New Approaches to Anticoagulation in Atrial Fibrillation

New Approaches to Anticoagulation in Atrial Fibrillation Hugh Calkins M.D. Nicholas J. Fortuin Professor of Cardiology Professor of Medicine Director of Electrophysiology Johns Hopkins Medical Institutions hcalkins@jhmi.edu 1

Outline Overview of Atrial Fibrillation Treatment Strategies Stroke Risk Anticoagulation Options Rate and Rhythm Control Conclusion 2

Disclosures Consultant, Research Support, or Honoraria Biosense Webster, CryoCor, ProRhythm, Ablation Frontiers, Medtronic, Boston Scientific, AtriCure, Sanofi Adventis 3

Epidemiology of AF Most common sustained cardiac arrhythmia 1 Currently affects 5.1 million Americans 2 Prevalence expected to increase to 12.1 million by 2050 (15.9 million if increase in incidence continues) 2 Preferentially affects men and the elderly 1,2 Lifetime risk of developing AF: ~1 in 4 for adults 40 years of age 3 1. Lloyd-Jones D, et al. [published online ahead of print December 17, 2009]. Circulation. doi:10.1161/circulationaha.109.192667. 2. Miyasaka Y, et al. Circulation. 2006;114(2):119-125. 3. Lloyd-Jones DM, et al. Circulation. 2004;110(9):1042-1046. 4

AF Is Associated With Increased Thromboembolic Risk Major cause of stroke in elderly 1 5-fold in risk of stroke 1,2 15% of strokes in US are attributable to AF 3 Stroke severity (and mortality) is worse with AF than without AF 4 Incidence of all-cause stroke in patients with AF: 5% 1 Stroke risk persists even in asymptomatic AF 5 1. Fuster V, et al. J Am Coll Cardiol. 2001;38(4):1231-1266. 2. Benjamin EJ, et al. Circulation. 1998;98(10):946-952. 3. Atrial Fibrillation Investigators. Arch Intern Med. 1994;154(13):1449-1457. 4. Dulli DA, et al. Neuroepidemiology. 2003;22(2):118-123. 5. Page RL, et al. Circulation. 2003;107(8):1141-1145. 5

AF Is the Leading Cause of Hospitalizations for Arrhythmia Hospital Admissions in US AF AFL Cardiac arrest Conduction disease Junctional Premature beats Sick sinus Unspecified VF VT 0 200 400 600 800 1000 Hospital Days (thousands) N=517,699 (representing 10% of CV admissions). VF, ventricular fibrillation; VT, ventricular tachycardia. Adapted from Waktare JE, et al. J Am Coll Cardiol. 1998;81(suppl 5A):3C-15C. 6

Mortality After Diagnosis of AF 100 80 4-month HR, 9.62 Post-4 months HR, 1.66 Survival, % 60 40 20 0 MN-white expected Observed P<.0001 0 2 4 6 8 10 0 2 4 6 8 10 Years From AF Dx P<.0001 Years After 4 Mo From AF Dx Reproduced with permission from Miyasaka Y, et al. J Am Coll Cardiol. 2007;49(9):986-992. 7

Impact on QoL: AF vs Other CV Illness 100 90 General population 1 Recent MI 1 AF 2 HF 1 SF-36 scale* 80 70 60 50 40 Physical functioning Vitality General health Mental health index Emotional role Social functioning *Higher numbers indicate higher QoL. SF-36 = Medical Outcomes Study Short Form 36. Baseline score 1. Ware JE, et al. New England Medical Center Health Survey; 1993. 2. Dorian P, et al. J Am Coll Cardiol. 2000;36(3):1303-1309. 8

Pathogenesis of AF Multiple-wavelet hypothesis 1 Focal mechanism with fibrillatory conduction 2 Autonomic hypothesis 3 1. Moe GK, Abildskov JA. Am Heart J. 1959;58(1):59-70. 2. Konings KT, et al. Circulation. 1994;89(4):1665-1680. 3. Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Circulation. 1996;93(5):1043-1065. 9

Conditions Frequently Associated With Nonvalvular AF 1-4 Hypertension Aging Male sex Obesity/metabolic syndrome/diabetes Ischemic heart disease Heart failure/diastolic dysfunction Obstructive sleep apnea Physical inactivity Thyroid disease Inflammation? 1. Wattigney WA, et al. Circulation. 2003;108(6):711-716. 2. Gersh BJ, et al. Eur Heart J Suppl. 2005;7(suppl C):C5-C11. 3. Fuster V, et al. J Am Coll Cardiol. 2006;48(4):854-906. 4. Mozaffarian D, et al. Circulation. 2008;118(8):800-807. 10

Prevalence of AF Increases With Severity of HF 0.6 0.5 % of Patients With AF 0.4 0.3 0.2 0.1 0 Class I II Class III IV 11

Classification of AF Recurrent AF* ( 2 episodes) Paroxysmal Persistent Arrhythmia terminates spontaneously AF is sustained 7 days Permanent Both paroxysmal and persistent AF can become permanent Arrhythmia does not terminate spontaneously AF is sustained >7 days *Termination with pharmacologic therapy or direct-current cardioversion does not change the designation. Fuster V, et al. Circulation. 2006;114(7):e257-e354. 12

Treatment 13

Treatment Goals and Strategies Rate control Maintenance of SR Stroke prevention Pharmacologic Ca 2+ blockers -blockers Digitalis Amiodarone Nonpharmacologic Ablate and pace Pharmacologic Class IA Class IC Class III -blocker Nonpharmacologic Catheter ablation Pacing Surgery Implantable devices Pharmacologic Warfarin Aspirin Thrombin Inhibitor Nonpharmacologic Removal/isolation LA appendage Prevent Remodeling CCB ACE-I, ARB Statins Fish oil 14

CHADS 2 Risk Criteria for Stroke in Nonvalvular AF Risk Factors Score C Recent congestive heart failure 1 H Hypertension 1 A Age 75 y 1 D Diabetes mellitus 1 S 2 History of stroke or transient ischemic attack 2 Gage BF, et al. JAMA. 2001;285(22):2864-2870. 15

Stroke Risk in Patients With Nonvalvular AF Not Treated With Anticoagulation Based on the CHADS 2 Index Warfarin 0 5 10 15 20 25 30 CHADS 2, Congestive heart failure, Hypertension, Age >75, Diabetes mellitus, and prior Stroke or transient ischemic attack. Gage BF, et al. JAMA. 2001;285(22):2864-2870. 16

ACC/AHA/ESC 2006 Atrial Fibrillation Guidelines Risk Stratification for AF: Antithrombotic Therapy Risk Category Low Risk No moderate-risk factors CHADS 2 = 0 Moderate Risk One moderate-risk factor CHADS 2 = 1 High Risk Any high-risk factor or 2 moderate-risk factors CHADS 2 = 2 Recommendation Aspirin, 81-325 mg a day Aspirin, 81-325 mg a day or warfarin (INR 2.0-3.0) Warfarin (INR 2.0-3.0*) *INR 2.5-3.5 for prosthetic valves. What to do about weaker risk factors? Fuster V, et al. Circulation. 2006;114(7):e257-e354. 17

www.escardio.org/guidelines

www.escardio.org/guidelines

www.escardio.org/guidelines

Limitations of Warfarin Limitations Slow onset of action Genetic variation in metabolism Multiple food and drug interactions Narrow therapeutic window Consequences Overlap with parenteral anticoagulant Variable dose requirements Frequent coagulation monitoring Frequent coagulation monitoring Hirsh J. N Engl J Med. 1991;324(26):1865-1875. Bates SM, Weitz JI. Br J Haematol. 2006;134(1):3-19. Courtesy of PR Kowey, MD. 21

Limitations of Warfarin Limitations Slow onset of action Genetic variation in metabolism Multiple food and drug interactions Narrow therapeutic window Consequences Overlap with parenteral anticoagulant Variable dose requirements Frequent coagulation monitoring Frequent coagulation monitoring Hirsh J. N Engl J Med. 1991;324(26):1865-1875. Bates SM, Weitz JI. Br J Haematol. 2006;134(1):3-19. Courtesy of PR Kowey, MD. 22

Targets of New Anticoagulant Agents Becattini Throm Res 2012 23

Main Features of New Anticoagulant Agents Becattini Throm Res 2012

Clinical Trials and new Anticoagulant Agents - A Summary - Becattini Throm Res 2012

Dabigatran versus Warfarin in Patients with Atrial Fibrillation (RE-LY) In patients with atrial fibrillation, dabigatran given at a dose of 110 mg was associated with rates of stroke and systemic embolism that were similar to those associated with warfarin, as well as lower rates of major hemorrhage Dabigatran administered at a dose of 150 mg, as compared with warfarin, was associated with lower rates of stroke and systemic embolism but similar rates of major hemorrhage Connolly SJ et al. N Engl J Med 2009;361:1139-1151

Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation (ROCKET AF) In this trial, 14,264 patients with atrial fibrillation were randomly assigned to receive either rivaroxaban or warfarin. In a per-protocol, as-treated analysis, rivaroxaban was noninferior to warfarin with respect to the primary end point of stroke or systemic embolism. Patel MR et al. N Engl J Med 2011;365:883-891

Apixaban in Patients with Atrial Fibrillation (AVERROES) In this trial, the factor Xa inhibitor apixaban was shown to reduce the risk of stroke or systemic embolism, as compared with aspirin, without a significant increase in the risk of major bleeding. Apixaban is an alternative to aspirin for patients who cannot take warfarin. Connolly SJ et al. N Engl J Med 2011;364:806-817

Apixaban versus Warfarin in Patients with Atrial Fibrillation (ARISTOTLE) Apixaban was superior to warfarin in preventing stroke or systemic embolism, caused less bleeding, and lowered mortality. Granger CB et al. N Engl J Med 2011;365:981-992

Which New Agent Should We Recommend? Raise the issue / Pop the question Variables to consider: - coumadin experience - approach to new drugs - cost considerations - h/o GI symptoms - compliance issues

Treatment Goals and Strategies Rate control Maintenance of SR Stroke prevention Pharmacologic Ca 2+ blockers -blockers Digitalis Amiodarone Nonpharmacologic Ablate and pace Pharmacologic Class IA Class IC Class III -blocker Nonpharmacologic Catheter ablation Pacing Surgery Implantable devices Pharmacologic Warfarin Aspirin Thrombin Inhibitor Nonpharmacologic Removal/isolation LA appendage Prevent Remodeling CCB ACE-I, ARB Statins Fish oil 31

Rate Control End point Resting and ambulatory ventricular rates similar to those expected in sinus rhythm Best assessed with Holter monitoring Determining pulse on exam and heart rate on ECG are not sufficient Methods Digitalis: in sedentary patients or CHF -blockers and/or CCBs (verapamil, diltiazem): needed in most active individuals AVN ablation plus pacemaker: in resistant patients Special considerations Brady-tachy syndrome (pindolol, or pacer plus drugs) Preexcitation (focus on the BT as well as the AVN) 32

2011 ACCF/AHA/HRS Focused Update on the Management of AF Rhythm Control Therapies to Maintain Sinus Rhythm Maintenance of SR No (or minimal) heart disease Hypertension CAD HF Dronedarone Flecainide Propafenone Sotalol Substantial LVH No Yes Dofetilide Dronedarone Sotalol Amiodarone Dofetilide Amiodarone Dofetilide Catheter ablation Amiodarone Catheter ablation Catheter ablation Dronedarone Flecainide Propafenone Sotalol Amiodarone Catheter ablation Amiodarone Dofetilide Catheter ablation Reproduced with permission from Wann LS, et al. Circulation. 2011;123(1):104-123. 33

Current Efficacy of AF Ablation: Estimates Surgical Ablation Single Procedure Multiple Optimal patient Less optimal patient Poor candidate 70%-90% 60%-80% 50%-60% Catheter Ablation Optimal patient Less optimal patient Poor candidate 60%-80% 50%-70% 40% 80%-90% 70%-80% 40%-60% Calkins H, et al; Heart Rhythm Society Task Force on catheter and surgical ablation of atrial fibrillation. Heart Rhythm. 2007;4(6):816-861. Calkins H, et al. Circ Arrhythmia Electrophysiol. 2009;2(4):349-361. 35

Patient Selection for Ablation Variable Symptoms Highly symptomatic Minimally symptomatic Class I and III drugs failed 1 0 AF type Paroxysmal Long-standing persistent Age Younger (<70 years) Older ( 70 years) LA size Smaller (<5.0 cm) Larger ( 5.0 cm) Ejection fraction Normal Reduced Congestive heart failure No Yes Other cardiac disease No Yes Pulmonary disease No Yes Sleep apnea No Yes Obesity No Yes Prior stroke/tia No Yes Courtesy of Hugh Calkins, MD. 37

Treatment Goals and Strategies Rate control Maintenance of SR Stroke prevention Pharmacologic Ca 2+ blockers -blockers Digitalis Amiodarone Nonpharmacologic Ablate and pace Pharmacologic Class IA Class IC Class III -blocker Nonpharmacologic Catheter ablation Pacing Surgery Implantable devices Pharmacologic Warfarin Aspirin Thrombin Inhibitor Nonpharmacologic Removal/isolation LA appendage Prevent Remodeling CCB ACE-I, ARB Statins Fish oil 38

Conclusions Atrial fibrillation is common Atrial fib is an important risk factor for stroke. Stroke risk can be determined using CHADS and CHADSvasc Patients at increased risk of stroke should be anticoagulated. Aspirin does little. The era of new anticoagulants is here and now.

Thank You 40