Disclosure/Conflict of Interest

NEW ORAL ANTICOAGULANTS: WHAT EVERY PHARMACIST SHOULD KNOW LORI B. HORNSBY, PHARMD, BCPS ASSOCIATE CLINICAL PROFESSOR AUHSOP CLINICAL PHARMACIST MIDTOWN MEDICAL CENTER OUTPATIENT CLINIC COLUMBUS, GEORGIA HALEY M. PHILLIPPE, PHARMD, BCPS ASSOCIATE CLINICAL PROFESSOR AUHSOP CLINICAL ASSOCIATE PROFESSOR UABFM CLINICAL PHARMACIST HUNTSVILLE REGIONAL CAMPUS HUNTSVILLE, ALABAMA JULY 18, 2015 Disclosure/Conflict of Interest I, Lori Hornsby, have no actual or potential conflict of interest in relation to this program. I, Haley Phillippe, have no actual or potential conflict of interest in relation to this program. Objectives Determine the appropriateness of the NOACs in a given patient Recognize appropriate dosing for the NOACs Provide instructions for transitioning a patient from one oral anticoagulant to another Describe appropriate pre surgical management of patients receiving a NOAC Recognize common errors during the prescribing and dispensing of the new NOACs 1

New Oral Anticoagulants (NOACs) Novel oral anticoagulants (NOACs) Target specific oral anticoagulants (TSOACs) Direct Thrombin Inhibitor Dabigatran (Pradaxa) Factor Xa Inhibitors Rivaroxaban (Xarelto) Apixaban (Eliquis) Edoxaban (Savaysa) Rivaroxaban Apixaban Edoxaban Dabigatran Image from: Nature Reviews Drug Discovery 10, 61 75 (January 2011) New Oral Anticoagulants (NOACs) Non vitamin K antagonist oral anticoagulants (NOACs) Dabigatran (Pradaxa) Rivaroxaban (Xarelto) Apixaban (Eliquis) Edoxaban (Savaysa) In clinical trials for stroke prevention in Atrial Fibrillation or the treatment of Venous Thromboembolism vs warfarin Found to be either non inferior or superior in regard to efficacy Similar or favorable rates of major bleeding and reduced rates of intracranial hemorrhage 2

NOACs Labeled Indications Dabigatran Rivaroxaban Apixaban Edoxaban Stroke prevention in Atrial Fibrillation VTE Treatment * * VTE prevention post TKR/THR *After 5 10 days of parenteral anticoagulation Pradaxa,Xarelto, Eliquis,and Savaysa Product Information Mechanical Valve Replacement Dabigatran RE ALIGN trial Phase II dose range study Randomized patients with mechanical valve replacement to Dabigatran (3 groups:150mg BID, 220mg BID, 300mg BID) or Warfarin (INR of 2 3 or 2.5 3.5 based on goal) Stopped early due to increased events in dabigatran group Stroke (5% vs 0%), valve thrombosis (3% vs 0%), bleeding (27% vs 12%; HR 2.45 95%CI 1.23 4.86) Prosthetic heart valve now listed as a CI to dabigatran therapy The NOACs are NOT indicated for mechanical valve replacement Boehringer Ingelheim Press Release December 11, 2012. NEJM 2013;369:1206 14. NOACs Advantages Favorable results in clinical trials Predictable dose response Routine monitoring not required Lack of dietary interactions Decreased drug interactions Fast onset Short half life Disadvantages Short half life Twice daily dosing for some Routine lab tests unavailable Lack of antidote Renal dosing complicated/not well studied Dosing in elderly/low body weight has been questioned Drug interaction potential Cost 3

NOACs Pharmacokinetics Dabigatran Rivaroxaban Apixaban Edoxaban Time to peak 1 3 hours 2 4 hours 3 4 hours 1 2 hours Half Life 12 17 hours CrCl <30: 28 hours 5 9 hours Elderly: 11 13 hours 8 15 hours 10 14 hours Renal Excretion 80% unchanged 36% unchanged 25% 50% Pradaxa,Xarelto, Eliquis,and Savaysa Product Information NOACs Dosing* Dabigatran Rivaroxaban Apixaban Edoxaban Stroke prevention in Atrial Fibrillation 150 mg BID 20mg daily 5mg BID** 60mg daily** VTE Treatment VTE prevention post TKR/THR 150mg BID 15mg BID x 21 days then 20mg daily 10mg daily for 12 days (TKR) 35 days (THR) 10mg BID x 7 days then 5mg BID x 6 months then 2.5mg BID 2.5mg BID for 12 days(tkr) 35 days (THR) *With normal creatinine clearance AND in the absence of drug interactions **See additional adjustments 60 kg: 60mg daily 60 kg: 30mg daily Pradaxa,Xarelto, Eliquis and Savaysa Product Information NOACs and Renal Dosing 4

NOACs Renal Dosing (per CrCl)* Stroke prevention in Atrial Fibrillation Dabigatran 15 30 ml/min: 75mg BID <15 ml/min: Avoid Rivaroxaban 15 50 ml/min:15mg daily <15 ml/min: Avoid VTE Treatment <30 ml/min: No recommendation <30 ml/min: Avoid VTE prevention post TKR/THR *In the absence of drug interactions CrCl = Creatinine Clearance Not Indicated 30 50 ml/min: Observe closely <30 ml/min: Avoid Pradaxa,Xarelto, Eliquis and Savaysa Product Information NOACs Renal Dosing* Stroke prevention in Atrial Fibrillation VTE Treatment VTE prevention post TKR/THR Apixaban 2.5mg BID with 2 of the following: SCr 1.5mg/dL Age 80 Weight 60 kg Edoxaban CrCl >95 ml/min: Avoid CrCl 15 50 ml/min: 30mg qday <15 ml/min: Avoid CrCl 15 50 ml/min: 30mg qday <15 ml/min: Avoid Not Indicated *In the absence of drug interactions CrCl = Creatinine Clearance Pradaxa,Xarelto, Eliquis and Savaysa Product Information NOACs and Renal Dosing Due to lack of clinical data (exclusion from clinical trials) many feel the safety of the NOACs is questionable for Dabigatran with CrCl <30 ml/min Rivaroxaban with CrCl <30 ml/min Apixaban with CrCl <25 ml/min 5

NOACs in the Elderly Anticoagulation in the Elderly Incidence of AFib <2% in patients <65 yoa 10% in patients 85 yoa and older ~25% of ischemic strokes in those 85 and older are due to AFib Incidence of a first VTE < 1 per 1000 person years in patients <50 yoa 6 per 1000 person years in pateints 80 yoa and older Anticoagulation therapy decreases the risk of stroke in AFib by ~65% Risk of major bleeding with warfarin is ~2 3% per year and increases with age JAMA 2001;285:370 5. Stroke 1991;22:983 8. Ann Intern Med 2007;146:857 67. J Thromb Haemost 2007;5:692 9. Arch Intern Med 1993;153:1557 62. Dabigatran Associated Bleeding 2012 case series 44 patients experiencing bleeding while taking dabigatran 12 categorized as major bleeding Two thirds were 80 yoa or older 58% had moderate or severe renal impairment 50% weighed <60 kg NEJM 2012;366:864 6. 6

NOACs in Elderly Patients Dabigatran RE LY Trial 18,113 patients 7258 (40%) 75 yoa 3027 (17%) 80 yoa Rivaroxaban ROCKET AF Trial 14,264 patients 6229 (44%) 75 yoa Apixaban ARISTOTLE Trial 18,201 patients 2850 (31%) 75 yoa Absolute risk of both thrombotic and bleeding events were increased with advanced age Risk was increased for both NOACs and warfarin Treatment effect/benefits maintained in elderly Exception: Major bleeding with dabigatran Best Practice and Research Clinical Haematology 2013;26:215 24. Incidence of Major Bleeding Based on Age Best Practice and Research Clinical Haematology 2013;26:215 24. Incidence of Major Bleeding Based on Age Best Practice and Research Clinical Haematology 2013;26:215 24. 7

Incidence of Major Bleeding Based on Age Best Practice and Research Clinical Haematology 2013;26:215 24. Drug Interactions Dabigatran Drug Interactions NSAIDS/Antiplatelets P glycoprotein Inducers: dabigatran Avoid use with rifampin Others: Carbamazepine, phenobarbital, phenytoin, St.John s wort Inhibitors : dabigatran Decrease dose to 75mg BID or Avoid with CrCl 30 50ml/min AND Dronedarone or Systemic ketoconazole Inhibitors : dabigatran Avoid with CrCl <30ml/min (AFib) or <50 ml/min (VTE) AND Dronedarone Systemic ketoconazole Verapamil Amiodarone Quinidine Clarithromycin Ticagrelor Other Pgp inhibitors? Combinations? *Lists may not be all inclusive Pradaxa Product Information 8

Rivaroxaban Drug Interactions NSAIDS/Antiplatelets P glycoprotein and CYP3A4 Inducers: rivaroxaban Avoid use with strong inducers of both Pgp AND CYP3A4 Rifampin Carbamazepine Phenytoin St.John s Wort *Lists may not be all inclusive Inhibitors: rivaroxaban Avoid use with strong inhibitors of both Pgp AND CYP3A4 Ketaconazole Itraconazole Ritonavir Indinavir Conivaptan Use with caution (weigh risk/benefit) with CrCl 15 80ml/min AND Amiodarone, diltiazem, verapamil, quinidine, felodipine, dronedarone, erythromycin, azithromycin Xarelto Product Information Apixaban Drug Interactions NSAIDS/Antiplatelets P glycoprotein and CYP3A4 Inducers: apixaban Avoid use with strong inducers of both Pgp AND CYP3A4 Rifampin Carbamazepine Phenytoin St.John s Wort Inhibitors : apixaban dose by 50% or avoid in those already on 2.5mg BID with strong inhibitors of both Pgp AND CYP3A4 Ketaconazole Itraconazole Ritonavir Clarithromycin *Lists may not be all inclusive Eliquis Product Information Edoxaban Drug Interactions P glycoprotein Inducers: edoxaban Avoid use with rifampin *Lists may not be all inclusive Savaysa Product Information 9

Transitioning between oral agents Warfarin NOAC NOAC NOAC Warfarin to NOAC To dabigatran and apixaban: Discontinue warfarin, initiate when INR <2 To rivaroxaban: Discontinue warfarin, initiate when INR <3 To edoxaban: Discontinue warfarin, initiate when INR <2.5 Pradaxa,Xarelto, Eliquis,and Savaysa Product Information NOAC to warfarin From dabigatran: Initiate based on CrCl: > 50 ml/min: start 3 days before discontinuing 30 50 ml/min: start 2days before discontinuing 15 30 ml/min: start 1 day before discontinuing < 15 ml/min: no recommendations From rivaroxaban: No clinical trial data; suggest discontinuing and initiating along with parenteral agent at time of next dose Pradaxa and Xarelto Product Information 10

NOAC to warfarin From apixaban: Discontinue and initiate along with parenteral agent at time of next dose From edoxaban: Reduce dose by 50% and initiate warfarin, monitor INR at least weekly before daily dose of edoxaban, once INR 2 achieved, discontinue edoxaban OR discontinue and initiate along with parenteral agent at time of next dose Eliquis and Savaysa Product Information NOAC to NOAC From rivaroxaban, apixaban, and edoxaban: Discontinue and administer first dose of new agent at time of scheduled next dose From dabigatran: No recommendation Pradaxa,Xarelto, Eliquis,and Savaysa Product Information Additional Transitioning 11

Parenteral to NOAC To dabigatran, rivaroxaban, and apixaban: Initiate 0 2 hours before time of next scheduled dose of low molecular weight heparin (LMWH) or at discontinuation of unfractionated heparin (UFH) infusion To edoxaban: Administer first dose of edoxaban at time of scheduled next dose of LMWH or 4 hours after discontinuation of UFH infusion Pradaxa,Xarelto, Eliquis,and Savaysa Product Information NOAC to parenteral From dabigatran: CrCl 30 ml/min: start 12 hrs after discontinuation CrCl < 30 ml/min: start 24 hrs after discontinuation From edoxaban: Start at time of scheduled next dose From rivaroxaban and apixaban: No recommendations Pradaxa,Xarelto, Eliquis,and Savaysa Product Information Invasive procedures 12

Management during surgery Dabigatran: CrCl 50ml/min: stop 1 2 days prior to surgery CrCl 50ml/min: stop 3 5 days prior to surgery Rivaroxaban and Edoxaban: Hold at least 24 hours prior to procedure Apixaban: Hold for at least 24 hrs prior to procedures with a low risk of bleeding Hold for at least 48 hrs prior to procedures with a moderate or high risk of unacceptable or clinically significant bleeding Pradaxa,Xarelto, Eliquis,and Savaysa Product Information Management during surgery Based on procedural bleeding risk Consider longer hold times for major surgeries/spinal procedures Typically, no need for bridge therapy High risk patients Unclear surgery schedule Restart when cleared after surgery Pradaxa,Xarelto, Eliquis,and Savaysa Product Information Other 13

Other Dabigatran Store capsules in original container Capsules should be swallowed whole Take with full glass of water Rivaroxaban Take 15mg and 20mg tablets with food If qday Take with evening meal Retrospective Reviews Appropriateness of NOACs in Two Outpatient Clinics Average Age: 74 26% (22/85) NOAC should have been avoided Inappropriate indication Renal Function Patient nonadherence 20% (17/85) NOAC needed adjustments Incorrect dosing for indication or renal function Incorrect dosing due to major drug interactions Increased GI bleed risk without GI protectant 54% (46/85) NOAC were appropriately prescribed 14

Appropriateness of NOACs in a LTCF Average Age: 79 23% (5/22) NOAC were contraindicated Inappropriate indication Renal function 27% (6/22) NOAC needed adjustments Incorrect dosing for indication and/or renal function Incorrect dosing due to major drug interactions Increased GI bleed risk without GI protectant 50% (11/22) NOAC were prescribed appropriately Appropriateness of NOACs in a Community Teaching Hospital Average Age: 71 20% (23/113) NOAC needed adjustments Inappropriate dose for indication, renal function, weight and/or age Incorrect dosing for major drug interactions 80% (90/113) NOAC were prescribed correctly 26% (10/38) Inappropriate transition between anticoagulants 33% (2/6) Inappropriate interruption prior to procedure Assessment Questions 15

Assessment Question #1 Dabigatran (Pradaxa) is indicated for all of the following EXCEPT: A. Stroke prophylaxis in AFib B. Mechanical valve replacement C. Deep vein thrombosis (DVT) D. Pulmonary embolism (PE) Assessment Question #2 Which of the following would you need in order to determine the appropriateness of an apixaban (Eliquis) prescription/order for a patient with Atrial Fibrillation? A. Age B. Weight C. SCr D. Concurrent medications E. All of the above Assessment Question #3 When transitioning a patient from warfarin to edoxaban (Savaysa), what should the patient s INR be before initiating edoxaban? A. <1 B. <2 C. <2.5 D. <3 16

Assessment Question #4 How long should rivaroxaban be held prior to a surgical procedure? A. It doesn t have to be held B. At least 24 hours C. 5 7 days D. It will depend on the patients renal function Assessment Question #5 True or False. Incorrect dosing was the most common error found in each of the three research studies discussed. References Go AS, Hylek EM, Phillips KA, et al. Prevalence of diagnoses atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. JAMA 2001;285:2370 5. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham study. Stoke 1991;22:983 8. Hart RG, Pearce LA, Aguilar MI. Meta analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med 2007;146:857 67. Naess JA, Christiansen SC, Romundstad P, et al. Incidence and mortality of venous thrombosis: a population based study. J Thromb Haemost 2007;5:692 9. Van der Meer FJ, Rosendaal FR, Vandenbroucke JP, et al. Bleeding complications in oral anticoagulant therapy. An analysis of risk factors. Arch Intern Med 1993;153:1557 62. Harper P, Young L, Merriman E. Bleeding risk with dabigatran in the frail elderly. N Engl J Med 2012;366:864 6. Barco S, Cheung Y, Eikelboom JW, Coppens M. New oral anticoagulants in elderly patients. 2013;26:215 24. Dabigatran (Pradaxa) Prescribing Information. Boehringer Ingelheim Pharmaceeuticals, Inc. Ridgefield, CT. January 2015. Accessed July 5, 2015. Rivaroxaban (Xarelto) Prescribing Information. Janssen Pharmaceuticals, Inc. Titusville, NJ. January 2015. Accessed July 5, 2015. Apixaban (Eliquis) Prescribing Information. Bristol Myers Squibb Company. Princeton, NJ. June 2015. Accessed July 5, 2015. Edoxaban (Savaysa) Prescribing Information. Daiichi Sankyo, Inc. Parsippany, NJ. January 2015. Accessed July 5, 2015. 17