An Update on DOACs and HAYLEY BLACKBURN, PHARM.D., BCACP

Transcription

1 An Update on DOACs and Treatment of VTE HAYLEY BLACKBURN, PHARM.D., BCACP

2 Learning Objectives Explain the crrent role of DOACs in the treatment and prevention of VTE Describe crrent evidence for giding the selection of DOACs in treatment of VTE based pon patient characteristics Discss the role of recently-approved betrixaban in the prevention of VTE in medically ill patients Discss the management of DOAC-associated bleeding, inclding crrently available and emerging treatment options for reversal of anticoaglation in DOAC-treated patients

3 Assessment Qestions: 1. Tre/false: Direct oral anticoaglants are a treatment of choice for venos thromboembolism in non-cancer patients. 2. Tre/false: There is no need to consider patientspecific characteristics when choosing a DOAC for treatment of VTE. 3. Tre/false: betrixaban is the first FDA-approved oral medication for the prevention of VTE in medically ill patients.

4 Venos Thromboembolism Venos thromboembolism, inclding DVT and PE, is a major case of morbidity and mortality Cost to US healthcare system estimated at $7-10 billion per year (375, ,000 newly diagnosed VTE cases) 1 Preventable medical costs of $20,000 per case 1 Appropriate management of VTE reqires prompt and aggressive treatment, while also weighing bleeding risk Noble, et al. Lancet. 2008, 6(1);

5 Risk Factors for Venos Thromboembolism Hospitalization for acte medical illness Major srgery Trama/fractre Active cancer Previos VTE Pregnancy Oral contraceptives Family history of VTE and/or known coaglopathy Age Obesity (BMI >30) Redced mobility Pal A. Kyrle, and Sabine Eichinger Blood 2009;114:

6 Direct Oral Anticoaglants Traditionally, treatment options were limited to warfarin, low moleclar weight heparins and/or nfractionated heparin Development of new direct-acting oral anticoaglants have changed the landscape of VTE treatment over the last decade NOACs novel oral anticoaglants TSOACs target-specific oral anticoaglants DOACs direct oral anticoaglants NOACs non-vka oral anticoaglants Indication Dabigatran Rivaroxaban Apixaban Edoxaban VTE treatment X X X X Secondary prevention of recrrent VTE VTE prophylaxis after hip replacement VTE prophylaxis after knee replacement X X X X X X X X X

7 2016 CHEST Gidelines: VTE Treatment Recommendations What to se? Treatment of VTE, no cancer: DOACs preferred over warfarin Warfarin preferred over LMWH Treatment of VTE with cancer: LMWH preferred over warfarin or DOAC Trials evalating se of DOACs are ongoing, preliminary sbgrop analyses of DOAC se in cancer-associate VTE sggest similar efficacy and safety verss LMWH

8 2016 CHEST Gidelines: VTE Treatment Recommendations How Long? Provoked VTE (srgery or transient risk factor): 3 months Unprovoked VTE, low to moderate bleeding risk: extended therapy preferred Unprovoked VTE, high bleeding risk: 3 months May assess risk: benefit at end of 3 months and consider discontining anticoaglation if high bleeding risk; Patient sex and d-dimer level one month after discontination may help gide decision (male = 1.75X risk, positive d-dimer = 2x risk) Cancer-associated thrombosis: extended therapy

9 2016 CHEST Gidelines: VTE Treatment Recommendations How Long? Recrrent VTE: extended therapy Recrrent VTE while anticoaglated: switch to LMWH In all those receiving extended therapy, treatment shold be reassessed annally, or as clinically appropriate If anticoaglation is stopped, shold assess ASA se may be preferred over non-treatment for prevention of VTE, may also have been discontined when anticoaglation was initiated

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11 Choosing An Anticoaglant: Factors That May Inflence Decisions Factor Preferred Anticoaglant Qalifying Remarks Cancer LMWH Stronger recommendation if recently diagnosed, extensive VTE, metastatic cancer, very symptomatic, or on chemotherapy Pregnancy/pregnancy risk LMWH Potential for other agents to cross the placenta Liver disease and coaglopathy LMWH DOACs contraindicated in severe hepatic impairment with INR elevation, dosing of warfarin is difficlt and INR may not be best measre Thrombolytic therapy se UFH infsion Most experience with this modality, short half-life Hospitalized with extensive DVT or PE with hemodynamic instability UFH infsion, LMWH May convert to DOAC once patient is stabilized Antithrombotic Therapy for VTE Disease: CHEST Gideline and Expert Panel Report. Chest 2016;149(2):

12 Choosing An Anticoaglant: Factors That May Inflence Decisions Factor Preferred Anticoaglant Qalifying Remarks Renal impairment VKA DOACs and LMWH mst be renally dose-adjsted and shold be avoided in severe renal impairment Reversal agent needed VKA, UFH Dabigatran crrently has approved reversal agent, other anti-xa reversal agents in the pipeline Thrombophilia VKA DOACs not well-stdied in this poplation Mechanical valve VKA Increased risk of adverse otcomes with dabigatran, not stdied in other DOACs Coronary artery disease VKA or FXa inhbitor Potential for increased risk of CAD events with dabigatran vs warfarin; warfarin and anti-xa agents have demonstrated efficacy for CAD Antithrombotic Therapy for VTE Disease: CHEST Gideline and Expert Panel Report. Chest 2016;149(2):

13 Good Candidates for DOACs No contraindications (pregnancy/breastfeeding, mechanical valve) Adeqate renal and hepatic fnction No significant drg-drg interactions P-gp and CYP3A4 indcers/inhibitors, antiplatelet agents, NSAIDs Likely to be adherent to therapy and follow-p Unlikely to miss doses Able to keep in commnication with all healthcare providers abot medical isses Able to go to lab at least annally, or more often if clinically indicated Ability to pay/insrance coverage Availability of drgs Not at a weight extreme (BMI >40 kg/m 2 or >120 kg) Not schedled for an immediate invasive procedre

14 Points for Consideration: Pros & Cons Advantages of DOACs No rotine monitoring Improved safety profile Fewer drg interactions Short half-life may minimize need for therapy interrption/bridging Fixed dosing Cost-effective, particlarly from healthsystem standpoint Disadvantages of DOACs Lack of a good assay for monitoring therapy, need to monitor renal/hepatic fnction, periodic labs for CBC, SCr, LFTs Reversal may be tricky, crrent lack of specific antidote in some cases Some drg interactions reslt in contraindication to DOAC Short half-life means missed doses reslt in sbtherapetic serm levels Lack of evidence in se in special poplations where alternative dosing may be necessary Potentially higher costs to patient pfront Adapted from Brnett AE, et al. Table 2. J Thromb Thrombolysis 2016;41:

15 Choosing a DOAC: Which One? Drg Characteristic Desire to avoid parenteral therapy Once daily dosing Need to crsh medications and/or NG administration Preferred Anticoaglant Rivaroxaban, apixaban Rivaroxaban, edoxaban Rivaroxaban, apixaban Qalifying Remarks No need for parenteral lead-in therapy, nlike dabigatran and edoxaban Others mst be dosed twice daily Dabigatran shold not be crshed, lack of evidence in edoxaban Cost/insrance coverage Varies Affordability for patients is hge factor in adherence

16 Choosing a DOAC: Which One? Patient Characteristic Preferred Anticoaglant Qalifying Remarks Renal impairment Apixaban Renal elimination: apixaban < edoxaban < rivaroxaban < dabigatran; apixaban approved for ESRD based on pharmacokinetic stdies Hepatic impairment History of GI bleeding, PUD, or gastric bypass Coronary artery disease Apixaban, dabigatran (CTP A & B) Rivaroxaban (CTP A) Apixaban (or VKA) Rivaroxaban, apixaban or edoxaban (or VKA) All DOACs are contraindicated in CTP C Dabigatran, rivaroxaban, and edoxaban may be associated with greater risk of GIB vs warfarin, fewer GI bleeding events with apixaban vs warfarin Potential for increased risk of CAD events with dabigatran vs warfarin; warfarin and anti-xa agents have demonstrated efficacy in CAD Age >75 Apixaban, edoxaban Dabigatran has increased risk of GI bleed, rivaroxaban eqivalent risk of major bleeding, while others had lower risk vs warfarin in sbgrop analysis

17 Important Considerations In Dosing Dosing for different indications (Afib verss VTE treatment verss prophylaxis) may be different Dose adjstments in renal impairment and contraindications may be different Dose de-escalation in VTE treatment can reslt in confsion Rivaroxaban Indication Dose Renal Adjstment Dose A Fib 20mg daily CrCl=15-50ml/min 15mg daily DVT Prophylaxis Hip replacement DVT Prophylaxis Knee Replacement Recrrent DVT/PE Prophylaxis DVT/PE Treatment 10mg daily x 35 days 10mg daily x 12 days CrCl<15ml/min CrCl 30-50ml/min CrCl<30ml/min CrCl 30-50ml/min CrCl<30ml/min Contraindicated Cation Avoid Cation Avoid 20mg daily CrCl<30 Avoid se 15mg BID x 21 days Then 20mg daily CrCl<30ml/min Avoid se

18 Starting a DOAC: What Dose? Initiation of DOAC Dose switch or deescalation Renal dose adjstments Dabigatran At least 5 days of parenteral lead-in None, start at 150mg BID CrCl <50ml/min + P-gp inhibitor OR CrCl <30ml/min: avoid se Rivaroxaban No parenteral lead-in, start with 15mg BID 15mg BID X3 weeks, then 20mg daily; may decrease to 10mg daily after at least 6 months of therapy* CrCl <30ml/min: avoid se **Beers Criteria recommends dose redction in those >65 years old and CrCl ml/min Apixaban No parenteral lead-in, start with 10mg BID 10mg BID X 7 days, then 5mg BID; may decrease to 2.5mg BID after at least 6 months of therapy* No specific recommendations (SCr >2.5 mg/dl or CrCl <25 ml/min not stdied) Edoxaban At least 5 days of parenteral lead-in Weight >60kg: 60 mg daily Weight <60kg: 30mg daily Concrrent P-gp inhibitor: 30mg daily CrCl ml/min: 30mg once daily; not recommended in those with CrCl <15 ml/min IMPORTANT: doble-checking doses, cation in care transitions, thorogh patient edcation

19 Redced Dosing in Extended Therapy Apixaban: stdied patients after receiving 6-12 months of therapetic anticoaglation in those with clinical eqipoise for extension of treatment Randomized to apixaban 5mg BID, apixaban 2.5mg BID or placebo No difference in efficacy (prevention of recrrent VTE) between two doses of apixaban, no increase in major bleeding Rivaroxaban: stdied patients after receiving 6-12 months of therapetic anticoaglation in those with clinical eqipoise for extension of treatment Randomized to rivaroxaban 20mg daily, rivaroxaban 10mg daily, or ASA No significant difference in VTE recrrence between two doses of rivaroxaban after 1 year, more effective than aspirin Safety profile: similar rates of bleeding vs aspirin Reslts from these trials may help tip the balance toward extending therapy in those who are on the fence BUT reslts cannot be extended to those at high risk of VTE with a definite indication for extended therapy (exclded from these trials)

20 Thromboprophylaxis with DOACs Preventing VTE in Srgical and Acte Medical Patients

21 Prevention of VTE in High Risk Patients Hospitalization for acte medical illness Major srgery Trama/fractre Active cancer Previos VTE Pregnancy Oral contraceptives Family history of VTE and/or known coaglopathy Age (>70 years) Obesity (BMI >30) Risk Category Low Moderate High Risk Very High Patient Type/Srgery Type Uncomplicated minor srgery in patients nder 40 with no clinical risk factors Major srgery in patients over 40 with no other clinical risk factors Major srgery in patients over 40 who have additional risk factors or MI Major Srgery in patients over 40 with: previos VTE, malignant disease, orthopedic srgery, hip fractre, stroke, or spinal cord injry.

22 DOACs in Thromboprophylaxis for Srgical Patients Indication Dabigatran Rivaroxaban Apixaban Edoxaban VTE treatment X X X X Secondary prevention of recrrent VTE VTE prophylaxis after hip replacement VTE prophylaxis after knee replacement X X X X X X X X X

23 Risk Factors for VTE in Medically Ill Patients Hospitalization for acte medical illness Major srgery Trama/fractre Active cancer Previos VTE Pregnancy Oral contraceptives Family history of VTE and/or known coaglopathy Age (>70 years) Obesity (BMI >30) D-dimer >2X ULN Additional risk factors: Bed rest/redced mobility Central line Admission to ICU Acte MI or ischemic stroke Heart and/or respiratory failre Infection Rhematologic disorder Pada score for hospitalized patients: score of 4 or greater considered high risk and a candidate for pharmacologic prophylaxis

24 2012 CHEST Gidelines for Prevention of VTE in Nonsrgical Patients For those at an increased risk of VTE, thromboprophylaxis with one of the following is recommended: LMWH Low-dose UFH BID-TID Fondaparinx For those at low risk of VTE, pharmacologic/mechanical prophylaxis is NOT recommended For those at high risk of VTE + high risk of bleeding/active bleeding, mechanical prophylaxis is recommended Conversion to pharmacologic prophylaxis if bleeding risk decreases

25 2012 CHEST Gidelines for Prevention of VTE in Nonsrgical Patients Corse of thromboprophylaxis NOT recommended to be extended past the corse of the hospital stay, and may be discontined earlier if deemed appropriate EXCLAIM trial evalating initial corse (5-14 days) verss extended corse (>14 days, p to 35 days) Extended corse: prevented 6 more DVTs per 1000 patients verss initial corse BUT associated with 5 more major bleeding events Increased cost and brden to patient

26 DOACs in Thromboprophylaxis for Medically Ill Patients: Apixaban & Rivaroxaban ADOPT Trial (2011) Apixaban 2.5mg BID verss enoxaparin 40mg daily Efficacy: no difference between the two treatments in prevention of VTE (RR=0.87, CI ) Safety: apixaban associated with significantly more bleeding (RR = 2.58, CI ) MAGELLAN Trial (2013) Rivaroxaban 10mg daily verss enoxaparin 40mg daily Efficacy: rivaroxaban sperior to enoxaparin (RR = 0.77, CI ) in prevention of VTE Safety: rivaroxaban associated with significantly more bleeding (RR = 2.5, CI ) Overall, DOACs did not demonstrate a favorable risk:benefit profile when compared with standard treatment with LMWH

27 DOACs in Thromboprophylaxis for Medically Ill Patients: Betrixaban (Bevyxxa ) FDA Approval Jne 2017 New indication: prophylaxis of VTE in adlt patients hospitalized for acte medical illness at risk of VTE de to limited mobility and other VTE risk factors MOA: Factor Xa inhibitor Dose: 160mg PO X1 dose, then 80mg PO once daily WITH FOOD Renal impairment CrCL 15-30ml/min: half dose (80mg X1, then 40mg once daily) Not recommended in CrCl <15ml/min P-gp interactions Dration of treatment: 5-6 weeks Minimal renal clearance, minimal hepatic metabolism, long half-life

28 Betrixaban (Bevyxxa ) Clinical Trial Data Acte Medically Ill Prevention with Extended Dration Betrixaban (APEX) Stdy Patients treated with betrixaban for median of 36 days verss treatment with enoxaparin for median of 9 days ~3700 per grop Primary otcomes: Efficacy: composite of VTE/PE otcomes Secondary: Major bleeding p to 7 days after discontination of stdy drg Enrichment strategies - the prospective se of any patient characteristic to select a stdy poplation in which detection of a drg effect (if one is in fact present) is more likely than it wold be in an nselected poplation. Image:

29 Betrixaban (Bevyxxa ) Clinical Trial Data Acte Medically Ill Prevention with Extended Dration Betrixaban (APEX) Stdy Patients treated with betrixaban for median of 36 days verss treatment with enoxaparin for median of 9 days ~3700 per grop Primary otcomes: Efficacy: composite of VTE/PE otcomes Secondary: Major bleeding p to 7 days after discontination of stdy drg Enrichment strategies - the prospective se of any patient characteristic to select a stdy poplation in which detection of a drg effect (if one is in fact present) is more likely than it wold be in an nselected poplation. Separated into non-mtally exclsive cohorts based pon anticipated risk of VTE: Cohort 1: D-dimer >2X ULN Cohort 2: Cohort 1 + patients >75 years old Cohort 3: Overall stdy poplation

30 Betrixaban APEX Clinical Trial Reslts Primary efficacy analysis (VTE) Primary safety analysis (major bleeding) RR P vale RR P vale Cohort 1: Elevated D- Dimer Cohort 2: Elevated D- dimer or age 75 years Overall stdy poplation * Cohen AT. N Engl J Med 2016; 375: Gibson CM. J Am Heart Assoc Jl; 6(7): e

31 Betrixaban APEX Clinical Trial Reslts Safety otcomes (APEX): Similar rates of major bleeding between enoxaparin and betrixaban Major or clinically relevant nonmajor bleeding: RR = 1.97 (CI ), NNH = 67 86% were mild or moderate in severity - primarily epistaxis or hematria 38% of events reqired medical intervention Otherwise well-tolerated, no significant difference in adverse events Bottom line: Demonstrated speriority of betrixaban in overall stdy poplation verss enoxaparin in extended thromboprophylaxis No difference in major bleeding, bt more mild/moderate bleeding events with betrixaban Other considerations: Benefit of oral verss injectable agent Enoxaparin ~$30/day verss betrixaban $10-15/day (overall greater cost with extended therapy)

32 Reversal and Management of Bleeding with DOACs Crrent and Ftre Therapies

33 Management of DOAC-Associated Bleeding Major bleeding events in ~4% of patients while on DOAC therapy Standard measres: spportive with flid and blood prodcts, treatment of the sorce of bleed as indicated with carefl management to avoid flid overload Activated charcoal: for dabigatran ingested within last 6 hors Hemodialysis: dabigatran only (particlarly in poor renal fnction), not effective for FXa inhibitors PCC active PCC (apcc, FEIBA) or inactive for-factor (KCentra) concentrates of clotting factors II, VII, IX, and X, +/- protein C and S Low-qality evidence of normalization of prothrombin time with varying degrees of efficacy Reasonable option for the management of DOAC-associated bleeding De to the risk of increased thrombs indction, jdicios se of PCC is advised

34 Reversal of DOACs Crrent: dabigatran-specific monoclonal antibody Praxbind (idarcizmab) Ftre: a single agent that will reverse mltiple anti-fxa medications Andexanet alfa FXa decoy (ANNEXA-4 trial) Ciraparantag small synthetic molecle that binds to mltiple anticoaglants

35 Idarcizmab (Praxbind ) Indicated only for reversal of anticoaglation with dabigatran in emergency procedres or life-threatening/ncontrolled bleeding REVERSE-AD: bleeding stopped within 24 hors in 97% of those treated with idarcizmab (median time = 11.4 hors) Total dose of 5mg IV administered in two divided doses no more than 15 mintes apart Generally well tolerated Low potential for immnogenicity Potential need for repeat dosing in some cases hors after first dose, as nbond dabigatran is redistribted from tisses into the intravasclar space (limited evidence), bt only in the case of recrrent bleeding

36 Xa Reversal Agents: Andexanet Alfa and Ciraparantag Designed to reverse all anticoaglants that work on Factor Xa in the coaglation cascade Apixaban, rivaroxaban, edoxaban Fondaparinx and LMWHs Demonstrated ability to decrease anti-xa activity in healthy hman volnteers Andexanet alfa: FXa decoy; short half-life, reqires bols + continos infsion ANNEXA-4: Effective hemostasis in 79% of patients 12 hors post-infsion Well-tolerated, no increase in thrombotic events observed Ciraparantag: Binds non-covalently to factor Xa inhibitors

37 DOACs: Other Updates DOACs in cancer-associated VTE, ongoing trials Meta-analyses of sbgrops within other VTE trials show similar efficacy and safety, bt no pblished RCTs sing DOACs exclsively in cancer-associated VTE Edoxaban vs dalteparin completion date December 2017 Rivaroxaban vs LMWHs completion date March 2018 Ongoing registries: COSIMO, ISRCTN DOACs for prevention of VTE in antiphospholipid syndrome: Observvational cohort stdy (n =26): Event-free srvival rate 87.9% at 12 months with dabigatran or rivaroxaban Ongoing trials (RAPS, TRAPS, and ASTRO-APS) Crrently VKA remains standard of care

38 DOACs: Other Updates COMPASS Trial: Rivaroxaban 5mg BID vs rivaroxaban 2.5mg BID + ASA, vs ASA alone in patients with CAD and/or PAD Stopped early de to overwhelming efficacy, with rivaroxaban 2.5mg + ASA having better otcomes; more bleeding vs ASA alone bt overall net clinical benefit RE-DUAL PCI Dabigatran + P2Y12 inhibitor vs triple therapy sing warfarin in patients ndergoing PCI for 1-3 months post-intervention EMANATE Apixaban in anticoaglation naïve patients prior to cardioversion (following X-VeRT with rivaroxaban), may allow shorter anticoaglation prior to procedre

39 Conclsions DOACs contine to be sed more widely for a nmber of indications Evolving evidence is helping gide choice of DOAC based pon patient-specific factors Use of DOACs represents a major opportnity for pharmacists in the dosing, monitoring and stewardship of these medications Approval of betrixaban represents a new role for DOACs in prevention of VTE Althogh we crrently only have a specific reversal agent for dabigatran, FXa reversal agents in the pipeline are promising developments intended for se across mltiple different anticoaglants

40 Assessment Qestions: 1. Tre/false: Direct oral anticoaglants are a treatment of choice for venos thromboembolism in non-cancer patients. 2. Tre/false: There is no need to consider patientspecific characteristics when choosing a DOAC for treatment of VTE. 3. Tre/false: betrixaban is the first FDA-approved oral medication for the prevention of VTE in medically ill patients.

41 Assessment Qestions: 1. Tre/false: Direct oral anticoaglants are a treatment of choice for venos thromboembolism in non-cancer patients. 2. Tre/false: There is no need to consider patientspecific characteristics when choosing a DOAC for treatment of VTE. 3. Tre/false: betrixaban is the first FDA-approved oral medication for the prevention of VTE in medically ill patients.

42 References 1. Grosse SD, et al. The economic brden of incident venos thromboembolism in the United States: A review of estimated attribtable healthcare costs. Thrombosis 2016; 137: Kearon C, Akl EA, Ornelas J, et al. Antithrombotic Therapy for VTE Disease: CHEST Gideline and Expert Panel Report. Chest 2016; 149: Mekaj YH, Mekaj AY, Dci SB, Miftari EI. New oral anticoaglants: their advantages and disadvantages compared with vitamin K antagonists in the prevention and treatment of patients with thromboembolic events. Ther Clin Risk Manag 2015;11: Kim JH, Lim KM, Gwak HS. New anticoaglants for the prevention and treatment of venos thromboembolism. Biomol Ther (Seol) Sep 1;25(5): Barbosa M, Menezes Falcão L. Oral anticoaglation in the elderly: new oral anticoaglants-innovative soltion for an old problem? Am J Ther Sardar P, Chatterjee S, Chadhari S, Lip GY. New oral anticoaglants in elderly adlts: evidence from a meta-analysis of randomized trials. J Am Geriatr Soc 2014; 62: Martin K, Beyer-Westendorf J, Davidson BL, et al. Use of the direct oral anticoaglants in obese patients: gidance from the SSC of the ISTH. J Thromb Haemost 2016; 14: Riley P, Maan A, Korr KS. Direct Oral Anticoaglants (DOACs): crrent stats among distinct patient sbgrops. R I Med J. 2017;100: Agnelli G, Bller HR, Cohen A. Apixaban for extended treatment of venos thromboembolism. N Engl J Med Feb 21;368(8): Weitz JI, Lensing AW, Prins MH, Baersachs R, Beyer-Westendorf J, Bonameax H, Brighton TA, Cohen AT, Davidson BL, Decoss H, Freitas MC, Holberg G, Kakkar AK, Haskell L, van Bellen B, Pap AF, Berkowitz SD, et al. Rivaroxaban or aspirin for extended treatment of venos thromboembolism. N Engl J Med 2017;376(13): Imberti D, Mastroiacovo D. Is it reasonable to se a lower DOACs dose in some patients with VTE? Yes. Intern Emerg Med Ag;12(5): Garland SG, DeRemer CE, Smith SM, Gms JG. Betrixaban: A New Oral Factor Xa Inhibitor for Extended Venos Thromboembolism Prophylaxis in High-Risk Hospitalized Patients. Ann Pharmacother Jan 1: doi: / [Epb ahead of print] 12. Dickneite G, Hoffman M. Reversing the new oral anticoaglants with prothrombin complex concentrates (PCCs): what is the evidence? Thromb Haemost 2014; 111: Pollack CV Jr, Reilly PA, Eikelboom J, et al. Idarcizmab for Dabigatran Reversal. N Engl J Med 2015; 373: Siegal DM, Crntte JT, Connolly SJ, et al. Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity. N Engl J Med 2015; 373: Lalicht B, Bakhr S, Jiang X, et al. Antidote for new oral anticoaglants: Mechanism of action and binding specificity of PER977. ISTH abstract 2013; :AS 47.1.