1. Dr. Ryan Clark, DO Grandview Medical Center, Dayton, OH NOVEL ORAL ANTICOAGULANTS

2. OBJECTIVES This presentation will focus on the use of new oral anticoagulants for treatment of venous thromboembolism and CVA prophylaxis in atrial fibrillation Review the history of traditional anticoagulation therapy Review basic pharmacology, mechanism of action, and dosing considerations of the new oral anticoagulants Transitioning patients from one agent to another Review current management of bleeding complications How to tailor anticoagulant therapy to each patient

3. QUESTION #1 A 55 year old obese white male presents to your office in follow up for progressive chronic kidney disease. He has a history of paroxysmal atrial fibrillation and has been on Apixaban for CVA prophylaxis for the past 2 years. His renal function has deteriorated and he is going to initiate hemodialysis in the near future. What is the appropriate dose of Apixaban for this particular patient? *5mg PO twice daily* 2.5mg PO twice daily 5mg PO once daily Apixaban is not indicated for use in patients with ESRD

4. QUESTION #2 Your patient has a history of multiple PE’s and is on long-term anticoagulation with warfarin. He is a big fan of Chris Bosh and heard that he was on some new pill called Xarelto for his PE, and wants to be like Bosh. What is the appropriate method for transition from warfarin to Rivaroxaban? Stop warfarin, start IV heparin once INR <2, and then start oral Rivaroxaban with 2 days of overlap therapy Stop warfarin, start oral Rivaroxaban once INR <1.5 Continue warfarin within therapeutic range, start oral Rivaroxaban with 2 days of overlap therapy, then stop warfarin *Stop warfarin, start oral Rivaroxaban once INR <3*

6. HUMAN INGENUITY AT ITS FINEST

7. Estimate embolic risk CHADS2VASC Estimate bleeding risk HAS-BLED Prevention of new thrombus formation Prevention of thrombus extension or embolization to cerebral or other vascular beds Treatment duration is indefinite Prevention of new thrombus formation Prevention of thrombus extension or embolization Rapidly acting parenteral anticoagulation overlapped with oral vitamin K antagonist Overlap of at least 5 days, discontinued once INR deemed therapeutic Treatment for at least 3 months TRADITIONAL THERAPY Venous ThromboembolismAtrial Fibrillation

8. EMBOLIC RISK

9. BLEEDING RISK

10. TRADITIONAL THERAPY Vitamin K antagonist is effective therapy Ease of use leaves much to be desired Each therapeutic agent has its own unique difficulties Unfractionated Heparin Low Molecular Weight Heparin Warfarin

11. UNFRACTIONATED HEPARIN Parenteral administration requiring IV access Frequent monitoring of aPTT with adjustment of infusion Can be difficult to titrate and maintain therapeutic window Risk of heparin induced thrombocytopenia Reported in up to 5% of patients treated with heparin for > 4 days Absolute risk of HIT with prophylactic UFH – 2.6%

12. LOW MOLECULAR WEIGHT HEPARIN Twice daily subcutaneous injections Patient discomfort Patient compliance with bridging therapy at home Increased cost Laboratory monitoring is available, albeit not readily, and cumbersome Risk of heparin induced thrombocytopenia Absolute risk of 0.2% Risk higher if patient previously exposed to UFH or LMWH

13. WARFARIN Frequent monitoring of INR Slow onset Need for parenteral overlap Slow offset Frequent dose adjustments Narrow therapeutic window Multiple drug interactions Genetic polymorphism Patient compliance issues can be catastrophic

14. WARFARIN How many drugs have known interactions with warfarin? 807

15. WE HAVE COME A LONG WAY The limitations of warfarin therapy prompted much research to find alternatives that were more appealing Feature Warfarin New Agents OnsetSlowRapid DosingVariableFixed Food effectYesNo InteractionsManyFew MonitoringYesNo OffsetLongShorter

16. THE NEW KIDS IN TOWN Pradaxa (Dabigatran etexilate) Xarelto (Rivaroxaban) Eliquis (Apixaban) Savaysa (Edoxaban)

21. NOVEL ORAL ANTICOAGULANTS Specific Targets 2 Categories Direct thrombin inhibitors IV: Hirudin, Lepirudin, Bivalirudin, Argatroban Oral: Dabigatran Factor Xa inhibitors Oral: Rivaroxaban, Apixaban, Edoxaban

22. MECHANISM OF ACTION Specific targets within the coagulation cascade

23. COAGULATION CASCADE

25. DRUG INTERACTIONS

26. DRUG-DRUG INTERACTIONS Novel oral anticoagulants are substrates for CYP3A4 or P-glycoprotein Strong inducers of both CYP3A4 and P-glycoprotein lead to 50% decrease in NOAC Rifampicin Phenytoin Carbamazepine phenobarbital Strong P-glycoprotein inhibitors Verapamil Quinidine Amiodarone dronedarone Strong inhibitors of both CYP3A4 and P-glycoprotein Ketoconazole HIV protease inhibitors

27. DABIGATRAN ETEXILATE Dosage for both VTE and CVA prophylaxis is 150mg PO BID Prodrug that is activated in the liver Capsule that cannot be chewed, opened, or crushed Absorption is impaired with proton pump inhibitors and achlorhydria Side effect of dyspepsia 12% of patients P-glycoprotein mediated Do not use in CKD patients with CrCl <30 ml/min

32. FACTOR XA INHIBITORS Rivaroxaban Dosage for VTE: 15mg PO BID x 21 days, then 20mg PO daily Dosage for Afib: 20mg PO daily Needs to be given with meals to enhance absorption Renal impairment VTE: CrCl 30 to <50 ml/min observe closely for signs of bleeding VTE: CrCl <30 ml/min avoid use Afib: CrCl 15-50 ml/min decrease dose to 15mg PO daily Afib: CrCl <15 ml/min avoid use

37. FACTOR XA INHIBITORS Apixaban Dosage for VTE 10mg PO BID x 7 days, then 5mg PO BID Dosage for Afib 5mg PO BID Approved for use in patients with ESRD on HD Dosage adjustment to 2.5mg PO BID necessary if 2 of the 3 are present: Serum creatinine >1.5 mg/dL Age >80 years Weight <60 kg

42. FACTOR XA INHIBITORS Edoxaban Dosage for VTE 60 mg PO daily for weight >60kg, 30mg PO daily for weight <60kg or CrCl 15-50 ml/min Decrease dosage to 30mg PO daily if on concomitant P-glycoprotein inhibitor Dosage for Afib 60mg PO daily, 30mg PO daily for CrCl 15-50 ml/min BLACK BOX WARNING Do not use in patients with CrCl >95 ml/min Increased risk of ischemic stroke

47. TRANSITIONING FROM VKA TO NOAC Dabigatran Converting from warfarin Discontinue warfarin and initiate Dabigatran when INR < 2 Converting from parenteral Give Dabigatran 0-2 hours before time of next parenteral dose, or initiate at the time of discontinuation of unfractionated heparin Converting to warfarin If CrCl >50ml/min, start warfarin 3 days before discontinuing dabigatran If CrCl 30-50ml/min, start warfarin 2 days before discontinuing dabigatran If CrCl 15-30ml/min, start warfarin 1 day before discontinuing dabigatran Converting to parenteral If CrCl >30ml/min, wait 12 hours after last dose before initiating parenteral therapy If CrCl <30ml/min, wait 24 hours after last dose before initiating parenteral therapy

48. TRANSITIONING FROM VKA TO NOAC Rivaroxaban Converting from warfarin Discontinue warfarin and start rivaroxaban as soon as INR <3 Converting from parenteral Start rivaroxaban 0-2 hours prior to next scheduled parenteral administration, or start rivaroxaban when unfractionated heparin infusion is stopped Converting to warfarin No clinical trial data available Stop rivaroxaban and start parenteral anticoagulant along with warfarin at the time the next dose would have been given Converting to parenteral No clinical trial data available Stop rivaroxaban and start parenteral anticoagulant at the time the next dose would have been given

49. TRANSITIONING FROM VKA TO NOAC Apixaban Converting from warfarin Discontinue warfarin and start Apixaban when INR < 2 Converting from parenteral Discontinue parenteral and start Apixaban at the next scheduled dose Converting to warfarin Discontinue Apixaban and start both a parenteral anticoagulant and warfarin at time the next dose would be due Converting to parenteral Discontinue Apixaban and start a parenteral anticoagulant at the time the next dose would be due

50. TRANSITIONING FROM VKA TO NOAC Edoxaban Converting from warfarin Discontinue warfarin and start Edoxaban when INR < 2.5 Converting from parenteral Discontinue parenteral and start Edoxaban at the time the next scheduled dose would have been Discontinue heparin infusion and begin Edoxaban 4 hours later Converting to warfarin If taking Edoxaban 60mg PO daily Reduce dose to 30mg PO daily and start warfarin Check INR, once stable > 2, stop Edoxaban If taking Edoxaban 30mg PO daily Reduce dose to 15mg PO daily and start warfarin Check INR, once stable >2, stop Edoxaban Converting to parenteral Discontinue Edoxaban and start parenteral anticoagulant at the time of next scheduled dose

51. PERIOPERATIVE MANAGEMENT Novel oral anticoagulants should be stopped 1-2 days before surgery Factors to consider Renal function Surgical risk for bleeding

52. PERIOPERATIVE MANAGEMENT Factor Xa Inhibitors Hold 24 hours for low risk surgery Hold 48 hours for high risk bleeding surgery and/or renal dysfunction Direct Thrombin Inhibitor Hold 24 hours for low risk bleeding surgery and normal renal function Hold 48 hours for high risk bleeding surgery or renal dysfunction Hold 96 hours for high risk bleeding surgery and renal dysfunction

53. Diabetes Frequent falls Age >75 Cancer EtOH abuse Hypertension Abnormal renal/liver function Stroke Bleeding Labile INR’s Elderly Drugs or EtOH MANAGEMENT OF BLEEDING COMPLICATIONS HAS-BLEDDFACE

54. OLD SCHOOL IS EASIER Heparin Stop the drug Protamine sulfate Warfarin Stop the drug Vitamin K FFP Prothrombin Complex Concentrates in cases of ICH

55. NOACS Stop the drug Short half life Local hemostasis Nasal packing Hold pressure? Blood transfusion when appropriate GI evaluation when suspected GI bleed

56. EMERGENT REVERSAL Needed in certain life-threatening emergencies Intracranial Intraspinal Pericardial Hemorrhagic shock Drug overdose Emergency surgery

57. XA INHIBITORS No standard reversal agents available Unfortunately not removed by dialysis 4-factor PCC normalizes prolonged PT from rivaroxaban in healthy volunteers Can be given prior to urgent surgery Factor Xa assay can help determine if inhibition is still present R-antidote (PRT064445) binds Xa inhibitor site PER-977 directly binds Xa and IIa, potentially reversing dabigatran, rivaroxaban, and apixaban

58. PRAXBIND Idarucizumab Humanized monoclonal antibody that targets Dabigatran binding site with greater than 350x affinity than thrombin Reversal of anticoagulation effect in minutes Give 2 doses of 2.5mg no more than 15 minutes apart 5mg = $4200

59. CHOOSING THE RIGHT NOAC FOR MY PATIENT

60. Medical History Patient preference Social Support Financial impact Patient Education

61. CHOOSING THE RIGHT NOAC FOR MY PATIENT

63. DON’T LET THIS HAPPEN TO YOUR PATIENT

64. THANK YOU FOR YOUR ATTENTION Questions?