014 Disclosures I have no disclosures relevant to this presentation Contents I. The

More information

NHS FORTH VALLEY Rivaroxaban for Stroke Prevention in Atrial Fibrillation

NHS FORTH VALLEY Rivaroxaban for Stroke Prevention in Atrial Fibrillation NHS FORTH VALLEY Rivaroxaban for Stroke Prevention in Atrial Fibrillation Date of First Issue 06/06/2012 Approved 06/06/2012 Current Issue Date 06/06/2012 Review Date 06/06/2014 Version 1.1 EQIA Yes /

More information

3/3/2015. Patrick Cobb, MD, FACP March 2015

3/3/2015. Patrick Cobb, MD, FACP March 2015 Patrick Cobb, MD, FACP March 2015 I, Patrick Cobb, MD, DO NOT have a financial interest/arrangement or affiliation with one or more organizations that could be perceived as a real or apparent conflict

More information

QUICK REFERENCE. Mary Cushman 1 Wendy Lim 2 Neil A Zakai 1. University of Vermont 2. McMaster University

QUICK REFERENCE. Mary Cushman 1 Wendy Lim 2 Neil A Zakai 1. University of Vermont 2. McMaster University QUICK REFERENCE Clinical Practice Guide on Antithrombotic Drug Dosing and Management of Antithrombotic Drug- Associated Bleeding Complications in Adults February 2014* Mary Cushman 1 Wendy Lim 2 Neil A

More information

The Role of the Newer Anticoagulants

The Role of the Newer Anticoagulants The Role of the Newer Anticoagulants WARFARIN = Coumadin DAGIBATRAN = Pradaxa RIVAROXABAN = Xarelto APIXABAN = Eliquis INDICATION DABIGATRAN (Pradaxa) RIVAROXABAN (Xarelto) APIXABAN (Eliquis) Stroke prevention

More information

Disclosure. Outline. Objectives. I have no actual or potential conflict of interest in relation to this presentation.

Disclosure. Outline. Objectives. I have no actual or potential conflict of interest in relation to this presentation. Disclosure I have no actual or potential conflict of interest in relation to this presentation. Sarah Lombardo, MD., MSc. General Surgery, University of Utah September 9, 2015 Objectives Outline Recognize

More information

East Kent Prescribing Group

East Kent Prescribing Group East Kent Prescribing Group Rivaroxaban (Xarelto ) Safety Information Approved by the East Kent Prescribing Group. Approved by: East Kent Prescribing Group (Representing Ashford CCG, Canterbury and Coastal

More information

The use of oral anticoagulant

The use of oral anticoagulant for reversing the effects of oral anticoagulants James S. Kalus The use of oral anticoagulant medications has become quite frequent in clinical practice. Warfarin is the most common oral anticoagulant

More information

New Oral Anticoagulants Increase Risk for Gastrointestinal Bleeding - A Systematic Review and Meta-Analysis

New Oral Anticoagulants Increase Risk for Gastrointestinal Bleeding - A Systematic Review and Meta-Analysis New Oral Anticoagulants Increase Risk for Gastrointestinal Bleeding - A Systematic Review and Meta-Analysis Holster IL, Valkhoff VE, Kuipers EJ, Tjwa ET Departments of Gastroenterology and Hepatology,

More information

FDA Approved Oral Anticoagulants

FDA Approved Oral Anticoagulants FDA Approved Oral Anticoagulants Generic (Trade Name) Warfarin (Coumadin, Jantoven ) 1 FDA approved indication Prophylaxis and treatment of venous thromboembolism (VTE) Prophylaxis and treatment of thromboembolic

More information

New Anticoagulants: What to Use What to Avoid

New Anticoagulants: What to Use What to Avoid New Anticoagulants: What to Use What to Avoid Bruce Davidson, MD, MPH Clinical Professor of Medicine Pulmonary and Critical Care Medicine Division University of Washington School of Medicine Seattle USA

More information

10/16/2013. Reversal of Anticoagulants: Something New Under the Sun? Disclosures. Pharmacist Objectives

10/16/2013. Reversal of Anticoagulants: Something New Under the Sun? Disclosures. Pharmacist Objectives Reversal of Anticoagulants: Something New Under the Sun? Zachariah Thomas, PharmD, BCPS Clinical Associate Professor Ernest Mario School of Pharmacy Rutgers, the State University of New Jersey Clinical

More information

1/12/2016. What s in a name? What s in a name? NO.Anti-Coagulation. DOACs in clinical practice. Practical aspects of using

1/12/2016. What s in a name? What s in a name? NO.Anti-Coagulation. DOACs in clinical practice. Practical aspects of using What s in a name? Practical aspects of using DOACs (Direct Oral Anticoagulants) James L. Sebastian, MD, MACP Professor of Medicine (GIM) Medical College of Wisconsin February 5, 2016 DOAC NOAC NOAC ODI

More information

New Oral Anticoagulants. How safe are they outside the trials?

New Oral Anticoagulants. How safe are they outside the trials? New Oral Anticoagulants How safe are they outside the trials? Objectives The need for anticoagulant therapy Indications for anticoagulation Traditional anticoagulant therapies Properties of new oral anticoagulants

More information

Recommendations on Use of Dabigatran in Atrial Fibrillation

Recommendations on Use of Dabigatran in Atrial Fibrillation Recommendations on Use of Dabigatran in Atrial Fibrillation Developed by participants from the Section of Hematology/Oncology and Section of Cardiology, and Faculty of Pharmacy, University of Manitoba

More information

Committee Approval Date: September 12, 2014 Next Review Date: September 2015

Committee Approval Date: September 12, 2014 Next Review Date: September 2015 Medication Policy Manual Policy No: dru361 Topic: Pradaxa, dabigatran Date of Origin: September 12, 2014 Committee Approval Date: September 12, 2014 Next Review Date: September 2015 Effective Date: November

More information

New Oral Anticoagulants. July 2012

New Oral Anticoagulants. July 2012 New Oral Anticoagulants July 2012 Objectives Review coagulation cascade and previous treatment options for anticoagulation Understand points of interaction within coagulation cascade and new oral agents

More information

Low Molecular Weight Heparin. All Wales Medicines Strategy Group (AWMSG) Recommendations and advice

Low Molecular Weight Heparin. All Wales Medicines Strategy Group (AWMSG) Recommendations and advice Low Molecular Weight Heparin All Wales Medicines Strategy Group (AWMSG) Recommendations and advice Starting Point Low Molecular Weight Heparin (LMWH): Inhibits factor Xa and factor IIa (thrombin) Small

More information

Oral Anticoagulants: What s New?

Oral Anticoagulants: What s New? Oral Anticoagulants: What s New? Sallie Young, Pharm.D., BCPS (AQ-Cardiology) Clinical Pharmacy Specialist, Cardiology Penn State Hershey Medical Center syoung1@hmc.psu.edu August 2012 Oral Anticoagulant

More information

HERTFORDSHIRE MEDICINES MANAGEMENT COMMITTEE (HMMC) RIVAROXABAN RECOMMENDED see specific recommendations for licensed indications below

HERTFORDSHIRE MEDICINES MANAGEMENT COMMITTEE (HMMC) RIVAROXABAN RECOMMENDED see specific recommendations for licensed indications below Name: generic (trade) Rivaroxaban (Xarelto ) HERTFORDSHIRE MEDICINES MANAGEMENT COMMITTEE (HMMC) RIVAROXABAN RECOMMENDED see specific recommendations for licensed indications below What it is Indications

More information

New anticoagulants: Monitoring or not Monitoring? Not Monitoring

New anticoagulants: Monitoring or not Monitoring? Not Monitoring The 2 nd World Congress on CONTROVERSIES IN HEMATOLOGY (COHEM) Barcelona, Spain September 6 8, 2012 New anticoagulants: Monitoring or not Monitoring? Not Monitoring Anna Falanga, MD Immunohematology and

More information

New Oral Anticoagulants

New Oral Anticoagulants Laboratory Monitoring of New Oral Anticoagulants.....What you need to know Rita Selby MD Medical Director, Coagulation Laboratories Uniersity Health Network & Sunnybrook HSC Uniersity of Toronto The 15

More information

Laboratory Testing in Patients on Novel Oral Anticoagulants (NOACs)

Laboratory Testing in Patients on Novel Oral Anticoagulants (NOACs) Laboratory Testing in Patients on Novel Oral Anticoagulants (NOACs) Dr. Art Szkotak artur.szkotak@albertahealthservices.ca University of Alberta Hospital Edmonton, AB NOACs Direct Thrombin Inhibitors (DTI):

More information

New Anticoagulation Agents and Their Reversal Agents. Objectives. Background 12/21/2015

New Anticoagulation Agents and Their Reversal Agents. Objectives. Background 12/21/2015 New Anticoagulation Agents and Their Reversal Agents Jay Hazelcorn, Pharm.D. PGY-1 Pharmacy Resident Broward Health Medical Center Objectives Review the pharmacology, indications, and place in therapy

More information

DOACs. What s in a name? or TSOACs. Blood Clot. Darra Cover, Pharm D. Clot Formation DOACs work here. Direct Oral AntiCoagulant

DOACs. What s in a name? or TSOACs. Blood Clot. Darra Cover, Pharm D. Clot Formation DOACs work here. Direct Oral AntiCoagulant DOACs NOACs or TSOACs Generic Name DOACs Brand Name Mechanism of Action Direct Xa Inhibitor Direct Thrombin Inhibitor Dabigatran Pradaxa X Rivaroxaban Xarelto X Darra Cover, Pharm D Apixaban Eliquis X

More information

The New Anticoagulants are Here! Do you know how to use them? Arrhythmia Winter School February 11 th, 2012. Jeff Healey

The New Anticoagulants are Here! Do you know how to use them? Arrhythmia Winter School February 11 th, 2012. Jeff Healey The New Anticoagulants are Here! Do you know how to use them? Arrhythmia Winter School February 11 th, 2012 Jeff Healey RELY: A New Era in AF Connolly SJ et al. N Engl J Med 2009;361:1139-1151 ROCKET-AF:

More information

Management for Deep Vein Thrombosis and New Agents

Management for Deep Vein Thrombosis and New Agents Management for Deep Vein Thrombosis and New Agents Mark Malesker, Pharm.D., FCCP, FCCP, FASHP, BCPS Professor of Pharmacy Practice and Medicine Creighton University 5 th Annual Creighton Cardiovascular

More information

MCHENRY WESTERN LAKE COUNTY EMS SYSTEM OPTIONAL CE ADVANCED LEVEL (EMTP, PHRN, ECRN) August 2013. Anticoagulants

MCHENRY WESTERN LAKE COUNTY EMS SYSTEM OPTIONAL CE ADVANCED LEVEL (EMTP, PHRN, ECRN) August 2013. Anticoagulants MCHENRY WESTERN LAKE COUNTY EMS SYSTEM OPTIONAL CE ADVANCED LEVEL (EMTP, PHRN, ECRN) August 2013 Anticoagulants Anticoagulants are agents that prevent the formation of blood clots. Before we can talk about

More information

Now We Got Bad Blood: New Anticoagulant Reversal

Now We Got Bad Blood: New Anticoagulant Reversal Now We Got Bad Blood: New Anticoagulant Reversal Kellie Rodriguez, PharmD, BCPS PGY2 Emergency Medicine Pharmacy Resident UF Health Jacksonville January 2016 Objectives 1. Review current treatment strategies

More information

indications November 2 nd, 2012 Dalhousie University

indications November 2 nd, 2012 Dalhousie University + New oral anticoagulants: A review of current indications November 2 nd, 2012 Dr. Sudeep Shivakumar, Hematology Dalhousie University + Objectives es To review indications for anticoagulation To discuss

More information

UHS CLINICAL CARE COLLABORATION: Outpatient & Inpatient

UHS CLINICAL CARE COLLABORATION: Outpatient & Inpatient Guidelines for Anticoagulation Initiation and Management Y2014 UHS CLINICAL CARE COLLABORATION: Outpatient & Inpatient Topic Page Number MEDICATION FLOW AND PATIENT FLOW... 2 AND 3 PARENTERAL ANTICOAGULANTS...

More information

Disclosure. New Agents for Treatment of DVT. Prevalence of DVT VTE. Normal Hemostasis 7/17/2015. Mark Oliver, MD, RVT, RPVI,FSVU

Disclosure. New Agents for Treatment of DVT. Prevalence of DVT VTE. Normal Hemostasis 7/17/2015. Mark Oliver, MD, RVT, RPVI,FSVU New Agents for Treatment of DVT Disclosure PI Adopt and Amplify trials Mark Oliver, MD, RVT, RPVI,FSVU BMS and Pfizer Speaker VTE Venous Thromboembolism Recognized DVT s New : 170,000 Recurrent : 90,000

More information

CONTEMPORARY REVERSAL OF ANTICOAGULATION

CONTEMPORARY REVERSAL OF ANTICOAGULATION CONTEMPORARY REVERSAL OF ANTICOAGULATION Michael S. McHale, M.D., F.A.C.P. Avera Medical Group Hematology & Oncology Medications Coumadin / Warfarin Unfractionated Heparin Low Molecular Weight Heparin

More information

CHADS score of 5 or 6 Recent (within 3mo) stroke or TIA Rheumatic valvular heart disease CHADs score of 3 or 4

CHADS score of 5 or 6 Recent (within 3mo) stroke or TIA Rheumatic valvular heart disease CHADs score of 3 or 4 LAMC Department of Pharmacy Services: ANTICOAGULATION: Surgical Intervention Table 1: Classification of Surgical interventions according to bleeding risk t required to discontinue anticoagulation Dental

More information

Antiplatelet and Antithrombotics From clinical trials to guidelines

Antiplatelet and Antithrombotics From clinical trials to guidelines Antiplatelet and Antithrombotics From clinical trials to guidelines Ashraf Reda, MD, FESC Prof and head of Cardiology Dep. Menofiya University Preisedent of EGYBAC Chairman of WGLVR One of the big stories

More information

NON-VITAMIN K ORAL ANTICOAGULANT REVERSAL

NON-VITAMIN K ORAL ANTICOAGULANT REVERSAL DISCLAIMER: These guidelines were prepared by the Department of Surgical Education, Orlando Regional Medical Center. They are intended to serve as a general statement regarding appropriate patient care

More information

American Journal of Health-System Pharmacy

American Journal of Health-System Pharmacy Encompassing the full scope of pharmacy practice American Journal of Health-System Pharmacy Volume 70 NUMBER 0 supplement may 5, 203 in hospitals and health systems New approaches to reversing oral anticoagulant

More information

2/17/2015 ANTICOAGULATION UPDATE OBJECTIVES BRIEF REVIEW: CLASSES OF ORAL ANTICOAGULANTS

2/17/2015 ANTICOAGULATION UPDATE OBJECTIVES BRIEF REVIEW: CLASSES OF ORAL ANTICOAGULANTS ANTICOAGULATION UPDATE C AR R I E P AL M E R, D N P, RN, AN P - BC OBJECTIVES At the end of the presentation, the NP will be able to: Identify new indications for target-specific oral anticoagulants (TSOACs),

More information

Traditional anticoagulants

Traditional anticoagulants TEGH Family Practice Clinic Day April 4, 03 Use of Anticoagulants in 03: What s New (and What Isn t) Bill Geerts, MD, FRCPC Director, Thromboembolism Program, Sunnybrook HSC Professor of Medicine, University

More information

MANAGING BLEEDING IN THE

MANAGING BLEEDING IN THE MANAGING BLEEDING IN THE SETTING OF NEW ANTICOAGULANTS: HOW DO OLD METHODS MEASURE UP? Michelle Zeller MD Clinical Hematology Fellow November 5th, 2011 A FRIDAY NIGHT ON-CALL WITH DR. B. LUD Very keen

More information

Novel oral anticoagulant (NOAC) for stroke prevention in atrial fibrillation Special situations

Novel oral anticoagulant (NOAC) for stroke prevention in atrial fibrillation Special situations Novel oral anticoagulant (NOAC) for stroke prevention in atrial fibrillation Special situations Dardo E. Ferrara MD Cardiac Electrophysiology North Cascade Cardiology PeaceHealth Medical Group Which anticoagulant

More information

Xarelto (Rivaroxaban)

Xarelto (Rivaroxaban) Xarelto (Rivaroxaban) Hightly selective, reversible, direct oral FXa inhibitor Maxium concentratiion after 2 to 4 hrs High bioavailability(66%),increase with food ( suggest with food) 1/3 from renal excretion,

More information

Current and Emerging Therapies for Perioperative Anticoagulation Reversal

Current and Emerging Therapies for Perioperative Anticoagulation Reversal Current and Emerging Therapies for Perioperative Anticoagulation Reversal Eric Johnson, PharmD, BCCCP Critical Care Pharmacist- Perioperative Services Objectives Detail the approach to perioperative anticoagulation

More information

The speakers have attested that their presentation will be free of all commercial bias toward a specific company and its products.

The speakers have attested that their presentation will be free of all commercial bias toward a specific company and its products. Update on New Anticoagulants (Apixaban, Dabigatran and Rivaroxaban) Patient Safety Daniel B. DiCola, MD and Paul Ament,, Pharm.D Excela Heath, Latrobe, PA Disclosures: Paul Ament discloses that he receives

More information

Title of Guideline. Thrombosis Pharmacist)

Title of Guideline. Thrombosis Pharmacist) Title of Guideline Contact Name and Job Title (author) Guideline for patients receiving Rivaroxaban (Xarelto ) requiring Emergency Surgery or treatment for Haemorrhage Julian Holmes (Haemostasis and Thrombosis

More information

New Oral Anticoagulant (Rivaroxaban [Xarelto])

New Oral Anticoagulant (Rivaroxaban [Xarelto]) TABLE OF CONTENTS New Oral Anticoagulant (Rivaroxaban [Xarelto]) 1-2 New Antiplatelet (Ticagrelor [Brilinta]) 2-3 Update on Dabigatran (Pradaxa) Safety and Use at UIMCC 3-4 What Methods are Available for

More information

TA 256: Rivaroxaban for the prevention of stroke and systemic embolism in people with atrial fibrillation

TA 256: Rivaroxaban for the prevention of stroke and systemic embolism in people with atrial fibrillation Service Notification in response to DHSSPS endorsed NICE Technology Appraisals TA 256: Rivaroxaban for the prevention of stroke and systemic embolism in people with atrial fibrillation 1 Name of Commissioning

More information

DISCLOSURES CONFLICT CATEGORY. No conflict of interest to disclose

DISCLOSURES CONFLICT CATEGORY. No conflict of interest to disclose DISCLOSURES CATEGORY Employment Research support Scientific advisory board Consultancy Speakers bureau Major stockholder Patents Honoraria Travel support Other CONFLICT No conflict of interest to disclose

More information

1/7/2012. Objectives. Epidemiology of Atrial Fibrillation(AF) Stroke in AF. Stroke Risk Stratification in AF

1/7/2012. Objectives. Epidemiology of Atrial Fibrillation(AF) Stroke in AF. Stroke Risk Stratification in AF Objectives Atrial Fibrillation and Prevention of Thrombotic Complications: Therapeutic Update Andrea C. Flores Pharm.D Pharmacy Resident at the Miami VA Healthcare System Review the epidemiology, pathophysiology

More information

Rivaroxaban shared care guidelines for the prevention of stroke and embolism in adult patients with nonvalvular atrial fibrillation.

Rivaroxaban shared care guidelines for the prevention of stroke and embolism in adult patients with nonvalvular atrial fibrillation. South West Essex Rivaroxaban Shared Care Guideline (SCG) Rivaroxaban shared care guidelines for the prevention of stroke and embolism in adult patients with nonvalvular atrial fibrillation. Introduction

More information

Oral anticoagulants new and old: bleeding risk and management strategies. Logan Tinsen Pharm.D. Benefis Hospitals

Oral anticoagulants new and old: bleeding risk and management strategies. Logan Tinsen Pharm.D. Benefis Hospitals Oral anticoagulants new and old: bleeding risk and management strategies Logan Tinsen Pharm.D. Benefis Hospitals Disclaimer! I am not receiving any compensation from any drug company! Any opinions I may

More information