AF 2011: Therapeutic Update Gerald V. Naccarelli M.D. Research support: Boston-Scientific, sanofi-aventis, Boehringer-Ingelheim, Glaxo-Smith-Kline, Astellas Consultant: Glaxo-Smith-Kline, Boston-Scientific, Medtronic, Pfizer, sanofi-aventis, Xention, Gilead, Novartis, Astra- Zeneca, Boehringer-Ingelheim, Merck, Bristol Myers Squibb, Otsuka, Blue Ash Therapeutics, St. Jude’s, Cordis- Webster, Ortho-McNeill, Daiichi-Sankyo

Projected Number of Patients with AF by 2050 ATRIA = Anticoagulation and Risk Factors in Atrial Fibrillation. Go AS, et al. JAMA. 2001;285(18): Miyasaka Y, et al. Circulation. 2006;114: Naccarelli GV, et al. Am J Cardiol. 2009;104(11): Year Patients with AF (millions) MarketScan and Thomson Reuters Medicare Databases, 2009 Olmsted County Data, 2006 (assuming a continued increase in AF incidence) ATRIA Study Data, 2000 Olmsted County Data, 2006 (assuming no further increase in AF incidence)

AF: Prevalence of Common Co-morbidities Naccarelli GV, et al. Am J Cardiol 2009; 104:

The Consequences of AF Thromboembolism  Stroke: 4.5  increased risk  Microemboli: reduced cognitive function  Prothrombotic state Mortality  2  increased risk independent of comorbid CV disease  Sudden death in HF and HCM Hospitalizations  Most common arrhythmia requiring hospitalization  2-3  increased risk for hospitalization Impaired Hemodynamics  Loss of atrial kick  Irregular ventricular contractions  HF  Tachycardia-induced cardiomyopathy Reduced QoL  Palpitations, dyspnea, fatigue, reduced exercise tolerance HCM=hypertrophic cardiomyopathy; QoL=quality-of-life. Van Gelder IC, et al. Europace. 2006;8: ; Narayan SM, et al. Lancet. 1997;350: ; Wattigney WA, et al. Circulation. 2003;108: ; Wyse DG, et al. Circulation. 2004;109: ; Favale S, et al. PACE. 2003;26: AF is an enormous contributor AF is an enormous contributor to the growing cost of medical care

What Are the Goals of AF Therapy? Improve survival Reduce sequelae –Stroke, systemic emboli, heart failure Reduce hospitalizations Improve symptoms Improve QoL Restore atrial function/reverse the remodeling process Minimize adverse effects of therapies employed QoL = quality of life.

Cost Increases With Each AF Recurrence, Mainly Driven by Hospital Costs FRACTAL Registry—Annual Costs of AF-Related Medical Care 0 2,000 4,000 6,000 8,000 10,000 12,000 Permanent AF (n=34) 0 (n=620) 1-2 (n=286) ≥3 (n=33) Documented Recurrences $2,372 $3,385 $6,331 $10,312 Cost ($) Outpatient costs Drug costs Hospital costs P<.05 Reynolds MR et al. J Cardiovasc Electrophysiol. 2007;18:

AF: CV Hospitalization Implications AF accounts for more hospitalizations than any other arrhythmia 1 –1/3 of hospitalizations for cardiac arrhythmia 2 During the past 20 years hospital admissions for AF have increased by 66% 2 Except cardioversion, hospitalization is motivated by the severity of an AF episode or an AF-related complication such as a cardiovascular event 3 Hospitalization is an important negative determinant of QoL in patients with AF 4 50 to 70% of the cost of AF management is driven by in-patient care 5 Direct cost of AF in USA: $6.65 billion annually Adapted from A.J. Camm. 1. Bialy D, et al. J Am Coll Cardiol 1992;19:41A. 2. ACC/AHA/ESC 2006 guidelines Eur Heart J 2006;27:1979– Stewart S, et al. Eur Heart J 2001;22: Dorian P, et al. Circ Arrhythmia Electrophysiol 2009; Le Heuzey J.Y.et al. Am. Heart J. 2004; 47 : Bajpai A, et al. US Cardiovascular Disease. 2007:14-17.

Guideline-Based AF Treatment Options CCB = calcium channel blocker; SR = sinus rhythm; ACE-I = angiotensin-converting enzyme inhibitor; ARB = angiotensin II receptor blocker; LA = left atrial. Fuster V, et al. J Am Coll Cardiol. 2006;48(4): Maintenance of SR Pharmacologic Class IA Class IC Class III  -blockers Nonpharmacologic Catheter ablation Pacing Surgery Implantable devices Stroke prevention Pharmacologic Warfarin Aspirin +/- clopidogrel Dabigatran Factor Xa inhibitors Nonpharmacologic Removal/isolation LA appendage Rate control Prevent remodeling CCBs ACE-Is, ARBs Statins Fish oil Pharmacologic CCBs  -blockers Digitalis Amiodarone Dronedarone Nonpharmacologic Ablate and pace

Intermittent AF Permanent AF Annual Stroke Rate (%) AF and Stroke AF increases stroke risk 4- to 5-fold Stroke is the most common and devastating complication of AF –Incidence of all-cause stroke in patients with AF is 5% AF is an independent risk factor for stroke –Approximately 15% of all strokes in the United States caused by AF –Risk for stroke increases with age Stroke risk persists even in asymptomatic AF Stroke risk persists in patients with a “high-risk” profile despite a strategy of rhythm control (AFFIRM study, RACE study) RACE II = Rate Control Efficacy in Permanent Atrial Fibrillation. Fuster V, et al. J Am Coll Cardiol. 2006;48(4):e149-e246. Kannel WB, et al. Med Clin North Am. 2008;92(1): Page RL, et al. Circulation. 2003;107(8): Hart RG, et al. J Am Coll Cardiol. 2000; 35(1): Dulli DA, et al. Neuroepidemiology. 2003;22(2): Low Risk Moderate Risk High Risk

Stroke Risk Stratification in AF CHADS 2 CHA 2 DS 2 -VASc Risk FactorScore Cardiac failure1 HTN1 Age ≥75 y1 Diabetes1 Stroke2 Risk FactorScore Cardiac failure1 HTN1 Age ≥75 y2 Diabetes1 Stroke2 Vasc dz (MI, PAD, aortic ath)1 Age y1 Sex category (female)1 Lip GY, Halperin JL. Am J Med. 2010;123(6): Stroke Rate, % CHA 2 DS 2 -VASc Score Relationship between CHA 2 DS 2 -VASc score and annual risk of stroke Total ScoreAnnual Risk of Stroke (%)

ESC AF Guidelines EHJ 2010 HAS-BLED Bleeding Risk Score

ESC AF Guidelines EHJ 2010 Approach to Thrombo-prophylaxis in AF

Atrial Fibrillation Investigators. Arch Intern Med. 1994;154(13): AFASAK27811 BAATAF15922 CAFA14478 SPAF23508 SPINAF29972 Combined Warfarin BetterWarfarin Worse No. of Events Patient- Years Risk Reduction, % Compared With Control in 5 Studies Efficacy of Warfarin 62% to 67% RRR with warfarin vs placebo

ACTIVE = AF Clopidogrel Trial with Irbesartan for Prevention of Vascular Events. ACTIVE Investigators. Lancet. 2006;367: ACTIVE Investigators. N Engl J Med. 2009;360(20): Antiplatelet Therapy in AF ACTIVE-W: 6706 randomized patients; trial stopped Outcome/Year (%) StrokeVascular Event Major Bleeding P =.0003 P =.001P =.53 Warfarin Clopidogrel + ASA ACTIVE-A: 7554 randomized patients; median follow-up of 3.6 years Outcome/Year (%) StrokeVascular Event Major Bleeding P =.01 P<.001 ASA Clopidogrel + ASA

Potential Advantages of New Oral Anticoagulants Oral administration Rapid onset of action -- eliminates 2 AC regimen Predictable effect with fixed or weight-based dosing -- no monitoring Less food/drug interactions Short half- life: ease of reversal/ no bridging More convenient -- potentially leading to greater use More cost effective − No routine monitoring − Fewer ADEs requiring ER visits and hospitalizations Possible superior efficacy -- demonstrated for dabigatran Possible superior safety -- demonstrated for dabigatran

Characteristics of New Oral Anticoagulants 1,2 DrugDabigatranRivaroxabanApixabanBetrixaban Edoxaban Mechanism of action Thrombin inhibitor FXa inhibitor Half-life14-17 h5-9 h12 h19-24 h6-12 h RegimenBIDQD, BIDBIDQD Peak to trough~7x12x (QD)3-5x~3x Renal excretion of absorbed drug ~80%36-45%25-30%~15% 35% Potential for drug interactions P-glycoprotein inhibitor CYP3A4 substrate and P-glycoprotein inhibitor Not substrate for major CYPs CYP3A4 substrate and P-glycoprotein inhibitor 1.Usman MH, et al. Curr Treat Cardiovasc Med. 2008;10(5): Piccini JP, et al. Curr Opin Cardiol. 2010;25(4):

Dabigatran Dabigatran etexilate is a pro-drug that undergoes metabolism to dabigatran which is a competitive inhibitor of thrombin that binds clot-bound and free thrombin with high affinity and specificity and also inhibits thrombin-induced platelet aggregation Bioavailability 6.5%; low protein binding No known food or CYP450 drug interactions No need for INR monitoring Hepatotoxicity <1% Half-life: 8 hours after single dose and hours after multiple doses BID dosing 80% renal excreted Usman MH, et al. Curr Treat Cardiovasc Med. 2008;10(5):

Design of the RE-LY ® Trial Study Parameters Open label, noninferiority, intent-to-treat trial Blinded adjudication of outcome events 50% patients VKA-naïve* Primary outcome: incidence of stroke (ischemic and hemorrhagic) and systemic embolism in patients with non-valvular atrial fibrillation Primary safety outcome: incidence of major bleeds † Patient Flow Randomized N= 18,113 Blinded to dose Warfarin (INR ) N= 6022 Dabigatran 110 mg twice daily N= 6015 Dabigatran 150 mg twice daily N= 6076 Avg CHADS score 2.2, with 32% CHADS 3 or higher Minimum 1-year follow-up, maximum 3 years, median of 2 years of follow-up. INR: international normalized ratio; VKA: vitamin K antagonist. *Total lifetime exposure of < 2 months. † Major bleeds fulfilled one or more of the following criteria: bleeding associated with a reduction in hemoglobin of at least 2 grams per deciliter or leading to a transfusion of at least 2 units of blood, or symptomatic bleeding in a critical area or organ. A life-threatening bleed met one or more of the following criteria: fatal, symptomatic intracranial bleed, reduction in hemoglobin of at least 5 grams per deciliter, transfusion of at least 4 units of blood, associated with hypotension requiring the use of intravenous inotropic agents, or necessitating surgical intervention, Intracranial hemorrhage included intracerebral (hemorrhagic stroke), subarachnoid, and subdural bleeds. Connolly SJ, Ezekowitz MD et al. N Engl J Med. 2009;361:

*Noninferiority; † Superiority MI = myocardial infarction; RE-LY = Randomized Evaluation of Long-term Anticoagulation Therapy. Connolly SJ, et al. N Engl J Med. 2009;361(12): Stroke Prevention in AF Dabigatran Etexilate vs Warfarin (RE-LY) Stroke/Systemic Embolism Major BleedIntracranial Hemorrhage Percent/Year Dabigatran 110 mg is not FDA approved for this indication; for informational purposes only MI Dabigatran 150 mg Warfarin INR Dabigatran 110 mg P =.003 † P<.001 *P<.001 P<.001 P<.048 Avg TTR: 67%

Dabigatran: DC Cardioversion N (Pts/CV)CVA/SEE Dabigatran 110 mg409/6475 (0.8%) Dabigatran 150 mg415/6722 (0.3%) Warfarin431/6644 (0.6%) Nagarakanti R, et al. Circulation 2011:123:

ROCKET AF Trial: Rivaroxaban 1,2 1.ROCKET AF Study Investigators. Am Heart J. 2010;159(3): e1. 2.ClinicalTrials.gov identifier: NCT Warfarin target INR, 2.5 (INR range, ) N =14,264 Nonvalvular AF, history of stroke, TIA, or embolism, or at least 2 of the following: heart failure, hypertension, age  75 y, or diabetes mellitus Day 1 Rivaroxaban 20 mg once daily Rivaroxaban 15 mg once daily (CrCL mL/min at entry) Day 30 after last dose Treatment period months In AF patients with a moderate to high risk of stroke, does rivaroxaban reduce the risk of major vascular events compared with warfarin? 1 0 study end point: composite of all-cause stroke and non-CNS systemic embolism 2 0 end points: composite of transient ischemic attack, all-cause death, vascular death, and MI 1 0 safety end point: composite of major and clinically relevant nonmajor bleeding events Randomization completed in June 2009; follow-up completed 2010 Follow-up: up to 4 years (until 405 primary outcome events have been observed) End of treatmentFollow-up R

Rivaroxaban*Warfarin Event Rate HR (95% CI) P-value On Treatment N= 14, (0.65,0.95) ITT N= 14, (0.74,1.03) Rivaroxaban better Warfarin better ROCKET AF: Primary Efficacy Outcome Stroke and non-CNS Embolism *Rivaroxaban is not FDA approved. Event Rates are per 100 patient-years Based on Safety on Treatment or Intention-to-Treat thru Site Notification populations TTR 57.8% Avg CHADS score 3.7

RivaroxabanWarfarin Event Rate HR (95% CI)P-value Vascular Death, Stroke, Embolism (0.84, 1.05)0.265 Stroke Type Hemorrhagic Ischemic Unknown Type (0.38, 0.89) 0.99 (0.82, (0.55, 2.01) Non-CNS Embolism (0.42, Myocardial Infarction (0.72, 1.16)0.464 All Cause Mortality Vascular Non-vascular Unknown Cause (0.82, 1.03) 0.94 (0.81, 1.08) 0.94 (0.75, 1.18) 0.80 (0.57, 1.12) ROCKET AF: Key Secondary Efficacy Outcomes Event Rates are per 100 patient-years Based on Intention-to-Treat Population

ROCKET AF Compared With RE-LY ROCKET AF 1 RE-LY 2 N14,17118,000 VKA naive37%50% DesignRandomized, double-blind, double-dummy study PROBE design TreatmentRivaroxaban 1 dose (with dose adaptation for moderate renal impairment) Dabigatran 2 doses RegimenOnce dailyTwice daily Primary outcome Efficacy: Composite of all-cause stroke and non-CNS systemic embolism Safety: Composite of major and clinically relevant nonmajor bleeding events Efficacy: Incidence of stroke (including hemorrhagic) and systemic embolism Safety: Major bleeding events Secondary outcome Each category of bleeding events, and adverse events Composite of TIA, all-cause death, vascular death, and MI Incidence of stroke (including hemorrhagic), systemic embolism, all death, pulmonary embolism, MI, TIA, vascular deaths (including deaths from bleeding), and hospitalizations 1.ROCKET AF Study Investigators. Am Heart J. 2010;159(3): Connolly SJ, et al. N Engl J Med. 2009;361(12):

ROCKET AF Compared With RE-LY ROCKET AF 1 RE-LY 2 TTR (median) 58%67% CHADS2 (mean) Previous TIA/CVA 55%20% Primary outcome HR (150 dose) Hem CVA rate (150 dose) Ischemic CVA: HR (150 dose) Major Bleeding rate 3.6%3.3% (150 dose) 1.ROCKET AF Study Investigators. Am Heart J. 2010;159(3): Connolly SJ, et al. N Engl J Med. 2009;361(12):

AVERROES Trial 1,2 ASA ( mg daily; up to 36 mo/end of study) Apixaban (5 mg twice daily; 2.5 mg in selected patients a ; up to 36 mo/end of study) E Unsuitable for warfarin therapy N= 5600 Double-blind AVERROES, Apixaban Versus ASA to Reduce the Risk Of Stroke. 1.Eikelboom JW, et al. Am Heart J. 2010;159(3): e1. 2.ClinicalTrials.gov identifier: NCT a At least 2 of: age  80 y, weight  60 kg, or serum Cr  1.5 mg/dL Is apixaban more effective than ASA in preventing stroke and systemic embolism in moderate to high-risk (stroke; at least 1 risk factor) AF patients? 1 0 efficacy end point: confirmed ischemic or hemorrhagic stroke or systemic embolism 2 0 study end points: as above, including MI or vascular death 1 0 safety end point: major bleeding Study period: until 226 primary outcome events have been observed In June 2010, BMS-Pfizer announced that the study had been stopped early because a predefined interim analysis revealed clear evidence of a clinically important reduction in stroke and systemic embolism. Results presented at ESC 2010, Stockholm, Sweden. R

Cumulative Risk ASA Apixaban* No. at Risk ASA Apix Months RR= % CI, P<.001 AVERROES: Stroke or Systemic Embolic Event Connolly S., et al N Engl J Med 2011 *Apixaban is not FDA approved.

Cumulative Risk ASA Apixaban No. at Risk ASA Apix Months RR= % CI, P=.57 AVERROES: Major Bleeding 28 Connolly S, et al. N Engl J Med 2011

ARISTOTLE Trial: Apixaban 1,2 Double-blind 1.Lopes RD, et al. Am Heart J. 2010;159(3): ClinicalTrials.gov identifier: NCT AF or atrial flutter 18,206 randomized Warfarin INR, Apixaban (5 mg twice daily; 2.5 mg twice daily in selected patients a ) a At least 2 of: age  80 y, weight  60 kg, or serum Cr  1.5 mg/dL Is apixaban noninferior to standard therapy (warfarin) in preventing stroke and systemic embolism in moderate- to high-risk (stroke; at least 1 risk factor) AF patients? 1 0 efficacy end point: confirmed ischemic or hemorrhagic stroke, or systemic embolism 2 0 efficacy end points: composite of confirmed ischemic or hemorrhagic stroke, systemic embolism, and all-cause death 1 0 safety end point: time to first occurrence of confirmed major bleeding Treatment period: up to 4 years (until 448 primary outcome events have been observed — >90% power to demonstrate noninferiority); –Stratified by warfarin-naïve status E R

ENGAGE AF–TIMI 48: Edoxaban Warfarin INR, Edoxaban (60 mg vs 30 mg qd) Double-blind AF >20,000 pts Is edoxaban noninferior to standard therapy (warfarin) in preventing stroke and systemic embolism in moderate- to high-risk (CHADS 2 score ≥2) AF patients? 1 0 efficacy end point: composite primary end point of stroke and systemic embolic events 2 0 efficacy end points: composite clinical outcome of stroke, systemic embolic events, and all-cause mortality; also major bleeding events Treatment period: up to 2 years 3 treatment arms ClinicalTrials.gov identifier NCT R E

CVA = cerebrovascular accident; LV = left ventricular; RHD = rheumatic heart disease. Fuster V, et al. J Am Coll Cardiol. 2006;48(4):e149-e246. Connolly SJ, et al. N Engl J Med. 2009;361(12): Anticoagulation in AF Anticoagulation is needed in patients at increased thromboembolic risk –CHADS 2 : Age ≥75 years, prior CVA/TIA, diabetes, HTN, LV dysfunction. Highest risk: RHD –Anticoagulation usually should be continued chronically Drugs, herbals, diet, genetic patterns, generics must all be considered in choosing and during anticoagulation Warfarin has been more effective than ASA in all comparative studies, without excess risk; dabigatran 150 mg bid is superior to warfarin Anticoagulation is necessary prior to cardioversion of nontransient (>48 hours) AF New oral direct thrombin inhibitors and factor Xa drugs may replace warfarin in the future for many/most patients with AF

Favors Rate ControlFavors Rhythm Control Persistent AFParoxysmal AF Newly Detected AF Less SymptomaticMore Symptomatic >65 years of age< 65 years of age HypertensionNo Hypertension No History of Congestive Heart Failure Congestive Heart Failure clearly exacerbated by AF Previous Antiarrhythmic Drug FailureNo Previous Antiarrhythmic Drug Failure Canadian Cardiovascular Society Recommendations Canadian Cardiovascular Society AF Guidelines. Accessed January 25, 2011.

Hynes BJ, et al. Future Cardiol. 2005;1(2): Dronedarone Amiodarone-like compound lacking the iodine moiety Similar electrophysiologic properties to amiodarone –Low propensity to cause TDP 13 to 30-hour T ½, but administered as bid regimen Food effect (2x-3x increase in levels) Extensive first-pass hepatic metabolism through CYP4503A4 system –Only 15% bioavailability –Elevates serum creatinine 10% to 15% without a change in glomerular filtration rate Drug interactions similar to amiodarone, except no significant interaction with warfarin No evidence of thyroid or pulmonary toxicity but rare cases of serious hepatotoxicity

Amiodarone Dronedarone Iodine moiety YesNo T½T½ 53 days14-30 hours Blocks I Kr ; I Ks ; B 1 ; I Ca ; I to ; I Na Yes Dosing Daily after loadingbid with meals Food effect Yes CYP4503A4 metabolism NoYes Inhibits tubular secretion of creatinine Yes Increase QT but low TDP Yes Efficacy in suppressing AF 65%50% Efficacy in suppressing ventricular tachyarrhythmias YesNot well studied Decreases CV hospitalization NoYes Warfarin interaction YesNo Pulmonary/thyroid toxicity YesNo Safety concerns in CHF SCD-HEFT NYHA IIIANDROMEDA SCD-HEFT = Sudden Cardiac Death in Heart Failure Trial. Wolbrette DL, et al. Vasc Health Risk Manag. 2010;(6): Clinical Profiles for Amiodarone and Dronedarone

Months HR = 0.76 P< % reduction in relative risk ATHENA = A Trial With Dronedarone to Prevent Hospitalization or Death in Patients With Atrial Fibrillation. Hohnloser SH, et al. N Engl J Med. 2009;360(7): ATHENA: Primary Endpoint (CV Hospitalization or Death) Dronedarone Placebo Cumulative Incidence (%) 4628 patients with paroxysmal or persistent AF were randomized if they met the following: ≥75 years of age with or without additional risk factors or ≥70 years of age and ≥1 risk factor (HTN, diabetes, prior stroke/TIA, LA diameter ≥50 mm, LVEF ≤0.40)

Outcome Placebo (N = 2327) Dronedarone (N = 2301) HR95% CI P Value Primary Endpoint First CV hospitalization or death 917 (39.4%)734 (31.9%) <.001 First CV hospitalization859 (36.9%)675 (29.3%) <.001 First hospitalization for AF 510 (21.9%)335 (14.6%) <.001 Secondary Endpoints Death from any cause139 (6.0%) 116 (5.0%) Death from non-CV causes49 (2.1%)53 (2.3%) Death from CV causes 90 (3.9%)63 (2.7%) Cardiac nonarrhythmic death 18 (0.8%) 17 (0.7%) Cardiac arrhythmic death 48 (2.1%) 26 (1.1%) Any CV hospitalization or death 1668 (71.7%) 1253 (54.5%) <.001 In a post-hoc analysis, dronedarone was also associated with a 34% reduction in relative risk of stroke, HR 0.66 (95% CI ), P =.027. Adapted from Hohnloser SH, et al. N Engl J Med. 2009;360(7): Connolly SJ, et al. Circulation. 2009;120(13): ATHENA: Primary and Secondary Endpoints

ATHENA: Stroke Incidence Post-Hoc Analysis Mean follow-up 21 ± 5 months HR=0.66 p=0.027 Connolly SJ, et al. Circulation. 2009;120(13):

*Limited interpretation; hospitalization was not reported in the same way in ATHENA, AFFIRM, and AF-CHF trials. NA = not applicable. Wyse DG, et al. N Engl J Med. 2002;347(23): Roy D, et al. N Engl J Med. 2008;358(25): Hohnloser SH, et al. N Engl J Med. 2009;360(7): Torp-Pedersen C, et al. Circulation. 2008;118:S828. Connolly SJ, et al. Circulation. 2009;120(13): CV Outcome Benefits: Amiodarone and Dronedarone in Large AF Trials ATHENAAF-CHFAFFIRM None82% of patients63% of patientsAmiodarone use P<.001P =.06P<.001 Hospitalization* P =.03NACV mortality P =.027Stroke P =.08Total mortality

ATHENA Post-Hoc Analysis Risk of unplanned CV hospitalization or death in "permanent" AF patients Months Cumulative Incidence (%) Placebo on top of standard therapy DR 400mg bid on top of standard therapy Placebo DR 400mg bid % reduction in relative risk Patients at risk: 0 HR=0.74 p=0.096 Mean follow-up 21 ±5 months. Page R, et al. AHA Scientific Sessions Page R, et al. Circulation. 2008;118:S_827. Any unplanned hospitalisation (i.e., admission with an overnight stay in the hospital) was classified by the investigator as a hospitalisation due to either CV or non-CV causes Patients with AF/AFL at each ECG recording were classified as having "permanent AF"

PALLAS Study Design Co-primary Endpoints Composite endpoint of first stroke, systemic arterial embolism, myocardial infarction or cardiovascular death Composite endpoint of first unplanned cardiovascular hospitalization or death from any cause Dronedarone 400 mg BID Placebo BID R Patients with permanent AF and additional risk factors* Event-Driven N~10800 On top of Standard of Care *Patients aged 65 years or older with at least one of the following risk factors or combination of risk factors: Coronary artery disease Prior stroke Symptomatic heart failure Left ventricular ejection fraction less than or equal to 0.40 Peripheral arterial occlusive disease Aged 75 years or older with both hypertension and diabetes mellitus

Køber L, et al. N Engl J Med. 2008;358(25): ANDROMEDA: Study Primary Endpoint and Results Primary endpoint –The primary composite endpoint was all-cause mortality or hospitalization for HF vs placebo Results Analysis Up to Study Discontinuation Placebo (n = 317) Dronedarone 800 mg/day (n = 310) Number of patients who died 1225 Relative risk (relative to placebo) % CI 1.07, 4.25 P value.03

Tschuppert Y, et al. Br J Clin Pharmacol. 2007;64: US Food and Drug Administration (FDA). CardiovascularandRenalDrugsAdvisoryCommittee/UCM pdf. Accessed July 9, Dronedarone Safety Profile Safety profile of dronedarone has been established in >6700 patients –Low risk of extracardiac toxicities (<0.1%) (thyroid, pulmonary, dermatologic) –Low risk of proarrhythmia (<0.1%) –Most frequently reported adverse events Gastrointestinal effects (24% vs 21% for placebo) General disorders and administration site conditions (16% vs 15% for placebo) Serum creatinine increase without indications of renal toxicity (4% vs 1% for placebo) Rare cases of serious hepatotoxicity were reported in 2010 within 6 months of beginning therapy, two required transplantation

FDA = US Food and Drug Administration; AFL = atrial flutter. Multaq [package insert]. Bridgewater, NJ: sanofi-aventis U.S. LLC; Dronedarone Indication Approved by the FDA in July 2009 to –Reduce the risk of CV hospitalization in patients with paroxysmal or persistent AF or AFL, with a recent episode of AF/AFL, and 1 or more associated CV risk factors Age >70 HTN Diabetes Prior CVA LA diameter ≥50 mm or LVEF <40% –Treat patients who are in SR, or who will be cardioverted Contraindicated in class IV HF or lesser HF with recent decompensation

Efficacy of AADs in AF Trials *At 6 months; † Mean follow-up 7 months. CTAF = Canadian Trial of Atrial Fibrillation; SAFE-T = Sotalol Amiodarone Atrial Fibrillation Efficacy Trial; DAFNE = Dronedarone Atrial Fibrillation Study after Electrical Cardioversion; EURIDIS = European Trial in Atrial Fibrillation or Flutter Patients Receiving Dronedarone for the Maintenance of Sinus Rhythm; ADONIS = American-Australian-African Trial with Dronedarone in Atrial Fibrillation or Flutter for the Maintenance of Sinus Rhythm; DIONYSOS = Randomized, Double-blind Trial to Evaluate the Efficacy and Safety of Dronedarone vs Amiodarone for at Least 6 Months for the Maintenance of Sinus Rhythm in Patients with AF. Courtesy of G Naccarelli, MD. Roy D, et al. Am J Cardiol. 1997;80: Singh BN, et al. N Engl J Med. 2005;352(18): AFFIRM Investigators. J Am Coll Cardiol. 2003;42: Touboul P, et al. Eur Heart J. 2003;24: Singh BN, et al. N Engl J Med. 2007;357(10): Le Heuzey JY, et al. J Cardiovasc Electrophysiol. 2010;21: Dronedarone Sotalol Amiodarone Class IC Placebo Patients in SR at 1 Year (%) CTAFSAFE-TAFFIRMDAFNE*EURIDIS*ADONISEURIDIS/ ADONIS Pooled DIONYSOS †

A Safety-Driven Approach *Within each box, drugs are listed alphabetically and not in order of suggested use. HTN = hypertension; CAD = coronary artery disease; HF = heart failure; CHF = congestive heart failure. Wann LS, et al. Circulation. Published online Dec 20, Camm AJ, et al. Eur Heart J. Published online August 29, ACCF/AHA/HRS Guidelines: Antiarrhythmic Approaches to Maintain SR in Patients with Recurrent PAF or Persistent AF* HF Amiodarone Dofetilide Maintenance of SR Amiodarone Dofetilide Catheter ablation Dronedarone Flecainide Propafenone Sotalol No (or minimal) heart disease Dronedarone Flecainide Propafenone Sotalol Amiodarone NoYes Amiodarone Dofetilide Catheter ablation HTN Substantial LVH CAD Catheter ablation Amiodarone Catheter ablation Dofetilide Dronedrone Sotalol 2010 ESC Guidelines – Dronedarone recommended for patients with LVH and stable NYHA I/II CHF

In AFIn NSR HospitalOutpatientHospitalOutpatient IA*XX IC*X†X† X†X† SotalolXXX‡X‡ DofetilideXX DronedaroneXX AmiodaroneXX *After rate control; † No SHD or sinus node/conduction abnormalities; ‡ No risk factors for TDP (QT <450 ms, normal electrolytes). TDP = Torsades de pointes. Fuster V, et al. Circulation. 2006;114:e257-e354. Multaq [package insert]. Bridgewater, NJ: sanofi- aventis U.S. LLC; Outpatient vs Inpatient Initiation of Antiarrhythmics for AF

ACE-Is/ARBs Statins Glucocorticoids Physical activity Omega-3 fatty acids  Inflammation  Oxidative stress  RAAS activity  Endothelial function  Autonomic nervous system activity  Plaque stability  Atrial remodeling Stabilize LA endocardium  AF To date, large prospective trials have not confirmed benefit of upstream therapies in suppressing AF RAAS = renin-angiotensin-aldosterone system. Courtesy of CJ Pepine, MD. Possible “Upstream” Treatments and Mechanisms for AF Prevention

PUFA = polyunsaturated fatty acid; CABG = coronary artery bypass graft. Mozaffarian D, et al. Circulation. 2004;110(4): Calo L, et al. J Am Coll Cardiol. 2005;45(10): PUFA for Prevention of AF Post-Op AF (%)Hospital Days (n) Control PUFA AF Post-CABG P =.013 P =.017 Fish Oil/n-3 PUFA for Prevention of AF Prospective cohort of 4815 adults with 12-year follow-up –People who consumed tuna or other broiled/baked fish 1-4 times/week had 28% lower risk of AF (P =.005) compared to <1 time/month Randomized controlled trial of 160 patients treated pre- and post-bypass surgery (2 g PUFA/day)

OM 8: Primary Endpoint: Time to First Recurrence of Symptomatic AF/Flutter (PAF) HR: 1.15 CI: (0.90, 1.46) P value: PLA: 129/269 (48%) P-OM3: 135/258 (52%) Analysis based on Cox model: log (HR)=treatment+region+ACE/ARB+Statin Kowey PR, et al. JAMA 2010;302(21):

ACE-Is and ARBs reduced the RR of AF by 28% (P =.0002) Reduction in AF was similar with ACE-Is (28%, P =.01) and ARBs (29%, P =.00002) Effect was most pronounced in HF and only significant in HTN when associated with LVH RR = relative risk. Healey JS, et al. J Am Coll Cardiol. 2005;45(11): RR (95% CI) Total ARBs ACE-Is Favors TreatmentFavors Control ACE-Is and ARBs Reduce the Risk of AF Meta-analysis: 11 studies (N = 56,308) 4 in HF, 3 in HTN, 2 in patients following cardioversion for AF, and 2 in patients after MI

0 12 Probability of First Recurrence of AF Valsartan Placebo Log-rank test P =.829 Patients at Risk Time since Randomization (months) Valsartan Placebo Valsartan: 371/722 (51.4%) Placebo: 375/720 (52.1%) Adjusted HR % CI P =.73 The GISSI-AF Investigators. N Engl J Med. 2009;360: GISSI-AF Study Results: Probability of First Recurrence of AF

CS = coronary sinus; RA = right atrium. Haissaguerre M, et al. N Engl J Med. 1998;339(10): Calkins H, et al. Heart Rhythm. 2007;4(6): Triggers of AF: Focal Firing and Interplay with Reentrant Rotors SVC IVC PVs Septum Fossa Ovalis CS RALA

Extension of muscular fibers into PV Ganglia noted in yellow Large and small reentrant wavelets that play a role in initiating and sustaining AF Common locations of PV (purple) and common sites of origin of non-PV triggers (black) Composite of anatomic and arrhythmic mechanisms of AF LSPV LIPV RSPV IVC RIPV SVC LSPV LIPV RSPV IVC RIPV SVC LSPV LIPV RSPV IVC SVC RIPV LSPV LIPV RSPV IVC RIPV SVC Calkins H, et al. Heart Rhythm. 2007;4(6): Anatomy of PVs

A.Circumferential ablation around left and right PV antra B.and C. Additional linear lesion sets for the roof, mitral isthmus, carinae, SVC, and cavotricuspid isthmus D.Targeting fractionated electrograms and/or ganglionic plexi SVC = superior vena cava; PV = pulmonary vein; LSPV = left superior pulmonary vein; RSPV = right superior pulmonary artery; LIPV = left inferior pulmonary vein; RIPV = right inferior pulmonary vein; IVC = inferior vena cava. Calkins H, et al. Heart Rhythm. 2007;4(6): Common Lesions Performed in AF Ablation A.B. LSPV LIPV RSPV IVC RIPV LSPV LIPV RSPV IVC RIPV LSPV LIPV RSPV IVC RIPV SVC C.D. LSPV LIPV RSPV IVC RIPV SVC

>24 Rates (%) Range of Follow-Up (months) Cappato R, et al. Circulation. 2005;111: Success Rates with Ablation: Worldwide Survey Success with AADs Overall Success Success without AADs Additional recent studies suggest 5 yr success rates are <50%; LA size and function may not normalize despite control of the arrhythmia, and new MRI detected embolic CNS lesions occur in >10% of subjects Jeevanantham et al. AJC 2010; 105: * Ouyang et al. Circuation 2010;122: ** Weerasooriya et al. JACC 2011 *** Gaita F, et al. Circulation 2010; 122: **** Schwarz et al. Heart Rhythm 2010; 7:

Type of ComplicationNumber of PatientsRate (%) Death Tamponade Pneumo/hemo thorax Sepsis, abscesses, or endocarditis20.01 Permanent diaphragmatic paralysis Femoral pseudoaneurysm/AV fistula152/880.93/0.54 Valve damage/requiring surgery11/70.07 Atrium-esophageal fistulae30.02 Stroke/TIA37/ /9.71 PV stenoses requiring intervention TOTAL Heart Rhythm Society. Lessons from the Second International Ablation Registry Update. Accessed February Risks of AF Ablation: The Second International AF Ablation Registry Iatrogenic atrial flutter occurred in 8.3% of patients

Additional Ablation Data Longer term success (5 yr): –With a single procedure, sinus rhythm has been maintained at 5 yrs in just under 46.6% of pts in 1 study and just 29% in another* ** Recently appreciated additional embolic events: –Gaita et al *** studied 232 consecutive patients with PAF or persistent AF who underwent ablation (PVI +/- additional lesions). Standard anticoagulation was employed. All pts underwent preprocedural and postablation cerebral MRIs. Postablation MRIs, however, were positive for new lesions in 33 pts (14%).A periprocedural symptomatic CVA occurred in 1 pt (0.4%). Postablation MRIs, however, were positive for new lesions in 33 pts (14%). –Schwarz et al **** studied 23 pts in a similar study. 14.3% had new ischemic lesions on post-procedure imaging, and, compared to 23 controls, the ablation pts showed neuropsychological decline * Ouyang et al. Circuation 2010;122: ** Weerasooriya et al. JACC 2011 *** Gaita F, et al. Circulation 2010; 122: **** Schwarz et al. Heart Rhythm 2010; 7:

Additional Ablation Data Cont’d Atrial size and function post ablation: –17 studies enrolling 869 pts provided adequate data on LA size and function after RFA. –Compared to pre-ablation values, there were significant decreases in LA diameter and volumes at post-ablation follow up. –Decreases remained significant in those without AF recurrence but not in those with recurrent AF. –Compared to pre-ablation values, however, there were no improvements in LA EF or LA active emptying fraction, and LA size did not routinely decrease to normal. LAEF and LA emptying remained unchanged in pts without AF recurrence but decreased further in those with recurrent AF. Jeevanantham et al. AJC 2010; 105:

Minnesota Living with HF Questionnaire 6-Minute Walk Distance (m) Months P =.003 P<.001 Ejection Fraction (%) Months Ejection Fraction P =.03 P<.001 PVI = pulmonary vein isolation; CRT = cardiac resynchronization therapy; BiV = biventricular pacing. Khan MN, et al. N Engl J Med. 2008;359(17): PVI Is Superior to AVN Ablation/CRT in CHF Patients with Drug-Refractory AF Months Score P<.001 AVN Ablation + BiV PVI

Calkins H, et al. Heart Rhythm. 2007;4(6): Indications for Catheter AF Ablation Symptomatic AF refractory or intolerant to at least 1 class I or III AAD Selected symptomatic patients with HF and/or reduced ejection fraction As an alternative to device implantation to support AAD therapy in bradycardic patients Presence of an LA thrombus is a contraindication to catheter ablation of AF Discontinuation of anticoagulation is not an indication for ablation Circ.AHAjournals.org Dec 20, 2010

AF: atrial fibrillation; CV: cardiovascular; INR: international normalized ratio; LAA: left atrial appendage. Holmes DR, et al. Lancet. 2009;374: LAA Device for AF PROTECT-AF Study 707 patients with nonvalvular AF randomized to LAA device + 45 days of warfarin vs warfarin vs warfarin alone Primary efficacy end point of stroke, CV death, or systemic embolism was 3.0% ( ) with device and 4.9% ( ) with warfarin; [RR 0.62, 95% CI ( )] Primary safety end point of excessive bleeding, serious pericardial effusion, device embolization, or procedure-related stroke was 7.4% with device and 4.4% with warfarin; [RR 1.69, 95% CI ( )]

Outcome Parameters for Trials in AF Recommendations from a consensus conference organized by the German AF Competence NETwork (AFNET) and the EHRA EHRA = European Heart Rhythm Association. Kirchof P, et al. Europace. 2007;9(11): AF Trial Endpoints Symptoms QoL Recurrence of AF LV function Exercise tolerance Major adverse cardiac events All hospitalizations CV hospitalizations CV, all-cause mortality Thromboembolism

NIH = National Institutes of Health. Calkins H, et al. Heart Rhythm. 2007;4(6): Marrouche NF, et al. Pacing Clin Electrophysiol. 2009;32(8): Ongoing Ablation Trials CABANA: Catheter Ablation vs AAD for AF –NIH/industry-cooperative, 5-year study to investigate if mortality is improved with ablation compared to drug therapy (rate or rhythm control) CASTLE-AF: Catheter Ablation vs Standard Conventional Treatment in Patients with LV Dysfunction and AF –Time to first event of death or hospitalization for HF

Comprehensive management of AF should address its multiple impacts In addition to stroke prevention and reduction of AF burden,* successful management of AF should also aim at further reducing hospitalizations and costs, as well as CV morbidity and mortality Prevention of thrombo- embolism Reduction of AF burden*  QoL  Symptoms Reduction in the risk of CV events and hospitalizations and costs Reduction in mortality *Total percentage of time a patient has AF as determined by the number and duration of AF episodes. Wolf PA, et al. Stroke. 1991;22: Singh SN, et al. J Am Coll Cardiol. 2006;48: Prystowsky EN. J Cardiovasc Electrophysiol. 2006;17(Suppl 2):S7-S10. Hohnloser S, et al. J Cardiovasc Electrophysiol. 2008;19: Camm AJ, et al. Eur Heart J Suppl. 2008;10(Suppl H):H55-H78. New Goals of AF Management

Summary AF is a common disease that is increasing in prevalence For any patient with AF, decisions need to be made regarding antithrombotic therapy, rate control, and/or rhythm control Guidelines provide recommendations for the management of patients with AF Anticoagulation is essential in AF patients with risk markers, regardless of any restoration of SR New agents and procedures may provide antiarrhythmic and antithrombotic options with improved outcomes for managing AF