3/17/2014. No conflicts of interest to report

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1 No conflicts of interest to report Patrick M. Lewis, Pharm.D., BCPS, CACP Lahey Hospital & Medical Center Burlington, MA April 1 st 2014 Parts of this presentation discuss off-label use of reversal agents. Clinical judgment and evaluation of each agent in the context of the specific patient scenario is warranted Evaluate how target-specific anticoagulants compare to traditional oral anticoagulation with warfarin Compare and contrast the clinical evidence supporting the use of various reversal strategies for patients receiving oral anticoagulants Recommend reversal options for a patient receiving oral anticoagulants that develops bleeding complications 15 20% = incidence per year of warfarinrelated bleeding of any kind 1-3 % = incidence per year of warfarinrelated life-threatening bleeding 2 % = patients suffering an intracerebral hemorrhage or subdural hematoma during therapy (79% mortality rate) Holland L et al. Transfusion. 2009;49: Rubboli A et al. World J Cardiol. 2011;3(11): Factors associated with bleeding events Intensity and quality of anticoagulant therapy New initiation to anticoagulant therapy Patient-specific factors History of previous bleeding (especially GI) Advanced age Cancer Renal or liver impairment Prior stroke Alcohol abuse Concomitant therapy with medications known to increase bleeding or anticoagulation Procedures Smythe MA et al. J Pharm Pract. 2004;17: Drug RE-LY ROCKET-AF ARISTOTLE AVERROES Dabigatran 150mg & 110mg BID Rivaroxaban 20mg daily Renal Dose Not studied CrCl mg daily Design Randomized open label Randomized double blind Apixaban 5mg BID Apixaban 5 mg BID 2.5 mg BID 2.5 mg BID Randomized double blind Randomized double blind Previous 20% 55% 19% 13.5% Stroke/TIA 50.4% 37.5% 43% 60.5% Naïve Mean CHADS Comparator TTR: 67% TTR: 57.8% TTR: 66% Aspirin mg 1

2 Major Bleeding ICH 51% GI Bleeding Miller CS et al. Am J Cardiol. 2012;110: Parameter Dabigatran Rivaroxaban Apixaban Dosing BID Daily to BID BID Bioavailability ~7% ~66 100% (dependent on food) ~50% Time of Onset 1 2 hours 2 4 hours 3 4 hours Half life hours 9 13 hours 8 15 hours Elimination 85 % renal 36% renal 25% renal Metabolism Conjugation No CYP 450 involvement Primarily CYP3A4 CYP3A4 Substrates All are substrates for P glycoprotein Protein Binding ~35% ~95% ~87% Routine Lab Monitoring No routine monitoring required Pradaxa [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals; April Xarelto [package Insert]. Titusville, NJ: Janssen Pharmaceuticals; March Eliquis [package Insert]. Princeton, NJ: Bristol-Myers Squibb; December

3 INR Hold Vitamin K Comments < 4.5 No bleeding No bleeding > 10 No bleeding Bleeding regardless of INR Yes No Hold dose, consider dose reduction, monitor INR INRs 0.5 from goal may not require dose reductions Yes No Hold 1-2 doses, monitor INR Evaluate need for dose reduction Yes Yes Hold warfarin until INR in range Give Vitamin K PO 2.5-5mg Monitor INR, assess for cause and evaluate warfarin dosing Yes Yes Give Vitamin K IV 5-10 mg by slow infusion Consider factor replacement for major bleeding Which of the following patients would require their INR to be reversed pharmacologically? A. INR of 4.5 presenting to the ED with controlled epistaxsis B. INR of 2 requiring elective surgery in 3 days with goal INR <1.3 C. INR of 10.5 without signs/symptoms of bleeding D. Both B & C Holbrook A et al. Chest. 2012;141(2):e152s-84s; Angeno W et al. Chest. 2012;141(2):e44s-e88s. -related Major Bleeding Prothrombin Complex Concentrates (PCC) recommended over Fresh Frozen Plasma (FFP) (Grade 2C) Vitamin K IV 5-10 mg by slow IV infusion should be used in combination with factor replacement rather than using factors alone (Grade 2C) Vit K IV Vit K PO Holbrook A et al. Chest. 2012;141(2):e152s-84s; Angeno W et al. Chest. 2012;141(2):e44s-e88s. Dager WE. Am J Health-Syst-Pharm. 2013;70(Supp 1):s A 50 year-old female with a mechanical mitral valve presents to the ED with minor epistaxis that resolves spontaneously. She is otherwise stable but is worried about what her INR is given a previous bleeding event. Her INR test results back What would be the appropriate course of action for this patient s elevated INR? A. Give Vitamin K IV 5-10 mg x 1 and admit for monitoring of INR B. Give Vitamin K PO 2.5 mg x 1 and recheck the INR in 24 hours C. Give Vitamin K PO 5 mg x 1 and recheck the INR in 24 hours D. Patient should be considered for a novel anticoagulant because of her bleeding history and better bleeding outcomes with novels Inactivated factors II, VII, IX, X in a diluted form Dosing ml/kg IV infusion 1 unit of FFP is ~ ml Advantages Provides more rapid short-term reversal No excess risk of thrombosis Low cost Disadvantages Frozen takes times time to thaw (~30 minutes) Substantial volume limits rapid infusion and decreases tolerance Transfusion reactions Risk of disease transmission (low) Schulman S, Bijsterveld NR. Transfus Med Rev. 2007;21:

4 3-Factor PCC 4-Factor PCC Activated 4- Factor PCC Brand Name Profilnine SD Kcentra FEIBA Bebulin VH Prothromplex HT Factors Included II, IX, X II, VII, IX, X II, VIIa, IX, X Approved for No Yes No Reversal Dosing All agents are dosed based on the number of units/ml of Factor IX which varies from lot to lot Garcia DA, Crowther MA. Circulation. 2012;125: Factor PCC (Kcentra) vs. FFP for -Related Major Bleeding Population Dosing 103 PCC;109 FFP with major bleeding on warfarin with INR 2 Mean INR 3.9 (PCC) vs. 3.6 (FFP) 65% GI bleeds or other non-visible site 12% ICH PCC 25, 35, or 50 Factor IX units/kg FFP 10, 12, or 15 units/ml Dose adjusted for INR value All patients got Vitamin K IV Effective hemostasis through 24 hours Outcomes Reduction of INR to 1.3 at 30 minuets after infusion Sarode R et al. Circulation 2013 Aug 9. [Epub ahead of print] Outcome Results 95% CI Effective hemostasis PCC 72.4% 7.1% ( ) FFP 65.4% Reduction of INR 1.3 in 30 minutes PCC 62.2% FFP 9.6% 52.6% ( ) Other Advantages Less volume required for complete reversal of warfarin (105 ml vs. 865 ml) Faster infusion time with PCC than plasma (24 min vs. 169 min) Thromboembolic events (TEE) were low and no difference was found between plasma and PCC Greatest risk of TEE occurred in patients with a previous history of thrombosis Product Time to Effect Duration of Effect Evidence for Use Risk of Thrombosis Vitamin K PO 24 hours Days Vitamin K IV 8-12 hours Days FFP Immediate hours ++ - PCC Immediate hours rfviia Immediate 2-6 hours + ++ Sarode R et al. Circulation 2013 Aug 9. [Epub ahead of print] Adapted from Garcia DA, Crowther MA. Circulation. 2012;125: Data is mixed largely based on coagulation markers not hard outcomes Target-Specific Anticoagulants Most human data is in healthy volunteers limits extrapolation to bleeding patients Data on reversal in bleeding limited to animal models and case reports 4

5 Dabigatran Half-Life Stratified by Renal Function CrCl Estimated Half-Life in Hours mean (range) >80 13 (11-22) >50 to (12-34) >30 to (13-23) (22-35) Rivaroxaban Half-Life Stratified by Renal Function CrCl (ml/min) > <30 Half-life (hours) Anticoagulant PT aptt TT ECT Anti-Xa activity Dabiagtran or NC NE Rivaroxaban or NC or NC NE NE Apixaban or NC or NC NE NE NC = no change; = increase; NE = no effect PT = prothrombin time; aptt = activated partial thromboplastin time; TT = thrombin time; ECT = ecarin clotting time Preferred Test Dabigatran: TT may be useful in emergent situations Rivaroxaban: Anti-Xa activity Apixaban: Anti-Xa activity Van Ryn et al. Thromb Haemost. 2010;103(6): Kubitza D et al. Br J Clin Pharmacol. 2010;70: Siegal DM, Cuker A. J Thromb Thrombolysis. 2013;35: Which of the following laboratory assays may be most useful for determining whether dabigatran is present during an acute bleeding event? A. INR or PT B. aptt C. Thrombin time (TT) D. Lack of data for any test Dabigatran: aptt, ETP lag time, ECT, TT Rivaroxaban: PT, ETP Eerenberg ES. Circulation. 2011;124: Results for Dabigatran 4PCC had NO EFFECT seen ANY coagulation parameter measured Results for Rivaroxaban Complete normalization of the PT 15 minutes after infusion of PCC (p<0.001) ETP normalized 15 minutes after infusion (p<0.001) Effects sustained for 24 hours Eerenberg ES. Circulation. 2011;124: Marlu R et al. Thromb Haemost. 2012;108(2):

6 Results for apcc (FEIBA) Consistent effect on thrombin generation of rivaroxaban Less consistent effect for dabigatran Results for 4PCC and FVIIa Inconsistent impact on thrombin production Advantage for apcc? Possibly due to combining actions of FVIIa and 4PCC Marlu R et al. Thromb Haemost. 2012;108(2): CASE 67 y/o M on dabigatran 150mg BID for Afib Cardiac ablation (last dose 7 hours prior) Heparin 5000 unit bolus and drip at 200 units/hr Trans-septal perforation Dager WE et al. Crit Care Med. 2013;41(5):e42-6. OUTCOME Pericardiocentesis of 4.5 L 2 units FFP + protamine 100mg 6 units RBCs Epinephrine drip Last Resort: FEIBA 26 units/kg Visual cessation of bleeding No effect on TT or ECT; aptt and INR normalized Reversal Agent Dabigatran Rivaroxaban 3 Factor PCC Lack of data Limited Data 4 Factor PCC Yes/No Yes/No apcc Yes Yes FVIIa Lack of data Lack of data FFP No Lack of data Vitamin K No No Dialysis Yes No Activated Charcoal Yes Yes Tranexamic Acid Lack of data Lack of data Gaudu et al. Spine. 2012; 37(14):e863-e65. Eerenberg et al. Circulation. 2011;124(14): Marlu et al. Thromb Haemost. 2012;108: Dager et al. Crit Care Med. 2013;41(5):e42-6. Warkentin et al. Blood. 2012;119: Kalus et al. Am J Health-Syst Pharm. 2013;70(supp 1):s12-s19. PATIENT CASE 85 y/o M presents to ED with a severe GI bleed He takes dabigatran 150 mg BID for afib (last dose 8 hours ago) Also has HTN, HF, CKD III CrCl = 38 ml/min Noted to have decreased Hgb and Hct, hypotension, signs of multi-system organ failure QUESTION The team has elected to attempt to reverse dabigatran, which options are most appropriate in addition to supportive care? A. 3-Factor PCC + dialysis if possible B. apcc + dialysis if possible C. rfviia D. Activated charcoal Is goal to stop bleeding or prevent bleeding? Assess pharmacokinetic and dynamic aspects of the anticoagulant What patient specific factors are involved that may alter the plan 6

7 Adapted from Garcia DA, Crowther MA. Circulation. 2012;125: Adapted from Siegal DM, Cuker A et al. J Thromb Thrombolysis. 2013;35: Agent Cost per Unit of Drug Total Cost per Dose 4-Factor PCC (Kcentra ) $1.27/unit $3,175 3-Factor PCC (ProfilNine ) $0.91/unit $2,275 apcc (FEIBA ) $1.52/unit $3,800 rfviia (NovoSeven ) $1.52/mcg $3,800 FFP (15 ml/kg) $60/unit $300 Cost of a single dose based on an 80 kg patient receiving 25 units/kg or 25 mcg/kg for rfviia Average cost of FFP is $60/unit Price/unit based on GPO through Cardinal as of 10/2013 Improve the patient s time in therapeutic range (TTR) Ideally patients should be enrolled in an anticoagulation clinic Standardized dosing nomograms, education, periprocedural management Increase testing frequency Self-testing or even self-management of warfarin Improve transitions of care Consider novel anticoagulants for patients consistently out of goal range Characteristic Drug Choice Rationale Mechanical valve or valvular Afib Liver dysfunction CrCl < 30 ml/min CrCl ml/min Recent GI Bleed Recent ischemic stroke on warfarin Rivaroxaban Apixaban Apixaban Dabigatran Increased risk of stroke, MI, and valve thromboses New agents require hepatic metabolism Studies of new agents excluded patients with severe renal disease Factor Xa inhibitors rely much less on renal function for elimination compared to dabigatran Dabiagatran and rivaroxaban associated with increased GI bleeding Dabigatran 150mg BID associated lower risk of ischemic stroke than warfarin Weitz et al. Am Soc Hematol. 2012:

8 Triple therapy (dual antiplatelet therapy + anticoagulation) with newer agents at least doubles risk of bleeding after ACS No literature to compare bleeding risk between warfarin or newer agents in patients with ACS and Afib Personalize therapy based on risk factors Mega et al. N Engl J Med 2012;366:9-19. Alexander et al. N Engl J Med 2011;365: Oldgren et al. Eur Heart J 2011;32: Adapted from Heidbuchel et al. Europace 2013;15: Perioperative Management of Target Specific Oral Anticoagulants Drug Number of Doses to Hold Number of Doses to Hold Prior to Minor Surgery Prior to Major Surgery Dabigatran (CrCl > 50 ml/min) Hold 2 doses (1 day) Hold 4 doses (2 days) Dabigatran (CrCl 50 ml/min) Hold 4 doses (2 days) Hold 8 doses (4 days) Rivaroxaban Hold 1 dose (1 day) Hold 2 doses (2 days) Apixaban Hold 2 doses (1 day) Hold 4 doses (2 days) Assessment of both bleeding and thrombotic potential should be completed prior to holding therapy Note: patients with worsening renal function will likely require more time to achieve adequate hemostasis prior to procedure, especially for dabigatran consideration for holding therapy longer may be warranted. Pradaxa [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals; April Xarelto [package Insert]. Titusville, NJ: Janssen Pharmaceuticals; March Eliquis [package Insert]. Princeton, NJ: Bristol-Myers Squibb; December Viles-Gonzalez JF et al. Electrophysiol 2011;22: Van Ryn J et al. Thromb Heamost 2010;103(6): Surgical Risk Examples of Major Surgery (high bleeding risk): any surgical intervention requiring complete hemostasis, cardiac, neurosurgical, abdominal, involving a major organ, spinal, or need for spinal anesthesia Consider restarting therapy once hemostasis is achieved: Ideally 24 hours in low bleed risk hours in high bleed risk Be familiar with your institution s policies on reversal Limited data on reversal create consensus among key players in your organization Re-evaluate your anticoagulation patients for effective therapy Holland et al. Suboptimal effect of a 3 factor PCC in correcting supratherapeutic INR due to warfarin overdose. Transfusion. 2009;49(6): Rubboli A et al. Incidence, clinical impact and risk of bleeding during oral anticoagulation therapy. World J Cardiol. 2011;3(11): Smythe MA, Caffee A. Anticoagulation monitoring. J Pharm Pract. 2004;17: Connolly SJ et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361: Patel MR et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365: Granger CB et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365: Connolly SJ et al. Apixaban in patients with atrial fibrillation. N Engl J Med. 2011;364: Miller CS et al. Meta-analysis of efficacy and safety of new oral anticoagulants (dabigatran, rivaroxaban, apixaban) versus warfarin in patients with atrial fibrillation. Am J Cardiol. 2012;110: Pradaxa [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals; April Xarelto [package insert]. Titusville, NJ: Janssen Pharmaceuticals; March Eliquis [package insert]. Princeton, NJ: Bristol-Myers Squibb; December Holbrook A et al. Evidence-based management of anticoagulant therapy: antithrombotic therapy and prevention of thrombosis, 9 th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2_suppl):e152S-e184S. Ageno W et al. Oral anticoagulant therapy: antithrombotic therapy and prevention of thrombosis, 9 th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2_suppl):e44S-e88s. Dager WE. Developing a management plan for oral anticoagulant reversal. Am J Health-Syst-Pharm. 2013;70(Supp 1):s Schulman et al. Anticoagulants and their reversal. Transfus Med Rev. 2007;21: Garcia DA, Crowther MA. Reversal of warfarin: case-based practice recommendations. Circulation. 2012;125: Sarode R et al. Efficacy and safety of a 4-factor prothrombin complex concentrate in patients on vitamin K antagonists presenting with major bleeding: a randomised, plasma-controlled, phase IIIb study. Circulation. 2013;128(11): Van Ryn et al. Dabigatran etexilate a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost. 2010;103(6): Kubitza D et al. Effects of renal impairment on the pharmacokinetics, pharmacodynamics, and safety of rivaroxaban, an oral, direct Factor Xa inhibitor. Br J Clin Pharmacol. 2010;70(5): Siegal DM, Cuker A. Reversal of novel oral anticoagulants in patients with major bleeding. J Thromb Thrombolysis. 2013;35: Eerenberg ES et al. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation. 2011;124: Marlu R et al. Effect of non-specific reversal agents on anticoagulant activity of dabigatran and rivaroxaban. Thromb Haemost. 2012;108(2): Dager WE et al. Reversing dabigatran in life-threatening bleeding occurring during cardiac ablation with factor eight inhibitor bypassing activity. Crit Care Med. 2013;41(5):e42-6. Truumees E et al. Epidural hematoma and intraoperative hemorrhage in a spine trauma patient on pradaxa (dabigatran). Spine. 2012;37(14):e863-e65. Warkentin TE et al. Recombinant factor VIIa and hemodialysis to manage massive dabigatran-associated postcardiac surgery bleeding. Blood. 2012;119: Kalus JS. Pharmacologic interventions for reversing the effects of oral anticoagulants. Am J Health-Syst Pharm. 2013;70(supp1):s12-s19. Weitz JI, Gross PL. New oral anticoagulants: which one should my patient use? Am Soc Hematol. 2012; Mega JL et al. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med. 2012;336:9-19. Alexaner JH et al. Apixaban with antiplatelet therapy after acute coronary syndrome. N Engl J Med. 2011;365: Oldgren J et al. Dabigatran vs. placebo in patients with acute coronary syndromes on dual antiplatelet therapy: a randomized, double-blind, phase II trial. Eur Heart J. 2011;32(22): Heidbuchel h et al. European Heart Rhythm Association practical guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation. Europace. 2013;15: Viles-Gonzalez JF et al. New anticoagulants for prevention of stroke in patients with atrial fibrillation. Journal of Cardiovascular Electrophysiology. 2011;22(8):

9 Questions? 9