Updates in Anticoagulation Therapy for Stroke Prevention in Atrial Fibrillation

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1 Updates in Anticoagulation Therapy for Stroke Prevention in Atrial Fibrillation Edith Nutescu, Pharm.D., FCCP Clinical Professor Department of Pharmacy Practice Co-Director, Center for Pharmacoepidemiology & Pharmacoeconomic Research University of Illinois at Chicago College of Pharmacy

2 Learning Objectives Recognize the risks of stroke and anticoagulation when not managed appropriately in patients with atrial fibrillation (AF) Formulate appropriate care plans for anticoagulation therapy in patients with AF based on clinical trial data, practice guidelines, and quality measures Define strategies to improve communication among healthcare professionals, patients, and caregivers regarding long-term anticoagulation therapy

3 Prevalence of AF per 1000 Person-Years Atrial Fibrillation (AF) 1 : An Opportunity for Stroke Prevention Prevalence of AF Among Medicare Beneficiaries, Mean annual increase of 5%; P<0.001 AF affects ~2.7 million people in the US 2 Estimated 12 million by 2050 AF increases both mortality and stroke risk 2,3 1. Piccini JP, et al. Circ Cardiovasc Qual Outcomes. 2012;5: CDC. Atrial Fibrillation Fact Sheet. Accessed 11/11/ Cannon CP. Am J Manag Care. 2010;16(10 suppl):s

4 Cumulative mortality over 3 years (%) Atrial Fibrillation is Associated with Increased Mortality 80 With atrial fibrillation (n=13,558) * Without atrial fibrillation (n=13,195) * * * * 65 to 74 years of age 75 to 84 years of age 85 to 89 years of age * Significantly different from patients with atrial fibrillation (p < 0.05). Wolf PA et al. Arch Intern Med 1998;158:231.

5 Atrial Fibrillation (AF) 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(2)(Suppl):e531S e575s. Heart Disease and Stroke Statistics Update. Circulation. 2012;125:e2-e220.

6 Goal of Anticoagulation Therapy 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: Ansell J, et al. Chest. 2001;119:22S-38S. 3. Fuster V, et al. J Am Coll Cardiol. 2001;38:

7 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 Meds: Lisinopril, simvastatin, glipizide SH: ETOH (+), 2-3 drinks/day Patient started on oral diltiazem XR 120mg daily

8 Patient Case This patient s risk of a cardioembolic stroke is: a. Low b. Moderate c. High d. Super-High/Ticking-Time-Bomb

9 Risk Factors for Stroke in AF Patients: CHADS 2 Scoring System Specific factors have been found to increase the relative risk for stroke in patients with AF Clinical Features Relative Risk CHADS 2 Score A history of TIA or prior stroke is the strongest independent predictor of stroke in patients with AF C Congestive heart failure H History of hypertension A Advanced age (>=75) D Diabetes mellitus S Previous stroke or TIA Therefore, this risk factor is given 2 points when calculating CHADS 2 score Abbreviation: TIA = transient ischemic attack; CHADS 2 = Congestive heart failure, Hypertension, Age 75 years, Diabetes, and history of Stroke or TIA. Fuster V et al. J Am Coll Cardiol. 2011;57(11):e101-e198;

10 CHA 2 DS 2 -VASc Score for Estimating Stroke Risk in AF Score C: CHF/LV dysfunction 1 point 0 points: 0% H: HTN 1 point 1 point: 0.6% A: Age 75 years 2 points 2 points: 1.6% D: Diabetes 1 point 3 points: 3.9% S: Stroke/TIA 2 points 4 points: 1.9% V: Vascular disease 1 point 5 points: 3.2% A: Age years 1 point 6 points: 3.6% S: Sex (female) 1 point 7 points: 8.0% Prior MI, PAD, or aortic plaque Lip GYH et al. Chest 2010; 137: Lip GYH et al. Chest 2010; 137: TOTAL 8 points: 11.1% 9 points: 100% TE Rate at 1 Year LOW INTER HIGH

11 Stroke Prevention in Atrial Fibrillation Assessing Stroke Risk Risk Score Gage BF, et al. JAMA 2001;285: Lip GY, et al. Chest 2010;137:

12 Patient Case The CHADS 2 Score of this patient is: a. 0 b. 1 c. 2 d. 3

13 Stroke Prevention in Atrial Fibrillation Assessing Stroke Risk Risk Factor CHADS 2 Score Score Congestive Heart Failure 1 Hypertension 1 Age 75 years 1 Diabetes 1 Stroke or TIA history 2 MAXIMUM 6 Gage BF, et al. JAMA 2001;285: Lip GY, et al. Chest 2010;137: CHA 2 DS 2 -Vasc Score Risk Factor Congestive Heart Failure / LV dysfunction Score Hypertension 1 Age 75 years 2 Diabetes 1 Stroke/TIA/TE history 2 Vascular disease 1 Age years 1 Sex category, female 1 MAXIMUM 9 1

14 Stroke Prevention in Atrial Fibrillation Balancing Stroke & Bleeding Risk HEMORR 2 HAGES 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 HAS-BLED Score 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 Gage BF, et al. Am Heart J 2006;151: Pisters R, et al. Chest 2010;138:

15 Stroke Prevention in AF Balancing Stroke and Bleeding Risk HEMORR2HAGES HAS-BLED Risk Score Gage BF, et al. Am Heart J 2006;151: Pisters R, et al. Chest 2010;138:

16 Assessing Risk vs Benefit Bleeding Thrombosis

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

18 Stroke Prevention in Atrial Fibrillation US Guideline Recommendations CHADS 2 score Chest (Grade of rec) ACCF/AHA/HRS (Class of rec) 0 No therapy (2B)/ AP Aspirin (I) / No Tx 1 OAC (1B) Dabi > warfarin* 2 OAC (1A) Dabi > warfarin* OAC or aspirin (IIa) Dabi alt to warfarin OAC (I) Dabi alt to warfarin * Except in patients with CrCl < 30 ml/min, mitral stenosis, stable CAD, recent ACS, or s/p intracoronary stent Except in patients with prosthetic heart valves, hemodynamically signficant valvular heart disease, CrCl < 15 ml/min, or advanced liver disease Rivaroxaban & Apixaban not approved at time of guideline publication; not included You JJ, et al. Chest 2012 Feb;141(2 Suppl):e531S-75S. Fuster V, et al. Circulation 2011;123:e Wann LS, et al. Circulation 2011;123:

19 Stroke Prevention in AF European Society of Cardiology (ESC) 2012 Guidelines Camm JA. European Heart Journal. 2012;

20 Anticoagulation in AF Stroke Risk Reductions Warfarin Better Control Better AFASAK SPAF BAATAF CAFA SPINAF EAFT Aggregate RRR 64% 100% 50% 0-50% -100% Hart et al. Ann Intern Med. 1999;131: In addition: Reduction of All-Cause Mortality RRR 26%

21 Antithrombotic Therapy for Atrial Fibrillation - Stroke Risk Reduction Treatment Better Treatment Worse Warfarin vs. Placebo/Control 6 Trials n = 2,900 Antiplatelet drugs vs. Placebo 8 Trials n = 4, % 50% 0-50% Hart R, et al. Ann Intern Med 2007;146:857.

22 Patients (%) Using Warfarin Remains Challenging Only 55% of nonvalvular AF patients without contraindications receive warfarin *1 Mean TTR is low in patients receiving warfarin Rose et al (N=124,551) 2 58% 55% overall use 1 Baker et al (N=22,237) Rose et al (N=3104) % 67% Sarawate et al (N=470) 5 29% (n=1064) (n=1596) (n=3707) (n=3752) (n=963) Age (y) Go AS et al. Ann Intern Med. 1999;131(12): Used with permission from the American College of Physicians. McCormick et al (N=174) 6 51% 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): Rose AJ et al. Circ Cardiovasc Qual Outcomes. 2011;4(1): Baker WL et al. J Manag Care Pharm. 2009;15(3): Rose AJ et al. J Thromb Haemost. 2008;6(10): Sarawate C et al. J Thromb Thrombolysis. 2006;21(2): McCormick D et al. Arch Intern Med. 2001;161(20):

23 Odds Ratio Thrombembolic events vs. intracranial haemorrhage in atrial fibrillation: role of target INR ATRIA Study 10,19 11, Thrombembolic events Intracranial haemorrhage Target INR 2.0 bis 3.0 2, < >3.6 Singer DE et al. Circ CV Qual and Outcomes 2009;2: International Normalized Ratio (INR)

24 Warfarin Key Variables for Dosing Metabolism CYP system Drug interactions Initiation Loading vs predicted maintenance dose Variable response Half-life Food Age Concomitant disease states ETOH Ethnicity hours Peak effect single dose Steady state 2 weeks Ethnicity and average daily dose 6.1 mg: African-Americans 5.1 mg: Caucasians 3.4 mg: Asians Johnson JA. Circulation 2008;118:

25 New Oral Anticoagulants (NOAC): AF Clinical Trial Overview RE-LY 1 ROCKET-AF 2 ARISTOTLE 3 Drug, dose Adjusted dose? Dabigatran 110 or 150 mg BID No Rivaroxaban 20 mg QD Apixaban 5 mg BID Yes: 15 mg QD if CrCl ml/m Yes: 2.5mg BID if 2 of: age 80 y, weight 60 kg, Cr 1.5 mg/dl Design Randomized open-label (N=18,113) Randomized double blind, double dummy (N=14,264) Randomized double blind, double dummy (N=18,201) Mean age,y Prior stroke/tia 20% 55% 19% Mean CHADS Warfarin-naïve 50.4% 37.7% 43% Comparator Warfarin: INR % TTR Warfarin: INR % TTR Warfarin: INR % TTR Cr, serum creatinine; CrCl, creatinine clearance; INR, International Normalized Ratio; TIA, transient ischemic attack. 1. Connolly SJ et al. N Engl J Med. 2009;361(12): Patel MR et al. N Engl J Med 2011; 365: Granger CB et al. N Engl J Med. 2011;365(11):

26 NOAC vs Warfarin: Stroke 1. Connolly SJ et al. N Engl J Med. 2009;361(12): Patel MR et al. N Engl J Med 2011; 365: Granger CB et al. N Engl J Med. 2011;365(11):

27 NOAC vs Warfarin: Bleeding 1. Connolly SJ et al. N Engl J Med. 2009;361(12): Patel MR et al. N Engl J Med 2011; 365: Granger CB et al. N Engl J Med. 2011;365(11):

28 NOAC vs Warfarin: GI Bleeding 1. Connolly SJ et al. N Engl J Med. 2009;361(12): Patel MR et al. N Engl J Med 2011; 365: Granger CB et al. N Engl J Med. 2011;365(11):

29 NOAC vs Warfarin: Mortality 1. Connolly SJ et al. N Engl J Med. 2009;361(12): Patel MR et al. N Engl J Med 2011; 365: Granger CB et al. N Engl J Med. 2011;365(11):

30 Novel Oral Anticoagulants for SPAF: Myocardial Infarction RE-LY ROCKET - AF ARISTOTLE Dabigatran 150 mg BID: 0.74%/yr Rivaroxaban 20 mg QD: 1.02%/yr Apixaban 5mg BID: 0.53%/yr Warfarin: 0.53%/yr Warfarin: 1.11%/yr Warfarin: 0.61%/yr P = P = 0.46 P = 0.37 HR: 1.38 HR = 0.91 HR = 0.88 RE-LY: NEJM 2009;361: ROCKET-AF: NEJM 2011;365: ARISTOTLE: NEJM 2011;365:

31 Dabigatran Association With Higher Risk of Acute Coronary Events Arch Intern Med. 2012;172(5): doi: /archinternmed

32 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 (RR ; HR ,3 ) 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 1. Granger CB, et al. N Engl J Med. 2011;365: Connolly SJ, et al. N Engl J Med. 2009;361: Patel MR, et al. N Engl J Med. 2011;365: Alexander J, et al. N Engl J Med. 2011;365:

33 Overview and Pharmacology of NOACs Apixaban 1-4 Dabigatran 1,5 Rivaroxaban 1,6 Drug class 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 Tmax 3-4 hours 1-2 hours 2-4 hours Onset of anticoagulant effect Within 3 hours Within 2 hours Within 4 hours CYP metabolism 25% CYP3A4 No 30% CYP3A4, CYP2J2 Renal excretion 27% 80% 36% Half-life 12 hours hours 5-9 hours Dosage form Tablet Capsule Tablet Dosing frequency BID BID Once daily CYP=cytochrome P450; Tmax=time to maximum concentration 1. Wittkowsky AK. Pharmacotherapy. 2011;31: Zhang D, et al. Drug Metab and Disp. 2009;37: Eliquis (apixaban). Available at: 4. Eliquis (apixaban) [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Company; December Pradaxa (dabigatran etexilate mesylate) [prescribing information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals Inc.; November Xarelto (rivaroxaban) [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc.; November 2012.

34 Dosing of NOACs Depends on Renal Function Drug a Apixaban 1 Dabigatran 2 Rivaroxaban 3 Dose 5 mg PO BID Dose adjusted to 2.5 mg PO BID for patients 80 years of age, weight 60 kg, or SCr 1.5 mg/dl CrCl <15 ml/min: no data CrCl >30 ml/min: 150 mg PO BID CrCl ml/min: 75 mg PO BID b CrCl <15 ml/min: not recommended CrCl >50 ml/min: 20 mg PO once daily CrCl ml/min: 15 mg PO once daily CrCl <15 ml/min: not recommended a For dabigatran and rivaroxaban, 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; December Pradaxa (dabigatran etexilate mesylate) [prescribing information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals Inc.; November Xarelto (rivaroxaban) [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc.; November 2012.

35 Dosing of NOACs: Formulation Issues, Food Effects Formulation Food Effects 5 Apixaban 1 Dabigatran 2 Rivaroxaban 3,4 No information Capsules cannot be: crushed (no feeding tube), broken before administration, or chewed Expires 4 mo after bottle is opened Bioavailability not affected by food May be taken with or without food May be crushed and mixed with applesauce in a feeding tube (Gtube) 10-mg tablet: may be taken with/without food 15-mg and 20-mg tablets: should take with largest meal of the day 1. Eliquis (apixaban) [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Company; 12/ Pradaxa (dabigatran etexilate mesylate) [prescribing information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals Inc.; 11/ Xarelto (rivaroxaban) [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc.; 11/ Moore KT, et al. Pharmacotherapy. 2012;32:e Kubitza D, et al. J Clin Pharmacol. 2006;46:

36 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

37 Novel Anticoagulants for SPAF Metabolic Fate & Clearance Cytochrome P450 enzymes CYP3A4, CYP3A5 Rivaroxaban Apixaban CYP2J2 Rivaroxaban P-Glycoprotein Substrate Dabigatran Rivaroxaban Apixaban * Dabigatran metabolized by esterases to active form

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

39 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 Drug Interactions & Product Labeling 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

40 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 time the next dose Day -2 Day 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 1; 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 4

41 Apixaban 2 24 h 48 h Periprocedural Management of NOACs Timing of Interruption of NOACs Before Surgery or Invasive Procedures Calculated CrCl, ml/min Dabigatran 1 Half-life, h Timing of Last Dose Before Surgery Standard Risk of Bleeding a High Risk of Bleeding b >80 13 (11-22) 24 h 2 d > (12-34) 24 h 2 d > (13-23) 2 d 4 d (22-35) 4 d 6 d Rivaroxaban 1 >30 12 (11-13) 24 h 2 d 30 NA 2 d 4 d 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 1. Schulman S, et al. Blood. 2012;119: Reproduced with permission of American Society of Hematology. 2. Eliquis (apixaban) [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Company; Dec

42 Hematology Testing: The New Oral Anticoagulants Usefulness of lab test Dabigatran Rivaroxaban Apixaban Lab tests Strong ECT Chromogenic anti-xa Chromogenic anti-xa TT aptt, PT aptt Weak PT/INR Adapted from Am J Hematol 2012; s127-s132.

43 Effects of Nonspecific Reversal Agents on Anticoagulant Activity in an Ex-Vivo Model Measured Effect on Thrombin Generation: AUC, Peak, Time to Peak, and Lag Time Nonspecific Reversal Agent rfviia: NovoSeven 0.5,1.5,3 ug/ml Conclusions: If immediate reversal is needed, currently no clear evidence for any reversal agent clinically Feiba effective for rivaroxaban ex-vivo, but higher doses are associated with more thrombin generation; clinically may cause more thrombosis Marlu R, et al. Thromb Haemost. 2012;108: Not tested apcc: Feiba 0.25,0.5,1,2 U/mL Not tested 4-factor PCC a : Kanokad 0.25,0.5,1 U/mL Not tested Apixaban + (lag time) + (lag time) Dabigatran 150 mg + (increased AUC) Rivaroxaban 20 mg + (lag time) +++ (AUC, peak, lag time, and time to peak) ++ (strongly corrected AUC, modest peak) a PCCs contain significant quantities of factors II, IX, and X; 4-factor PCCs (not yet available in the US) also contain factor VII rfviia=recombinant activated clotting factor VII

44 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.

45 NOACs: Risk/Benefit Profiles Favor warfarin Mitral stenosis Mechanical valves TTR >70% + patient desire CrCl <30 ml/m Weight <50 kg or >150 kg (?) High GI bleed risk (?) CAD +/- PCI (?) Cost Adherence/monitoring Favor NOAC No contraindications Access to drug ($/insurance) TTR <65% Frequent interruption Monitoring is difficult DRUG INTERACTIONS CAD, coronary artery disease; GI, gastrointestinal; PCI, percutaneous cardiac intervention.

46 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!

47 QUESTIONS?