Pharmacist s Guide to Clinical Decision Making in Anticoagulant Therapy for Stroke Prevention in Atrial Fibrillation

Transcription

1 Pharmacist s Guide to Clinical Decision Making in Anticoagulant Therapy for Stroke Prevention in Atrial Fibrillation Jointly provided by Purdue University College of Pharmacy, the Academy for Continued Healthcare Learning (ACHL) Funds for this webcast have been provided by educational grants from Boehringer Ingelheim Pharmaceuticals, Inc. and Daiichi Sankyo, Inc.

2 Faculty Edith Nutescu, PharmD, MS, FCCP Clinical Professor Department of Pharmacy Practice Department of Pharmacy Systems Outcomes and Policy Co-Director, Center for Pharmacoepidemiology & Pharmacoeconomic Research University of Illinois at Chicago College of Pharmacy

3 Faculty Disclosures Grants/Research Support: Janssen Pharmaceuticals, Inc. Consultant/Speaker Bureau: Abbott Laboratories; Janssen Pharmaceuticals, Inc.; The Medicines Company Discussion of Off-Label, Investigational, or Experimental Drug/Device Use: Edoxaban

4 Learning Objectives Upon completion of this activity, participants will be able to: Recognize the risks of stroke and anticoagulation therapy in patients with atrial fibrillation according to patient characteristics, medical history, and additional patientspecific factors Discuss efficacy and safety data from clinical trials investigating the use of novel oral anticoagulants Select appropriate anticoagulation therapy in diverse atrial fibrillation patients, including those with comorbidities and concomitant medications Identify patient compliance issues that can inhibit anticoagulation therapy and appropriate long-term management

5 Prevalence and Burden of Atrial Fibrillation (AF) Prevalence of AF per 1000 Person-Years Prevalence of AF Among Medicare Beneficiaries, Mean annual increase of 5%; P< Global Burden of Disease 2010 Study 2 Data from population-based studies of AF Burden associated with AF (disabilityadjusted life-years) increased by approximately 19% from 1990 to 2010 Mortality associated with AF increased approximately 2-fold from 1990 to Piccini JP et al. Circ Cardiovasc Qual Outcomes. 2012;5:85-93; 2. Chugh SS et al. Circulation. 2014;129(8):

6 Atrial Fibrillation Stroke Risk AF is an independent risk factor for stroke Approximately 15% of all strokes in the U.S. are caused by AF Leading cause of adult disability Costs the US >$50 billion/year Average rate of stroke for AF patients not on antithrombotic therapy is 5% Stroke rates increase with presence of other risk factors Purpose of risk-scoring systems You JY. Chest. 2012;141(Suppl):e531S-e575S; Heart Disease and Stroke Statistics Update. Circulation. 2014;129(3):e28- e292.

7 Optimizing Benefit While Minimizing Risk Bleeding Risk assessment for bleeding Identification of red flags and control of modifiable risk factors Appropriate anticoagulant selection Dosage adjustment Monitoring/adherence Thrombosis Risk assessment for stroke Control modifiable risk factors Evidence-based anticoagulant regimen Monitoring/adherence An ideal anticoagulant will provide the greatest reduction in thromboembolism with the lowest incidence of bleeding 1. Camm JA et al. Eur Heart J. 2012;33: ; 2. Ansell J et al. Chest. 2001;119:22S-38S; 3. Fuster V et al. J Am Coll Cardiol. 2001;38:

8 Patient Case 69 year old African American woman HTN (uncontrolled 165/95), DM, CRI (CrCL 35mL/min) and HLD Presents to ER with dizziness and palpitations EKG: Atrial fibrillation, rate of 110bpm Exam: normal, Labs: WNL, Cr 1.5, Wt = 58Kg Meds: Lisinopril, simvastatin, glipizide SH: ETOH (+), 2-3 drinks/day Patient started on oral diltiazem XR 120mg daily

9 Patient Case (cont) This patient s risk of a cardioembolic stroke is: A. Low B. Moderate C. High D. Super-High/Ticking-Time-Bomb

10 Balancing Stroke and Bleeding Risk: Tools for Assessing Stroke Risk CHADS 2 Score 1 CHA 2 DS 2 -VASc Score 2 Risk Factor Congestive heart failure Score Hypertension 1 Age 75 y 1 Diabetes 1 Stroke or TIA history 2 1 MAXIMUM 6 LV, left ventricle; TE, thromboembolism; TIA, transient ischemic attack 1. Gage BF et al. JAMA. 2001;285: Lip GY et al. Chest. 2010;137: Risk Factor Congestive heart failure/lv dysfunction Score Hypertension 1 Age 75 y 2 Diabetes 1 Stroke/TIA/TE history 2 Vascular disease 1 Age years 1 Sex category, female 1 1 MAXIMUM 9

11 Patient Case The CHADS 2 Score of this patient is: A. 0 B. 1 C. 2 D. 3

12 Adjusted Risk for Stroke for CHADS 2 and CHA 2 DS 2 -VASc Scores Score CHADS 2 (%/y) CHA 2 DS 2 -VASc (%/y) Gage BF et al. JAMA. 2001;285: Lip GY et al. Chest. 2010;137:

13 Stroke Prevention in AF: Assessing Stroke Risk CHADS CHADS-Vasc Risk Score Gage BF et al. JAMA. 2001;285: ; Lip GY et al. Chest. 2010;137:

14 Stroke Prevention in AF Balancing Stroke & Bleeding Risk HEMORR 2 HAGES Score HAS-BLED Score Risk Factor Hepatic or renal disease Score 1 ea Ethanol use 1 Malignancy 1 Older age: > 75 years 1 Reduced platelet count or Fxn 1 ea Re-bleeding 2 Hypertension, uncontrolled 1 Anemia 1 Genetic factors 1 Elevated fall risk ± neuropsychiatric disease Stroke 1 1 Risk Factor Score Hypertension, SBP > 160mmHg 1 Abnormal renal or liver function 1 ea Stroke 2 Bleeding history or predisposition 1 Labile INRs 2 Elderly: age > 65 years 1 Drugs or alcohol Antiplatelet or NSAID Alcohol use: > 8 servings/week 1 1 Gage BF et al. Am Heart J. 2006;151: Pisters R et al. Chest. 2010;138:

15 Stroke Prevention in Atrial Fibrillation Balancing Stroke & Bleeding Risk HEMORRHAGES HAS-BLED Risk Score Gage BF et al. Am Heart J. 2006;151:713-9; Pisters R et al. Chest. 2010;138:

16 Patient Case The following is the preferred therapy option for stroke prevention in this patient: A. Aspirin B. Warfarin C. Dabigatran D. Rivaroxaban E. Apixaban

17 2014 AHA/ACC/HRS AF Guidelines CHA 2 DS 2 -VASc Score Recommended SPAF strategy 2 Warfarin (INR 2-3), apixaban, dabigatran, rivaroxaban 1 Warfarin (INR 2-3), apixaban, dabigatran, rivaroxaban OR Aspirin OR No antithrombotic therapy 0 No antithrombotic strategy January CT et al. Circulation Apr 10. [Epub ahead of print]

18 2014 AHA/ACC/HRS AF Guidelines (continued) Special Patient Population Recommended SPAF Strategy CKD: CrCl < 15 ml/min or hemodialysis and CHA 2 DS 2 -VASc Score 2 CKD: moderate to severe (not defined) and CHA 2 DS 2 -VASc Score 2 ACS and CHA 2 DS 2 -VASc Score 2 ACS and CHA 2 DS 2 -VASc Score 0 or 1 PCI and CHA 2 DS 2 -VASc Score 2 Unable to maintain a therapeutic INR with warfarin Warfarin (INR ) Warfarin or reduced doses of TSOAs but safety and efficacy not established Warfarin Consider dual antiplatelet therapy only; reconsider need for OAC at a later time Use of clopidogrel 75 mg daily concurrently with oral anticoagulation, without aspirin may be reasonable; exact timing not specified TSOA CKD, chronic kidney disease; ACS, acute coronary syndrome; TSOA, target-specific oral anticoagulant; OAC, oral anticoagulant; PCI, percutaneous coronary intervention January CT et al. Circulation Apr 10. [Epub ahead of print]

19 Stroke Prevention in AF European Society of Cardiology (ESC) 2012 Guidelines Atrial Fibrillation Valvular AF Yes Yes <65 Years and Lone AF (including females) Assess Risk of Stroke (CHA 2 DS 2 -VASc Score) No (ie, nonvalvular AF) No Oral Anticoagulant Therapy Assess Bleeding Risk (HAS-BLED Score) Consider patient values and preferences Adapted from: Camm JA. Europace. 2010;12: No Antithrombotic Therapy NOAC VKA

20 Structured Follow-Up of Patients on NOACs Initiator of anticoagulant treatment: Sets indication for anticoagulation Makes choice of anticoagulant Decides on need of proton pump inhibitor Baseline hemoglobin, renal and liver function Provides education Hangs out anticoagulation card Organizes follow-up (when, by whom, what?) Remains responsible coordinator for follow-up First FU: 1 month Follow-up: GP; anticoagulant clinic; initiator of therapy; 1 m? 3 m 6 m Checks: 1. Compliance 2. Thrombo-embolic events 3. Bleeding events 4. Other side effects 5. Co-medications and over-the-counter drugs 6. Need for blood sampling? In case of problems: contacts initiator of treatment Heidbuchel H et.al. Europace. 2013;15: Else: Fills out anticoagulant card and sets date/place for next follow-up

21 Checklist During Follow-Up of Patients on NOACs Interval Comments Compliance Each visit Instruct patients to bring remaining medication: note and calculate average adherence Re-educate on importance of strict intake schedule Inform about compliance aids (special boxes, smartphone applications ) Thrombo-embolism Each visit Systemic circulation (TIA, stroke, peripheral) Pulmonary circulation Bleeding Each visit Nuisance bleeding, preventive measures possible? (PPI, hemorrhoidectomy ) Other side effects Each visit Carefully assess relation with NOAC; decide for continuation (and motivate), temporary cessation (with bridging), or change of anticoagulant drug Co-medications Each visit Prescription drugs; over-the-counter drugs Careful interval history; also temporary use can be risk! Blood sampling Yearly 6 monthly 3 monthly On indication TIA=transient ischemic attack; PPI=proton pump inhibitor; CrCl=creatinine clearance Heidbuchel H et.al. Europace. 2013;15: Hemoglobin, renal and liver function Renal function if CrCl ml/min, or if on dabigatran and >75 years or fragile If CrCl ml/min If intercurring condition that may impact renal or hepatic function

22 Anticoagulation in AF Stroke Risk Reduction With Warfarin Warfarin Better Control Better AFASAK SPAF BAATAF CAFA SPINAF EAFT Aggregate RRR 64% 100% 50% 0-50% -100% Hart RG et al. Ann Intern Med. 1999;131: In addition: Reduction of all-cause mortality RRR 26%

23 Using Warfarin Remains Challenging Patients (%) 100 Only 55% of nonvalvular AF patients without contraindications receive warfarin * % 58% 61% Age (y) 57% 35% < (n=1064) (n=1596) (n=3707) (n=3752) (n=963) 55% overall use 1 Mean TTR is low in patients receiving warfarin 2 (N=124,551) Rose et al Baker et al (N=22,237) Rose et al (N=3104) Sarawate et al (N=470) McCormick et al (N=174) % 58% 55% 51% 67% Mean TTR (%) Abbreviation: TTR = time in therapeutic range. *Data from automated pharmacy, laboratory, and clinical administrative databases for 13,428 patients with nonvalvular AF were used to determine the prevalence of warfarin use in the 3 months before or after the identified diagnosis of AF. 1. Go AS et al. Ann Intern Med. 1999;131(12): ; 2. Rose AJ et al. Circ Cardiovasc Qual Outcomes. 2011;4(1):22-29; 3. Baker WL et al. J Manag Care Pharm. 2009;15(3): ; 4. Rose AJ et al. J Thromb Haemost. 2008;6(10): ; 5. Sarawate C et al. J Thromb Thrombolysis. 2006;21(2): ; 6. McCormick D et al. Arch Intern Med. 2001;161(20):

24 NOAC: AF Clinical Trial Overview RE-LY 1 ROCKET-AF 2 ARISTOTLE 3 ENGAGE AF-TIMI 48 4 Drug, dose Dabigatran 110 or 150 mg BID Rivaroxaban Apixaban Edoxaban 20 mg daily 5 mg BID 30 or 60 mg/d Adjusted dose? No Yes: 15 mg daily if CrCl ml/m Yes: 2.5mg BID if 2 of: age 80 y, weight 60 kg, Cr 1.5 mg/dl Yes: Both doses halved if: CrCl ml/min, weight 60 kg, use of verapamil, quinidine, or dronedarone Design Randomized open-label (N=18,113) Randomized double blind, double dummy (N=14,264) Randomized double blind, double dummy (N=18,201) Randomized doubleblind, double-dummy Mean age, y Prior stroke/tia 20% 55% 19% 28.5% Mean CHADS Warfarin-naïve 50.4% 37.7% 43% 41% Comparator Warfarin: INR % TTR Warfarin: INR % TTR Warfarin: INR % TTR Warfarin: INR % TTR Cr, serum creatinine; CrCl, creatinine clearance; INR, International Normalized Ratio; TTR, mean time in therapeutic range. 1. Connolly SJ et al. N Engl J Med. 2009;361(12): ; 2. Patel MR et al. N Engl J Med 2011; 365: ; 3. Granger CB et al. N Engl J Med. 2011;365(11): ; 4. Giugliano RP et al. N Engl J Med. 2013; 369:

25 HR=hazard ratio 1. Connolly SJ et al. N Engl J Med. 2009;363: Patel MR et al. N Engl J Med. 2011;365: Granger CB et al. N Engl J Med. 2011;365: Giugliano RP et al. N Engl J Med. 2013;369: NOAC vs Warfarin: Stroke All Stroke or SE Dabigatran 150 mg BID 1 HR=0.65 Rivaroxaban 20 mg daily 2 HR=0.88 Apixaban 5 mg BID 3 HR=0.79 Edoxaban 60 mg daily 4 HR=0.79 Edoxaban 30 mg daily 4 HR= Favors Comparator Favors Warfarin Ischemic Stroke HR=0.76 Dabigatran 150 mg BID 1 Rivaroxaban 20 mg daily 2 HR=0.94 Apixaban 5 mg BID 3 HR=0.92 Edoxaban 60 mg daily 4 HR=1.00 Edoxaban 30 mg daily 4 HR= Favors Comparator Favors Warfarin Hemorrhagic Stroke HR=0.26 Dabigatran 150 mg BID 1 HR=0.59 Rivaroxaban 20 mg daily 2 Apixaban 5 mg BID 3 HR=0.51 HR=0.54 Edoxaban 60 mg daily 4 HR=0.33 Edoxaban 30 mg daily Favors Comparator Favors Warfarin

26 NOAC vs Warfarin: Bleeding Major Bleeding HR=0.93 Dabigatran 150 mg BID 1 HR=1.04 Rivaroxaban 20 mg daily 2 HR=0.69 Apixaban 5 mg BID 3 HR=0.80 Edoxaban 60 mg daily 4 HR=0.47 Edoxaban 30 mg daily 4 Intracranial Hemorrhage HR=0.40 Dabigatran 150 mg BID 1 HR=0.67 Rivaroxaban 20 mg daily 2 HR=0.42 Apixaban 5 mg BID 3 HR=0.47 Edoxaban 60 mg daily 4 HR=0.30 Edoxaban 30 mg daily HR (95% CI) Comparator Better Warfarin Better HR (95% CI) Comparator Better Warfarin Better GI Bleeding Dabigatran 150 mg BID 1 Rivaroxaban 20 mg daily 2 Apixaban 5 mg BID 3 Edoxaban 60 mg daily 4 Edoxaban 30 mg daily 4 HR=0.89 HR=0.67 HR=1.50 HR=1.39 HR= HR (95% CI) HR=hazard ratio Comparator Better Warfarin Better 1. Connolly SJ et al. N Engl J Med. 2009;361(12): ; 2. Patel MR et al. N Engl J Med. 2011; 365: ; 3. Granger CB et al. N Engl J Med. 2011;365(11): ; 4. Giugliano RP et al. N Engl J Med. 2013; 369:

27 NOAC vs Warfarin: Mortality CV Mortality Dabigatran 150 mg BID 1 Rivaroxaban 20 mg daily 2 Apixaban 5 mg BID 3 Edoxaban 60 mg daily 4 Edoxaban 30 mg daily 4 HR=0.85 HR=0.89 HR=0.89 HR=0.86 HR=0.85 All-cause Mortality Dabigatran 150 mg BID 1 Rivaroxaban 20 mg daily 2 Apixaban 5 mg BID 3 Edoxaban 60 mg daily 4 Edoxaban 30 mg daily 4 HR=0.88 HR=0.85 HR=0.89 HR=0.92 HR= HR (95% CI) Comparator Better Warfarin Better HR (95% CI) Comparator Better Warfarin Better HR=hazard ratio 1. Connolly SJ et al. N Engl J Med. 2009;361(12): ; 2. Patel MR et al. N Engl J Med. 2011; 365: ; 3. Granger CB et al. N Engl J Med. 2011;365(11): ; 4. Giugliano RP et al. N Engl J Med. 2013; 369:

28 Key Takeaway Points Randomized Trials of NOACs vs Warfarin NOACs are at least as effective/safe as warfarin Similarities 1-4 : All noninferior to warfarin for prevention of total stroke and systemic embolism All reduce the risk of intracerebral hemorrhage All reduce mortality by ~10% per year Differences: Apixaban (5 mg twice daily) 1 Reduced major bleeding and all-cause mortality, but not cardiovascular mortality No difference in gastrointestinal bleeding Dabigatran (150 mg twice daily) 2 Reduced ischemic stroke more than warfarin Caused more extracranial / GI bleeding, especially in the elderly Rivaroxaban (20 mg once daily) 3 Reduced fatal bleeding Caused more extracranial / GI bleeding Edoxaban (60 mg or 30 mg once daily) 5 Reduced major bleeding Reduced hemorrhagic strokes and cardiovascular mortality compared with warfarin 1. Granger CB et al. N Engl J Med. 2011;365: ; 2. Connolly SJ et al. N Engl J Med. 2009;361: ; 3. Patel MR et al. N Engl J Med. 2011;365: ; 4. Alexander J et al. N Engl J Med. 2011;365: ; 5. Giugliano RP et al. N Engl J Med. 2013; 369:

29 Overview and Pharmacology of NOACs Drug class Apixaban 1-4 Dabigatran 1,5 Rivaroxaban 1,6 Edoxaban 7-11 Direct factor Xa inhibitor Direct factor IIa inhibitor Bioavailability 50% 3%-7% Direct factor Xa inhibitor 80%-100% for 10-mg dose 66% for 20-mg dose Direct factor Xa inhibitor 50-60% Tmax 3-4 hours 1-2 hours 2-4 hours 1-2 hours Onset of anticoagulant effect Within 3 hours Within 2 hours Within 4 hours Within 1-2 hours CYP metabolism 25% CYP3A4 No 30% CYP3A4, CYP2J2 62% fecal elimination Renal excretion 27% 80% 36% 35% of total dose, 49% of absorbed dose Half-life 12 hours hours 5-9 hours 9-11 h Dosage form Tablet Capsule Tablet Tablet Dosing frequency BID BID Once daily Once daily CYP=cytochrome P450; Tmax=time to maximum concentration 1. Wittkowsky AK. Pharmacotherapy. 2011;31: ; 2. Zhang D, et al. Drug Metab and Disp. 2009;37: ; 3. Eliquis (apixaban). Available at: 4. Eliquis (apixaban) [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Company; December 2012; 5. Pradaxa (dabigatran etexilate mesylate) [prescribing information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals Inc.; November 2012; 6. Xarelto (rivaroxaban) [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc.; November 2012; 7. Camm AJ et al. Drugs. 2011;71: ; 8. Ogata K et al. J Clin Pharmacol. 2010;50: ; 9. Eikelboom JW et al. Circulation. 2010;121: ; 10. Bathala M et al. Drug Metab Dispos. 2012;40: ; 11. Matsushima N et al. Clin Pharmacol Drug Dev. 2013;2:

30 Dosing of NOACs Depends on Renal Function Drug a Dose Apixaban 1 5 mg PO BID Dose adjusted to 2.5 mg PO BID for patients with any 2 of the following characteristics: 80 years of age, weight 60 kg, or SCr 1.5 mg/dl CrCl <15 ml/min: no data Dabigatran 2 CrCl >30 ml/min: 150 mg PO BID CrCl ml/min: 75 mg PO BID b CrCl <15 ml/min or on dialysis: not recommended Rivaroxaban 3 CrCl >50 ml/min: 20 mg PO once daily CrCl ml/min: 15 mg PO once daily CrCl <15 ml/min: not recommended Both doses (30 mg and 60 mg) halved if CrCl ml/min, low body weight Edoxaban 4 60 kg or taking concomitant verapamil, quinidine or dronedarone Patients with CrCL <30 ml/min were excluded from ENGAGE-AF TIMI 48 a For dabigatran, rivaroxaban, and edoxaban, patients with CrCl <30 ml/min were excluded from clinical trials; for apixaban, patients with CrCl <25 ml/min were excluded b The 75-mg dose of dabigatran was not evaluated in clinical trials, but is an FDA-approved dose 1. Eliquis (apixaban) [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Company; March 2014; 2. Pradaxa (dabigatran etexilate mesylate) [prescribing information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals Inc.; April 2014; 3. Xarelto (rivaroxaban) [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc.; March 2014; 4. Giugliano RP et al. N Engl J Med. 2013; 369:

31 Dosing of NOACs Formulation Issues, Food Effects Apixaban 1 Dabigatran 2 Rivaroxaban 3,4 Edoxaban Formulation Tablets may be crushed, mixed with D5W, and delivered through a nasogastric tube Capsules cannot be: crushed (no feeding tube), broken before administration, or chewed Expires 4 mo after bottle is opened May be crushed and mixed with applesauce in a feeding tube (G-tube) N/A Food Effects 5 Bioavailability not affected by food May be taken with or without food 10-mg tablet: may be taken with/without food 15-mg and 20-mg tablets: should take with largest meal of the day Can be administered without regard to food 6 1. Eliquis (apixaban) [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Company; March Pradaxa (dabigatran etexilate mesylate) [prescribing information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals Inc.; April Xarelto (rivaroxaban) [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc.; March Moore KT, et al. Pharmacotherapy. 2012;32:e Kubitza D, et al. J Clin Pharmacol. 2006;46: ; 6. Mendell J et al. J Clin Pharmacol. 2011;51(5):

32 NOACs: A New Drug Interaction Mindset Warfarin Drug interactions can be managed through increased monitoring and dose adjustment Interacting drugs are not contraindicated NOACs Drug interactions are contraindications or precautions No ability to monitor and adjust dose based on response

33 NOACs Metabolic Fate Cytochrome P450 enzymes CYP3A4, CYP3A5 Rivaroxaban Apixaban CYP2J2 Rivaroxaban P-Glycoprotein Substrate Dabigatran Rivaroxaban Apixaban * Dabigatran metabolized by esterases to active form

34 NOACs: Drug Interactions CYP3A4 P-Glycoprotein Inducer Inhibitor Inducer Inhibitor Carbamazepine Amiodarone Itraconazole Efavirenz Aprepitant Ketoconazole Glucocorticoids Cimetidine Nefazodone Nevirapine Clarithromycin Protease inhibitors Phenobarbital Cyclosporine Verapamil Midazolam Amiodarone Dronaderone Nifedipine Nifedipine Ceftriaxone Propranolol Phenobarbital Clarithromycin Quinidine Phenytoin Cyclosporine Tacrolimus Rifampin Diltiazem Verapamil Phenytoin Diltiazem Voriconazole St. John s wort Dipyridamole Primidone Rifampin Rifapentine St. John s wort Erythromycin Fluconazole Fluoxetine Fluvoxamine Erythromycin Hydrocortisone Itraconazole Ketoconazole

35 Drug Interactions & Product Labeling Dabigatran P-glycoprotein inducers (e.g. Rifampin) - AVOID P-glycoprotein inhibitors Ketoconazole or dronedarone & CrCl ml/min: dose to 75 mg BID AVOID if CrCl < 30 ml/min Rivaroxaban Combined strong CYP3A4 & p-glycoprotein inducers - AVOID rifampin, carbamazepine, phenytoin, St John s wort Combined CYP3A4 & p-glycoprotein inhibitors Strong: Avoid (ketoconazole, itraconazole, lopinavir/ritonavir, indinavir/ritonavir, conivaptan) Weak-moderate and Renal Insufficiency: use only if benefit outweighs risks Apixaban Combined strong dual CYP3A4 & p-glycoprotein inducers AVOID rifampin, carbamazepine, phenytoin, St John s wort Combined strong dual CYP3A4 & p-glycoprotein inhibitors ketoconazole, itraconazole, ritonavir, clarithromycin Decrease dose to 2.5mg bid; in patients already on 2.5 mg bid AVOID ALL: Coadministration of antiplatelet agents, fibrinolytics, heparin, aspirin, and chronic nonsteroidal antiinflammatory drugs increases the risk of bleeding

36 Periprocedural Management of NOACs Timing of Interruption of NOACs Before Surgery or Invasive Procedures Calculated CrCl, ml/min Dabigatran Half-life, h Timing of Last Dose Before Surgery Standard Risk of Bleeding a High Risk of Bleeding b > h 2 d h 2 d > d 4 d d 6 d Apixaban/Rivaroxaban Apix Riva > h 2 d d 3-4 d > d 3-4 d d 4d Edoxaban >80 (other data not available) 9-11 a Examples: cardiac catheterization, ablation therapy, colonoscopy without removal of large polyps, uncomplicated laparoscopic procedures b Examples: major cardiac/cancer/urologic/vascular surgery, insertion of pacemakers/defibrillators, neurosurgery, large hernia surgery N/A N/A

37 Recommended Strategy for Conversion: NOACs to/from Warfarin Suggested Strategy for Conversion from NOACs to Warfarin Calculated CrCl (ml/min) Apixaban Dabigatran: Start Day with Warfarin a Rivaroxaban: Start Day with Warfarin a,b >50 If continuous anticoagulation is necessary, Day -3 Day discontinue apixaban and begin both a parenteral anticoagulant and warfarin at the Day -2 Day time the next dose of apixaban would have been taken, discontinuing the parenteral anticoagulant when INR reaches an acceptable range. Day -1 Day -2 Suggested Strategy for Conversion from Warfarin to NOACs Apixaban Dabigatran Rivaroxaban Start when INR is <2 Start when INR is <2 Do not use point-of-care monitors to assess INR during transitions Start when INR is <3 a Dabigatran/Rivaroxaban is stopped on day 0; the longer overlap with rivaroxaban is justified by the half-life being shorter than that of dabigatran and by the concern about thromboembolic events shortly after transitioning from rivaroxaban to warfarin b Strategy recommended in rivaroxaban product labeling is to transition to an injectable anticoagulant

38 Reversal Considerations of New Agents Supportive care Discontinuation of drug Likely sufficient for many patients Dabigatran Rivaroxaban Apixaban Oral activated charcoal Yes Yes Yes Hemodialysis Yes No No Hemoperfusion with activated charcoal Yes Possible Possible FFP No No No Activated factor VIIa Unclear Unclear Unclear 3-factor PCC Unclear Unclear Unclear 4-factor PCC Possible Possible Possible Kaatz S. Am J Hematol. 2012;87:s

39 Management of Bleeding in Patients Taking NOACs Bleeding While Using a NOAC Mild Bleeding Moderate Severe Bleeding Life-threatening Bleeding Delay or discontinue next dose Reconsider concomitant medication + + Supportive measures: Mechanical suppression Surgical hemostasis Fluid replacement (colloids if needed) RBC substitution if needed Fresh frozen plasma (as plasma expander) Platelet substitution (if platelet count 60X109/L Consider: PCC (eg., CoFact ) 25 U/kg; repeat 1x/2x if indicated apcc (Feiba ) 50 IE/kg; max 200 IE/kg/day rfviia (NovoSeven ) 90 μg/kg: no data about additional benefit For dabigatran: Maintain adequate diuresis Consider hemodialysis Charcoal hemoperfusion? (await more data) Adapted from: Heidbuchel H et.al. Europace. 2013;15:

40 NOACs: Clinical Implications 1. Careful patient selection based on risk assessment 2. Consider patient-related and OAC-related factors and provider knowledge Comorbidities (eg, renal dysfunction) Extreme weights Adherence issues PK/PD, dosing, drug interactions Bleeding/Reversibility Periprocedure management 3. Choose the best agent for the patient, and provide: Patient education Ongoing risk assessment and support Communication Efficacy and safety in practice will not mimic clinicaltrial results without careful thought.

41 Summary Most important focus: Ensuring that all eligible AF patients receive an OAC Thrombosis vs bleeding risk In patients with AF, apixaban, dabigatran, and rivaroxaban are now options Selection between agents will be complex Warfarin remains the most appropriate choice for some patients!