Disclosures for Albert L. Waldo, M.D.

Alternative Anticoagulation Stgies in Atrial Fibrillation: Issues and Answers? Albert L. Waldo, MD The Walter H. Pritchard Professor of Cardiology, Professor of Medicine, and Professor of Biomedical Engineering Case Western Reserve University Disclosures for Albert L. Waldo, M.D. Research Contract: none Consulting: *Biotronik; *St. Jude Medical; *Daiichi Sankyo; **Medtronic Ablation Frontiers; **Astellas Pharma; Biosense Webster; sanofi-aventis; Bristol-Myers Squibb; Portola Pharmaceuticals; Ortho-McNeil-Janssen Pharmaceuticals; Boehringer Ingelheim; CardioInsight; Merck; AtriCure Speaker: sanofi aventis, Harrington-McLaughlin Heart & Vascular Institute HarringtonUniversity Hospitals Case Medical Center Division of Cardiovascular Medicine Cleveland, Ohio Characterizing Atrial Fibrillation Atrial Fibrillation (AF) is the most common sustained arrhythmia in the Western world > 8% of individuals with AF are > 5 years of age At present, just > 5% of individuals with AF are > 75 years of age Soon, 5% of individuals with AF will be > 8 years of age Projected prevalence of AF 5. to million Americans by 5 Lifetime incidence of AF: in individuals > years of age Go AS, et al. JAMA. ;85:37-375. Lloyd-Jones DM et al. Circulation. ;:-. Miyasaka Y, et al. Circulation. ;:9-5. Problems With Delayed onset/offset of action Narrow therapeutic range Unpredictable dose response Metabolized by CYP5s (especially C9) Common genetic polymorphisms (especially C9) affect dose requirements Numerous drug drug drug, drug drug food interactions Variable anticoagulant response necessitates coagulation monitoring and dose adjustments Slow reversibility Inconvenience for patient and physician The above most likely contribute to warfarin underuse Modified after Ansell et al. Chest. ;9:S-38S. Hirsh et al. Chest. ;9:S-9S. Preadmission Medications for Patients with Known AF Admitted with Stroke Prevalence of Eligible AF Patients Receiving Therapy is prescribed for only % to 5% of eligible patients with AF, many of whom are considered warfarin-unsuitable Percent patients treated with warfarin *clinical trial steering committee **clinical trial DSMB 5 55 5 5 5 5 ATRIA N=,8 NABOR N=95 N=53 Medicare N=7,7 N=,995 N=5,7 ATRIA=Anticoagulation and Risk Factors in Atrial Fibrillation, NABOR=National Anticoagulation Benchmark and Outcomes Report Gladstone DJ et al. Stroke 9;:35-.Go AS et al. Ann Intern Med. 999;3:97-93..Waldo AL et al. J Am Coll Cardiol. 5;:79-73. 3.Hylek EM et al. Stroke. ;37:75-8..Birman-Deych E et al. Stroke. ;37:7-7. Euro Heart Study7 N=,7 5.Walker AM, Bennett D. Heart Rhythm. 8;5:35-37..Williams CJ et al. American College of Cardiology 58th Scientific Session; March 9-3, 9; Orlando, FL. 7.Nieuwlaat R et al. Eur Heart J. ;7:38-3.

ACTIVE* W: Cumulative Risk of Stroke * Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events Cumulative hazard s. =.7 (.-.37) P=.. 8.%/yr. Clopidogrel + aspirin..%/yr. Oral anticoagulation therapy Number at risk.5.5 Clopidogrel + aspirin 3335 38 Years 9 9 Oral anticoagulation therapy 337 33 93 Primary outcome: Stroke, Systemic Embolus, MI, Vascular Death CL+ = 5.% Risk/Year vs W = 3.93% Risk/Year Connolly S, et al. Lancet. ;37:93-9. Key AF Stroke Risk Factors: CHADS Risk Stratification Scheme C Points Congestive heart failure (recent) H Hypertension A Age 75 years D Diabetes S Prior stroke or TIA TIA = transient ischemic attack Stroke Rate (%) Risk Factor 5.5 8.5 5 8. Based on,773 NRAF Pts.9.8 5.9 3 CHADS Score 5 Gage et al. JAMA. ;85:8-87. (A) Fang M et al. J Am Cardiol 8;5:8-5 Conclusions Fang MC et al. J Am Coll Cardiol 8;5:8-5

Conclusions. Current risk stratification schemes used to predict TE in persons with nonvalvular AF have similar discriminatory ability, but the ability is relatively poor.. Until better means of risk stratification are available, a large proportion of patients with AF who would not have developed TE may be exposed to the risks associated with warfarin therapy. 3. Differences across risk schemes could potentially lead to substantial variation in whether or not individual patients are recommended for warfarin therapy.. Need better discriminators to identify for those who will sustain a TE event or who will suffer complications from anticoagulant therapy. Fang MC et al. J Am Coll Cardiol 8;5:8-5. Stroke Risk Stratification in AF CHADS-VASc CHADS Risk Factor Cardiac failure HTN Age 75 y Diabetes Stroke Score Risk Factor Cardiac failure HTN Age 75 y Diabetes Stroke Vascular disease (MI, PAD, aortic atherosclerosis) Age 5-7 y Sex category (female) Score Total Score Risk of Stroke (%).9.8.3.. 3 CHADS 5.9 3. CHADS-VASc 8.5. 5.5.7 8. 9.8 7 9. 8.7 9 5. Lip GY, Halperin JL. Am J Med. ;3():8-88. Camm AJ, et al. Eur Heart J. ;3(9):39-9. CHADSVASc Thromboembolic Risk Score www.escardio.org Risk Factor / CHADSVASc and Therapy CCVS AF Guidelines Cairns JA, et al. Can J Cardiol ;7:7-9. www.escardio.org 3

Assessment of Bleeding Risk HAS-BLED Score Hypertension (SBP > mm Hg) Abnormal renal/liver function ( point each) Stroke Bleeding Labile INRs Elderly (age > 5) Drugs or alcohol ( point each) Maximum score Coagulation Cascade Score or or 9 HAS-BLED score of 3 suggests increased bleeding risk and warrants some caution and/or regular review. SBP = systolic blood pressure; INR = international normalized ratio. Initiation Vlla/TF Propagation IXa VllIa acts on II, VII, IX, and X Xa Prothrombin II Va IIa (Thrombin) Fibrin Formation Fibrin Fibrinogen Pisters R et al. Chest ; pub online March 8. DOI:/378/chest.-3. New Oral Anticoagulants X IX New Anticoagulants: Comparison Of RCTs Unmet Clinical Needs in the Treatment of AF - 9% of all strokes are due to AF - Stroke risk can be reduced by 7% with treatment - grossly underused - Use of new, effective, and safe oral agents offers the prospect of simplified (fixed) dosage, rapid onset of action, absence of need for monitoring, and few drug drug and drug food interactions AF Modified after Turpie AG Eur Heart J 8;9:55-5 Dabigatran Etexilate RE-LY: A Non-inferiority Trial Competitive inhibitor of thrombin Atrial fibrillation Risk Factor Absence of contra-indications 95 centers in countries Prodrug - converted completely to active dabigatran Orally active; peak plasma concentration at hours postdose; T ½: 7 hours Extensively metabolized, mainly by CYP3A; proton pump inhibitors reduce absorption; bioavailability is increased by meals Eliminated predominantly by kidneys (8%) Phase data identified mg BID and 5 mg BID as viable doses Stangier J et al. J Clin Pharmacol 5;5:555-53; Liesenfeld KH et al. Br J Clin Pharmacol ;:57-537; Stangier J et al. Br J Clin Pharmacol 7;:9-33 PROBE=Prospective Randomized Open Trial with Blinded Adjudication of Events. R open (INR.-3.) N= Blinded Dabigatran Etexilate mg b.i.d. N= Dabigatran Etexilate 5 mg b.i.d. N= efficacy outcome = stroke or systemic embolism safety outcome = major bleeding Non-inferiority margin. NEJM 3: 39, 9

Stroke or Systemic Embolism. Hemorrhagic Stroke.3 <. <. Dabigatran 5 vs. Margin =..75 Dabigatran better..5 HR (95% CI) Dabigatran.5 Dabigatran5 better.5 NEJM 3: 39, 9..5 Years of Follow-up..5 Cardioversion in RE-LY Bleeding D mg D 5mg warfarin 95% CI p 95% CI p Total.%.% 8.%.78.7-.83 <..9.8-.97. Major.7 % 3. % 3. %.8.9-.93.3.93.8-.7.3 LifeThreatening major. %.5 %.8 %.8.55-.83 <..8.-.99. Gastrointestinal Major. %.5 %. %..8-..3.5.9-.89 <. Major bleeding = D 5 mg vs. =. 95% CI =.-.9 P <...5 NEJM 3: 39, 9 D mg vs. =.3 95% CI =.7-.5 P <.. <. Cumulative Hazard Rates Dabigatran vs..3 Superiority p-value. Non-inferiority p-value D mg vs. D 5mg vs. HGB > g/l, transfusion > units, or sympt. bleeding in a critical area or organ Cardioversions (n=,983) were performed in,7 pts: 7 pts on mg bid, 7 pts on 5 mg bid, and pts on warfarin. DC: 53, 55, 553; and pharmacologic: 9,,, respectively. TEE was performed in 5.5%,.%, and 3.3% of D, D5, and warfarin, respectively, with.8%,.%, and.% positive, respectively. Stroke and systemic embolism by 3 days occurred in.77,.3, and. % of pts, respectively. These were not statistically different (with p=. for 5 bid vs warfarin and p=.7 for bid vs warfarin), but the RE-LY trial was not powered for this analysis. There were no differences in major bleeding. There were no differences with vs without TEE This is the largest cardioversion experience published to date! NEJM 3: 39, 9 Nagarakanti et al. Circulation ; 3:3-3 ROCKET AF Trial: Turpie ACG Eur Heart J E Pub Dec.7, 7 mg once daily R N =, 5 mg once daily (creatinine clearance 3-9 ml/min at entry) target INR,.5 (INR range,.-3.) Day Follow-up Nonvalvular AF, history of stroke, TIA, or embolism, or at least of the following: HF, HTN, age 75 years, or diabetes mellitus End of treatment Treatment period -3 months Direct inhibitor of coagulation Factor Xa Well toled Half-life up to hrs in elderly subjects; up to 9 hrs in healthy subjects No direct effect on platelet aggregation Potently inhibits free and clot-associated Factor Xa activity Rapid onset of action (Tmax - hrs) Elimination /3 renal (unchanged); /3 liver metabolism Low propensity for clinically relevant drug-drug interactions Day 3 after last dose In AF patients with a mode to high risk of stroke, does rivaroxaban reduce the risk of major vascular compared with warfarin? study end point: composite of all-cause stroke and non-cns systemic embolism end points: composite of TIA, all-cause death, vascular death, and MI safety end point: composite of major and clinically relevant nonmajor bleeding Randomization completed in June 9; follow-up completed Follow-up: up to years (until 5 primary outcome have been observed) TIA = transient ischemic attack; ROCKET = Randomized, Double-Blind Study Comparing Once Daily Oral With Adjusted-Dose Oral for the Prevention of Stroke in Subjects With Non-Valvular Atrial Fibrillation. ROCKET AF Study Investigators. Am Heart J. ;59(3):3-37.e. 5

Primary Efficacy Outcome Stroke and non-cns Embolism Rocket-AF: Baseline Demographics (N=79) 3.8 3 3 9 3 3. 3 8 Prior VKA Use (%) 3 Congestive Heart Failure (%) 3 Hypertension (%) 9 9 Diabetes Mellitus (%) 39 Prior Stroke/TIA/Embolism (%) 55 55 Prior Myocardial Infarction (%) 7 8 CHADS Score (mean) (%) 3 (%) (%) 5 (%) (%) Cumulative event (%) (N=78) 5 Event Rate HR (95% CI):.79 (.,.9) P-value Non-Inferiority: <. No. at risk: 958 7 3 8 7 8 9 37 578 59 58 55 37 378 7 539 9 538 3 55 Mahaffey KW et al. AHA presentation Chicago /5/ Event Rates are per patient-years Based on Protocol Compliant on Treatment Population Stroke and Non-CNS Embolism On Treatment * Event Rate Event Rate.7. N=,3 ITT N=,7 ROCKET-AF Outcome HR (95% CI) P-value.5.79 (.5,.95).5..88 (.7,.3).7 TTR 57.8% better Average CHADS score 3.7 * is not FDA-approved. Event s are per patient-years. Based on safety on treatment or ITT thru site notification populations. ITT = intention to treat. Califf RM. Presented at: American Heart Association Scientific Sessions; November 5, ; Chicago, IL. (n=78) (n=79) Hazard ratio (95% CI) p.7..79 (..9) <..5 Primary end point, noninferiority Primary end point, ontreatment superiority.7.5.79 (.5.95) Primary end point, intention-to-treat superiority...88 (.7.3).7 Vascular death, stroke, embolism 3. 3.3.8 9.7.99).3 Hemorrhagic stroke...59 (.37.93)..58.3 Ischemic stroke.3..9 (.75.7) Unknown stroke...5 (.5.7) Mahaffey KW et al. AHA presentation Chicago /5/ ROCKET AF: Key Secondary Efficacy Outcomes Event Rate Event Rate HR (95% CI) P-value.5.8.9 (.8,.5).5 Stroke Type Hemorrhagic Ischemic Unknown type...5....58 (.38,.89).99 (.8,..5 (.55,.)..9.87 Non-CNS Embolism...7 (.,.3.38 MI...9 (.7,.). All Cause Mortality Vascular Nonvascular Unknown cause.5.9.5..9 3...57.9 (.8,.3).9 (.8,.8).9 (.75,.8).8 (.57,.).5.35..95 Event s are per patient-years. Based on ITT population. Days from Randomization ROCKET AF: Primary Efficacy Outcome Vascular Death, Stroke, Embolism. 3 Based on Intention-to-Treat Population better.7 ROCKET-AF Outcome (n=78) (n=79) Hazard ratio (95% CI) p Major and nonmajor bleeding Major bleeding.9.5.3 (.9.). 3. 3.5. (.9.).57 > g/dl hemoglobin.77.. (.3.).9.5.3.5 (..55)..8.8.9 (.53.9).7..8.5 (.3.79).3.9.7.7 (.7.9).9 drop Transfusion Critical organ bleeding Bleeding causing death Intracranial hemorrhage Mahaffey KW et al. AHA presentation Chicago /5/ Mahaffey KW et al. AHA presentation Chicago /5/

Rocket-AF: Summary CHADS Scores: RE-LY and ROCKET-AF Efficacy: RE-LY (a) was non-inferior to warfarin for prevention of stroke and non-cns embolism. was superior to warfarin while patients were taking study drug. By intention-to-treat, rivaroxaban was non-inferior to warfarin but did not achieve superiority. (b) CHADS Score Dabigatran mg Dabigatran 5 mg Mean... 3.8 3. - 3.% 3.%.% 3.7% 35.% 37.% 3% 3% 3-3.7% 3.% 3.% 87% 87% Safety: Similar s of bleeding and adverse. ROCKET-AF Less ICH and fatal bleeding with rivaroxaban. Conclusion: a) Connolly SJ et al. N Engl J Med 9;3:39-5 is a proven alternative to warfarin for mode or high risk patients with AF. b) Data presented by Mahaffey KW. AHA; ; Chicago. ROCKET AF Compared with RE-LY ROCKET AF ROCKET AF Compared with RE-LY RE-LY ROCKET AF RE-LY 58% 7% N,7 8,3 VKA naive 37% 5% Design Randomized, double-blind, double-dummy study PROBE design Treatment Dabigatran CHADS (mean) 3.7. dose (with dose adaptation for mode renal impairment) doses Previous TIA/CVA 55% % Regimen Once daily Twice daily Primary outcome HR.79. (5 dose) Primary outcome Efficacy: Composite of all-cause stroke and non-cns systemic embolism Efficacy: Incidence of stroke (including hemorrhagic) and systemic embolism Hemorrhagic CVA.. (5 dose) Safety: Composite of major and clinically relevant nonmajor bleeding Secondary outcome Each category of bleeding, and adverse Composite of TIA, all-cause death, vascular death, and MI TTR (median) Safety: Major bleeding Incidence of stroke (including hemorrhagic), systemic embolism, all death, pulmonary embolism, MI, TIA, vascular deaths (including deaths from bleeding), and hospitalizations ROCKET AF Investigators. Am Heart J. ;59:3-7.e. Connolly SJ, et al. N Engl J Med. 9;3:39-5. Ischemic CVA: HR.99.75 (5 dose) Major Bleeding 3.% 3.3% (5 dose) ROCKET AF Study Investigators. Am Heart J. ;59:3-37.e. Connolly SJ, et al. N Engl J Med. 9;3:39-5. ARISTOTLE Trial: Oral, direct, selective factor Xa inhibitor N No formation of reactive intermediates No organ toxicity or liver function test abnormalities in chronic toxicology studies O N Double-blind N O No food effect Balanced elimination (~5% renal) T/: ~ hours R 5 mg twice daily.5 mg twice daily in selected patients* Low likelihood of drug interactions or QTc prolongation Good oral bioavailability E NH N O INR,.-3. AF or atrial flutter 8, randomized O Produces concentration-dependent anticoagulation Is apixaban noninferior to standard therapy (warfarin) in preventing stroke and systemic embolism in mode- to high-risk (stroke, at least risk factor) AF/AFL patients? efficacy end point: confirmed ischemic or hemorrhagic stroke, or systemic embolism efficacy end points: composite of confirmed ischemic or hemorrhagic stroke, systemic embolism, and all-cause death safety end point: time to first occurrence of confirmed major bleeding Treatment period: up to years (until 8 primary outcome have been observed >9% power to demonst noninferiority) Stratified by warfarin-naïve status *At least of the following: age 8 years, weight kg, or serum creatinine.5 mg/dl. ARISTOTLE = for reduction in stroke and other thromboembolic in atrial fibrillation. He K, et al. Blood. ;8:9. Lassen MR. Blood. ;8:57 Lopes RD, et al. Am Heart J. ;59(3):33-339. 7

AVEOES: Stroke or Systemic Embolic Event AVEOES Trial Unsuitable for warfarin therapy 8-3 mg daily up to 3 mo/end of study N= 5 R 5 mg twice daily.5 mg twice daily in selected patients* up to 3 mo/end of study Is apixaban more effective than in preventing stroke and systemic embolism in mode to high-risk (stroke, at least risk factor) AF patients? efficacy end point: confirmed ischemic or hemorrhagic stroke or systemic embolism study end points: as above, including MI or vascular death safety end point: major bleeding Study period: until primary outcome have been observed In June, the study was stopped early because a predefined interim analysis revealed clear Number at Risk 79 89 AVEOES = Versus to Reduce the Risk of Stroke. Eikelboom JW, et al. Am Heart J. ;59(3):38-353.e. http://www.theheart.org/article/879.do.. Connolly SJ, et al. Presented at: European Society of Cardiology; ; Stockholm, Sweden.. 89 79 Randomized Age (mean and SD) 7 ± yrs 7 ± yrs Male (59%) 5 (%) CHADS score (mean and SD) - 3+. ±. 5 (3%) (37%) 7 (7%).±. 7 (37%) 959 (3%) 8 (9%) Prior stroke/tia 389 (%) 375 (%) Diabetes 537 (9%) 558 (%) Hypertension (87%) (8%) CHF 3 (%) 5 (38%) Baseline (7%) 7 (7%) Prior VKA use and discontinued 83 (39%) 89 (39%) Outcome Stroke, MI, SEE or Vascular Death.3 MI Vascular Death 7 8 Months 5 53 7 39 353 Major 7 Clinically Relevant Nonmajor Minor vs. 95% CI P...8.77-.78.5 9 3.3 8.9.5.85-.53.37 55 5.7..35.5-.78. Fatal. 7..57.7-.9.38 Intra-cranial 3..3.9.53-..3 Connolly SJ, et al. N Engl J Med. Feb. [Epub ahead of print] AVEOES: Bleeding Events vs. 95% CI P 8.7.5.5-.8 <..7 7.9.8.-.3.7 75. 9 3..8.-..5 CV Hospitalization 339.8 3.3.79.8-.9. Total Death 3 3. 3.7.77.59-.99. Connolly SJ, et al. N Engl J Med. Feb. [Epub ahead of print] 9 5 57 Outcome AVEOES: and Other Efficacy Outcomes 7 7 AVEOES: Bleeding Events Connolly SJ, et al. N Engl J Med. Feb. [Epub ahead of print] 3 Connolly SJ, et al. N Engl J Med. Feb. [Epub ahead of print] Baseline Characteristics Characteristic evidence of a clinically important reduction in stroke and systemic embolism *At least of: age 8 years, weight kg, or serum creatinine.5 mg/dl..3 Cumulative Risk Relative Risk =. 95% CI,.33-. P<..5 Double-blind.. E Outcome Major 7. Clinically Relevant Nonmajor 9 3.3 Minor 55 Fatal Intra-cranial vs. 95% CI P..8.77-.78.5 8.9.5.85-.53.37 5.7..35.5-.78.. 7..57.7-.9.38 3..3.9.53-..3 Connolly SJ, et al. N Engl J Med. Feb. [Epub ahead of print] 8

Characteristics of Edoxaban...5 Relative Risk =. 95% CI,.7-.75 P=.5.5. Cumulative Risk AVEOES: Major Bleeding 3 Number at Risk 79 89 9 8 Months 7 57 5 57 3 73 57 9 3 5 357 Connolly SJ, et al. N Engl J Med. Feb. [Epub ahead of print]. Potent and specific inhibitor of factor Xa Bioavailability over 5% Rapidly absorbed - Cmax - hours Half-life of 8 to hours Multiple pathways of excretion: 3% renal and 5% hepatic Linear PK, providing a predictable and consistent exposure Exposure to edoxaban increases with renal dysfunction and low body wt (< kg) It is a subst for the efflux transporter p-glycoprotein (P-gp) reduced dosage of edoxaban may be needed when coadministered with strong P-gp inhibitors (e.g., verapamil, quinidine) Once daily regimens associated with less bleeding than twice daily regimens Weitz JI. Presented at the 5 th ASH meeting. -7-8 San Francisco, CA; Ruff CT et al. Am Heart J ;:35- ENGAGE AF TIMI 8: Edoxaban Summary. Once-daily edoxaban dosing regimens are associated with less bleeding than twice-daily regimens INR,.-3. AF >, patients E 3 treatment arms R Double-blind Edoxaban. Edoxaban, at 3 or mg OD, appears to have a safety profile similar to that of warfarin (target INR of to 3) mg vs 3 mg qd Weitz JI. Presented at the 5 th American Society for Hematology meeting. -7-8 San Francisco, CA Is edoxaban noninferior to standard therapy (warfarin) in preventing stroke and systemic embolism in modeto-high-risk (CHADS score ) AF patients? efficacy end point: composite primary end point of stroke and systemic embolic efficacy end points: composite clinical outcome of stroke, systemic embolic, and all-cause mortality; also major bleeding Treatment period: up to years ENGAGE AF TIMI = Global Study to Assess the Safety and Effectiveness of DU-7b vs Standard Practice of Dosing With in Patients with Atrial Fibrillation. ClinicalTrials.gov identifier NCT7839. Clinical Challenges With New Oral Anticoagulants No validated tests to measure anticoagulation effect No established therapeutic range No antidote for most agents Assessment of compliance more difficult than with vitamin K antagonists Potential for unknown long-term adverse Balancing cost against efficacy Lack of head-to-head studies comparing new agents Sobieraj-Teague M, et al. Semin Thromb Hemost. 9;35:55-5. Baseline Characteristics of the AF Ablation Treated Patients Measure AF type Paroxysmal Persistent Permanent CHADS > Total population, % (n=3355) Off OAC therapy, % (n=9) On OAC therapy, % (n=3) p 8 5 <. <..9 53 9 8 7 3 3 39 37 <. <. <. Themistoclakis S, et al. J Am Coll Cardiol ; 55:735-73. 9

PROTECT AF Trial: WATCHMAN LAA Closure Device in situ Themistoclakis S, et al. J Am Coll Cardiol ; 55:735-73. 3838-8