REVERSAL STRATEGIES FOR ORAL ANTICOAGULATION

Transcription

1 REVERSAL STRATEGIES FOR ORAL ANTICOAGULATION Wesley R. Zemrak, Pharm.D., BCPS Clinical Pharmacy Specialist, Anticoagulation Maine Medical Center, Portland, ME 1

2 OBJECTIVES 1. Discuss the pros and cons of agents used in the urgent reversal of warfarin 2. Identify the clinical pharmacology and pharmacokinetics of specific DOAC reversal agents 3. Analyze the clinical trial data for idarucizumab and andexanet alfa

3 ORAL ANTICOAGULATION

4 NOAC/DOAC/TSOAC Edoxaban for AF & VTE Warfarin discovered Warfarin first human use Dabigatran for AF Rivaroxaban for AF Apixaban for AF Apixaban for VTE Dabigatran for VTE Rivaroxaban for VTE Atrial Fibrillation: All have proven to be non-inferior (rivaroxaban/edoxaban) or superior (dabigatran/apixaban) to VKA Venous Thromboembolism: All have proven to be non-inferior to VKA

5 BLEEDING EVENTS Chai-Adisaksopha C, et al. Blood 2014;124(15):

6 BLEEDING EVENTS Chai-Adisaksopha C, et al. Blood 2014;124(15):

7 ANTICOAGULANT USE FOR AF: Barnes GD, et al. Am J Med 2015;128:

8 VTE CHEST UPDATE 2016 In patients with DVT of the leg or PE and no cancer, as longterm (first 3 months) anticoagulant therapy, we suggest dabigatran*, rivaroxaban, apixaban, or edoxaban* over vitamin K antagonist (VKA) therapy (all Grade 2B). *Initial parenteral therapy is given before dabigatran and edoxaban, is not given rivaroxaban and apixaban, and is overlapped with VKA therapy. ACC/AHA ATRIAL FIBRILLATION 2019 NOACs (dabigatran, rivaroxaban, apixaban, and edoxaban) are recommended over warfarin in NOAC-eligible patients with AF (except with moderate-to-severe mitral stenosis or a mechanical heart valve). (Grade 1A recommendation) Kearon C, et al. CHEST 2016;149(2): January CT, et al. Circulation 2019;139 epub ahead of print

9 IS MY PATIENT ANTICOAGULATED?

10 WHAT DOES AN INR MEAN TO YOU? Step 1: Don t panic

11 Gulati G, et al. Arch Pathol Lab Med 2011;135:490

12 FACTOR II LEVEL VS. INR NORMAL Sarode R, et al. Br J Haemotology 2006;132:

13 DABIGATRAN van Ryn J, et al. Thromb Haemost 2010;103:

14 RIVAROXABAN Samama MM, et al. Thromb Haemost 2010;103:

15 APIXABAN Douxfils J, et al. Thromb Haemost 2013;110:

16 EDOXABAN Ogata K, et al. J Clin Pharmacol 2010;50:

17 LABORATORY MONITORING Warfarin = INR Dabigatran = all coagulation labs prolonged TT and ECT most sensitive; PT/INR and aptt less sensitive Rivaroxaban = PT/INR prolonged, aptt may be PT/INR somewhat linear (depending on reagent) Apixaban = no prolongation unless at high plasma levels Edoxaban = PT/INR prolonged, aptt as well

18 WARFARIN REVERSAL

19 VITAMIN K Intake: Phylloquinones dietary vitamin K Green-leafy vegetables Menaquinones endogenous vitamin K Gram-positive, intestinal bacteria Provides substrate for the production of vitamin K dependent clotting factors Typical daily requirements = 1mcg/kg

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21 VITAMIN K KEY CHARACTERISTICS Replenishment of substrate for the production of functional vitamin-k dependent clotting factors Time to INR reversal: 8-12 hours Duration: Indefinite Adverse events: Anaphylaxis (IV; rare), Thromboembolic events

22 MMC Anticoagulation Reversal Guideline 2014

23 INR RESPONSE Tsu L, et al. Ann Pharmacother 2012;46:

24 VITAMIN K No difference in INR reversal at hours for PO vs. IV IV does provide an early response to INR reversal (~8 hours) Use of higher doses may contribute to over-correction of the INR and need for bridging therapy If time is available and patient is not major bleeding, PO should be the strategy

25 MMC GUIDELINE FOR REVERSAL OF WARFARIN-ASSOCIATED MAJOR/LIFE-THREATENING BLEEDING** MAJOR/LIFE-THREATENING BLEEDING* Yes WITHIN 30 MINUTES Massive Transfusion Coag Panel STAT (if no recent INR) Vitamin K 2.5 to 5 mg IV STAT If potential for massive transfusion exists, initiate massive transfusion protocol (call ) *Definition of major bleeding: Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intraarticular or pericardial, or intramuscular with compartment syndrome, and/or acute bleeding requiring transfusion of >2 units of packed red blood cells. **Exclusions: patients with arterial or venous thromboembolic events within previous 3 months (stroke, VTE, MI, etc.), urgent reversal for surgery in the absence of major bleeding, coagulopathy secondary to liver disease, disseminated intravascular coagulation (DIC), acute bleeding not due to warfarin, heparin-induced thrombocytopenia (HIT) CNS Related Bleeding (Goal INR 1.5) Non-CNS Major Bleeding (Goal INR 2.0) Kcentra (4-factor PCC) Dosing: INR : 15 units/kg (max 1500 units) INR 2.0: 25 units/kg (max 2500 units) If potential for massive transfusion exists, initiate massive transfusion protocol (call ) Kcentra (4-factor PCC) Dosing: INR <4.0: 15 units/kg (max 1500 units) INR 4.0: 25 units/kg (max 2500 units) If potential for massive transfusion exists, initiate massive transfusion protocol (call ) 30 minutes post dose: Massive Transfusion Coag Panel STAT INR >1.5: Consider hematology/blood bank input Consider FFP INR q 60 min until 2 Consider additional dose of Kcentra 10 units/kg (1 vial) Other coagulation abnormalities? Yes Fibrinogen <100 mg/dl: Transfuse cryoprecipitate 1 unit per 10kg Platelets <100,000: Transfuse 1 pheresis unit of platelets 30 minutes post dose: Massive Transfusion Coag Panel STAT INR >2.0 AND continued bleeding: Consider hematology/blood bank input Consider FFP INR q 60 min until 2 Consider additional dose of Kcentra 10 units/kg (1 vial) Repeat INR at 6 and hours

26 PCC VERSUS FFP PCC FFP Blood type matching No Yes Reconstitution Minutes minutes/unit Administration Rapid (< 30 min) Hours Volume Small (< 200 ml) ml/kg (~1-3 L) Time to normalize INR Quick Slow Increase in factor activity Infectious transmission Complications 40-80% 12.5 ml/kg 8-16% Inactivation process Thrombotic events Viral screening Transfusion reactions Transfusion-related acute lung injury (TRALI) Transfusion-associated circulatory overload (TACO) Bershad et al. Neurocrit Care 2010;12: Tanaka KA et al. J Thromb Haemost 2010;8:

27 FACTOR II LEVEL AFTER PCC Sarode R, et al. Br J Haematology 2006;132:

28 PCC VS. FFP DATA SUMMARY Study Patient population INR reversal (<1.3 w/in 30 minutes) Hemostatic efficacy Clinical outcome Sarode, et al. Circulation 2013 Major/lifethreatening bleeding with INR >2.0 N=202 PCC: 61/98 (62.2%) FFP: 10/104 (9.6%) PCC: 71/98 (72.4%) FFP: 68/104 (65.4%) Non-inferior Not assessed Goldstein, et al. Lancet 2015 Urgent surgery with INR >2.0 N=168 PCC: 48/87 (55%) FFP: 8/81 (10%) P<0.001 PCC: 78/87 (90%) FFP: 61/81 (75%) P=0.014 Time to OR PCC: 3.6 hrs ( ) FFP: 8.5 hrs ( ) P<0.01 Steiner, et al. Lancet Neurol 2016 Intracranial hemorrhage with INR >2.0 N=54 PCC: 18/27 (67%) FFP: 2/23 (9%) P<0.001 Hematoma expansion at 3 hrs: PCC: 12/27 (44%) FFP: 13/22 (59%) P=0.048 No difference in mortality at 90 days, mrs 0-3 at any time point, or QOL at day 90 Sarode R, et al. Circulation 2013;128: Goldstein JN, et al. Lancet 2015;385: Steiner T, et al. Lancet Neurol 2016;15:

29 PCC SUMMARY Preferred strategy to control major bleeding in many guidelines Clinical studies INR reversal and hemostatic efficacy Variable results and low quality evidence for hard clinical outcomes Reserved for patients with major/life-threatening bleeding or surgery that cannot be delayed by 8 hours Thrombotic risk (~7%) and high cost ($1.60/unit = ~$2,400/dose)

30 STRATEGIES FOR DOAC REVERSAL 1. Time 2. apcc (FEIBA) 3. rfviia 4. PCC (4-factor or 3-factor) 5. DOAC specific reversal agents

31 PCC FOR DOAC REVERSAL There is no clinical evidence that prothrombin complex concentrates effectively reverse major bleeding induced by these agents. Baron TH, et al. N Engl J Med 2013; 368: we suggest reversal of rivaroxaban, apixaban, and edoxaban with high-dose (25-50 units/kg) PCC. Spahn DR, et al. Crit Care 2013; 17: R76 In case of severe, life-threatening bleeding we recommend the use of PCC as the first choice. Turpie AGG, et al. Thromb Haemost 2012; 108: We suggest administering a 4-factor PCC (50 units/kg) or activated PCC (50 U/kg) if intracranial hemorrhage occurred within 3-5 terminal half-lives of drug exposure or in the context of liver failure (Conditional recommendation, low-quality evidence) Frontera JA, et al. Neurocrit Care 2016; 24: 6-46

32 PCC FOR DOAC REVERSAL Dabigatran: 12 healthy volunteer (non-bleeding) PCCs do not seem to be effective Rivaroxaban: 47 healthy volunteers (non-bleeding) Reverses INR and PTT prolongation, no effect on anti-fxa levels Apixaban 4-factor PCC available in US does not seem to be effective Edoxaban 17 healthy volunteer (bleeding induced by punch biopsy) Lab vs. bleeding, how do we translate this? Eereberg ES, et al. Circulation 2011;124: Levi M, et al. J Thromb Haemost 2014;12: Perlstein I, et al. Oral Presentation. ASH 2014 San Francisco, CA Dec 6-9, 2014 Zahir H, et al. Circulation 2015;131:82-90

33 SPECIFIC REVERSAL AGENTS

34 IDARUCIZUMAB Monoclonal antibody fragment 350x higher binding affinity than thrombin Phase II studies complete: Healthy young volunteers years old years with mild/moderate renal impairment Provides immediate and complete reversal of dabigatran Pollack CV, et al. N Engl J Med 2015;373:

35 RE-VERSE AD Multicenter, open-label, prospective cohort study 503 patients enrolled Two patient groups: A = overt, uncontrollable, or life-threatening bleeding (n=301) B = surgery or other invasive procedure that could not be delayed 8 hours and normal hemostasis required (n=202) 5 g dose (2.5 g given 15 minutes apart) Primary outcome: maximum % reversal from baseline to 4 hours after second infusion (dtt or ECT) Pollack CV, et al. N Engl J Med 2017; epub ahead of print

36 IDARUCIZUMAB Pollack CV, et al. N Engl J Med 2017; epub ahead of print

37 CLINICAL OUTCOMES Cessation of bleeding (group A): Not assessed in 98 patients with intracranial bleeding 134/203 (67.7%) confirmed cessation within 24 hours Median time = 2.5 hours Effective hemostasis (group B) = 184/197 (93.4%) 30 day mortality: 13.5% in group A, 12.6% in group B Thromboembolic events within 30 days: 24/503 (4.8%) Pollack CV, et al. N Engl J Med 2017; epub ahead of print

38 SUMMARY Concerns with study: 5 g dose based on lab prediction of reversing 99% of drug levels in RE-LY Median time since last dose = 15.6 hours 30% of patients had taken last dose >24 hours prior 61.8% of patients taking 110 mg BID 22.3% had normal dtt while 8.3% had normal ECT upon assessment by central lab (excluded from efficacy analysis) COST Current pricing = $3, for 5gm dose

39 USE AT MMC Approve to add to MMC formulary with restriction Requires page to on-call anticoagulation clinician for approval Criteria for use: Major/Life-threatening bleeding (ISTH definition) OR Urgent surgery/procedure that cannot be delayed by 8 hours AND Confirmed that patient is taking dabigatran and last dose <24 hours prior (CrCL 30 ml/min) or <36 hours (CrCL < 30 ml/min) Prolongation of baseline coagulation parameters: TT > 25 seconds

40 ANDEXANET ALFA: RECOMBINANT MODIFIED HUMAN FACTOR XA Factor Xa Decoy GLA domain removed to prevent anticoagulant effect S419A S419A High affinity Factor Xa Inhibitor Gla Catalytic Domain N terminal residues retained to reduce immunogenicity S S Activity eliminated to prevent thrombin generation MP-AnXa-US-0093 Nature Medicine, Volume 19, April 2013

41 ANDEXANET ALFA FDA review August 2016 for use in bleeding related to rivaroxaban, apixaban, edoxaban, enoxaparin: Denied status: Concerns regarding manufacturing Additional data required for enoxaparin and edoxaban prior to approval Filed for re-review August 2017 Limited to apixaban and rivaroxaban Data submitted included phase 3 healthy volunteer studies (anti-factor Xa levels) and limited (n=35) data from ANNEXA-4 major bleeding trial Approved in May 2018

42 ANNEXA-4 STUDY DESIGN Patient with acute major bleeding Patient Screening Within 18 hours of last dose of FXa inhibitor Assessments: IV Bolus Bleeding and Laboratory Assessment Andexanet 2-hour IV Infusion Day 1 After end of infusion 1 hr 4 hr 8 hr 12 hr Safety follow-up visit Day 3 Day 30 MP-AnXa-US-0093 Efficacy Outcomes Change in anti-fxa activity Clinical hemostatic efficacy through 12 hours Safety Measurements Thrombotic events Antibodies to FX, FXa, andexanet 30-day mortality

43 ANNEXA-4 DOSE SELECTION Acute major bleeding 18 hours of last dose of apixaban, edoxaban, rivaroxaban, or enoxaparin Andexanet IV bolus and 2 hour infusion Pts on apixaban or >7 h from last rivaroxaban dose Bolus 400 mg + Infusion mg/min Pts on enoxaparin, edoxaban or Pts 7 on h from enoxaparin last rivaroxaban or edoxaban dose or 7 h from last rivaroxaban dose Bolus Bolus mg mg + Infusion Infusion mg 8 mg/min mg/min MP-AnXa-US-0093

44 BASELINE CHARACTERISTICS MP-AnXa-US-0093 Safety Population N=227 Efficacy Population N=137 Age (yr), mean ± SD 77(±11) 77 (±12) Male 117 (52%) 70 (51%) Time from presentation until Andexanet (hrs) 4.7 ± ± 3.1 Estimated creatinine clearance < 30 ml/min, 21 (9%) 13 (10%) Indication for anticoagulation Atrial fibrillation 178 (78%) 104 (76%) Venous Thromboembolic Disease 52 (23%) 38 (28%) Atrial fibrillation and VTE 8 (4%) 6 (4%) Medical History Myocardial infarction 32 (14%) 15 (11%) Stroke 47 (21%) 32 (23%) Heart Failure 52 (23%) 36 (26%) Diabetes mellitus 67 (30%) 42 (31%)

45 SITE OF INITIAL BLEEDING Safety Population N=227 Efficacy Population N=137 Intracranial Bleeding 139 (61%) 78 (57%) Glasgow Coma Scale, mean ± SD 13.9 ± ± 1.70 Intracerebral site 74 (52%) 44 (54%) Sub-dural site 45 (32%) 24 (30%) Subarachnoid site 23 (16%) 13 (16%) Gastrointestinal Bleeding 62 (27%) 43 (31%) Other Bleeding site 26 (12%) 16 (12%) MP-AnXa-US-0093

46 Anti-factor Xa Activity (ng/ml) ANTI-FACTOR XA ACTIVITY: MP-AnXa-US-0093 RIVAROXABAN N= Baseline End of Bolus End of Infusion 4 Hr 8 Hr 12 Hr Median Percent Change -88% -87% -42% -49% -60% (95% CI) (-92 to -82) (-89 to -82) (-46 to -33) (-53 to -45) (-65 to -53)

47 Anti-factor Xa Activity (ng/ml) ANTI-FACTOR XA ACTIVITY: MP-AnXa-US-0093 APIXABAN N= Baseline End of Bolus End of Infusion 4 Hr 8 Hr 12 Hr Median Percent change -91% -91% -36% -30% -35% (95% CI) (-92 to -90) (-92 to -90) (-41 to -29) (-36 to -25) (-41 to -32)

48 EFFECTIVE HEMOSTASIS AT 12 HOURS POST ANDEXANET Number of Major Bleeds Adjudicated Number of Patients who Achieved Excellent or Good Hemostasis Percent of Patients who Achieved Excellent or Good Hemostasis 95% Confidence Interval % 76% - 89% MP-AnXa-US-0093

49 SAFETY ASSESSMENT Thrombotic events occurred within 3 days of andexanet in 6 (2.6%) patients and by 30 days in 24 (11%) Anticoagulation re-started in 129 patients (57%) by 30 days Therapeutic anticoagulation was re-started in only 9 patients before a thrombotic event occurred 27 deaths occurred by 30 days (12%), of which 11 were cardiovascular MP-AnXa-US-0093

50 COMPARISON WITH OTHER REVERSAL AGENTS Study ANNEXA-4 1 REVERSE-AD 2 Sarode, et al 3 INCH 4 Reversal Agent Anticoagulant Andexanet FXa inhibitors Idarucizumab Dabigatran 4F-PCC (Kcentra) Warfarin Plasma Warfarin 4F-PCC (Octaplex) Warfarin Plasma Warfarin Number of patients Hemostatic Efficacy Thrombotic Event Rate Mortality Total % ICH Total ICH Total ICH Total ICH % 81% 11% 12% 12% 12% % NR 5% 6% 14% 16% % 42% 8% NR 6% NR % 58% 6% NR 5% NR % % - 35% % - 8.7% - 19% - 1) Connolly SJ, et al. New Engl J Med 2016;375: ) Pollack CV, et al. New Engl J Med 2017;377: ) Sarode R, et al. Circulation 2013;128: ) Steiner T, et al. Lancet Neurol 2016;15:

51 HEMOSTATIC EFFICACY? Study Comparison Reversal Hematoma Expansion ANNEXA-4 No comparison, DOAC-ICH (n=40) Andexxa Baseline volume: 10 ml = 8/12 (67%) ml = 4/12 (33%) Mortality 12% for ICH 20 patients in hemostasis measurement: 80% (95% CI: 56-94) Majeed et al. NOAC major bleed (n=84) ICH (n=59) All patients received median dose of 2,000 units ( ) ISTH defined hemostatic efficacy: 58/84 (69.1%) 30 day = 27/84 (32%) Schulman et al. NOAC major bleed (n=66) Rivaroxaban 56% Apixaban 44% 4F-PCC 2,000 units Hemostatic Efficacy: good 65% moderate 20% poor/none 15% 30 day = 14% 1) Connolly SJ, et al. New Engl J Med 2016;375: ) Wilson D, et al. Neurology 2017;88: ) Allison TA, et al. J Intensive Care Med 2018: epub ahead of print

52 MMC EXPERIENCE - PCC Patient group DOAC Hemostatic efficacy All patients (n=25) Apixaban = 10 Rivaroxaban = 14 Edoxaban = 1 ICH (n=13) Apixaban = 7 Rivaroxaban = 5 Edoxaban = 1 Other bleed (n=11) Surgical reversal (n=4) Apixaban = 2 Rivaroxaban = 9 Apixaban = 2 Rivaroxaban = 2 Discharge disposition 16/25 (64%) Home = 13 Rehab = 4 SNF = 1 Death/hospice = 7 10/13 (76.9%) Home = 7 Rehab = 3 SNF = 1 Death/hospice = 2 5/11 (45.5%) Home = 5 Rehab = 1 SNF = 0 Death/hospice = 5 3/4 (75%) Home = 3 Death = 1

53 COST Supplied as 100 mg vials, stable for up to 8 hours at room temp $2,750 per vial 75 yo M on Rivaroxaban 20 mg daily presents with ICH at 2200 Last dose at 0700 (15 hours prior) Andexxa dose low dose : 400 mg IV bolus, followed by 480 mg x 2 hours = $24,750 Last dose at 1800 (4 hours prior) Andexxa dose high dose : 800 mg IV bolus, followed by 960 mg x 2 hours = $49,500 Idarucizumab (Praxbind) - ~$3,500 for 5 gm dose 4 Factor PCC (Kcentra) - ~$3,000 for 2,000 unit dose

54 REVERSAL SUMMARY Always a balance between bleeding and thrombosis Limited options for novel anticoagulants, though bleeding risk may be lower Warfarin reversal: Vitamin K preferred less is more? PO vitamin K preferred route Major bleed PCC over FFP, though efficacy is not fully understood

55 QUESTIONS?? Wes Zemrak, Pharm.D., BCPS Clinical Pharmacy Specialist, Anticoagulation