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Thrombosis Reduction for Heart Disease Thrombosis Risk Reduction: An Overview New Frontiers in Thrombosis Reduction for Heart Disease Focus on Novel Agents Across the ACS and AF Risk Spectrum— A Year 2010 Advanced Practice Summit for the Cardiovascular Specialist   Deepak L. Bhatt, MD, MPH, FACC, FAHA, FSCAI Program Chairman Chief of Cardiology, VA Boston Healthcare System Director, Integrated Interventional Cardiovascular Program Brigham and Women’s Hospital and the VA Boston Healthcare System Associate Professor of Medicine, Harvard Medical School Senior Investigator, TIMI Group

Welcome and Program Overview CME-certified symposium jointly sponsored by the Postgraduate Institute of Medicine and CMEducation Resources, LLC Commercial Support: Sponsored by an independent educational grant from the Bristol-Myers Squibb/Pfizer Partnership Faculty disclosures: Listed in program syllabus

Program Faculty Deepak L. Bhatt, MD, MPH, FACC, FAHA, FSCAI Program Chairman Chief of Cardiology, VA Boston Healthcare System Director, Integrated Interventional Cardiovascular Program Brigham and Women’s Hospital and the VA Boston Healthcare System Associate Professor, Harvard Medical School Senior Investigator, TIMI Group Boston, Massachusetts USA    Gregory Y.H. Lip, MD, FRCP, FACC, FESC Consultant Cardiologist and Professor of Cardiovascular Medicine Director, Haemostasis Thrombosis & Vascular Biology Unit University of Birmingham Centre for Cardiovascular Sciences City Hospital Birmingham, England   Shamir Mehta, MD, MSc, FACC, FRCPC Director, Interventional Cardiology Hamilton Health Sciences Associate Professor McMaster University Hamilton, Ontario, Canada   David A. Garcia, MD Associate Professor, Division of General Internal Medicine University of New Mexico Co-Director, University of New Mexico Anticoagulation Management Service President, Anticoagulation Forum Albuquerque, New Mexico USA Richard C. Becker, MD Professor of Medicine School of Medicine Duke University Director, Duke Cardiovascular Thrombosis Center Duke Clinical Research Institute Durham, North Carolina USA

Issues We Will Address Changing landscape for AFIB with Factor II and Xa inhibitors, and how cardiologists will respond The various risk groups for AFIB including de novo patients, patients who have failed coumadin for one reason or another (erratic TTRs or bleeding) and patients who do not want to take coumadin or are not deemed suitable candidates Pushing the envelope on ACS prevention with triple therapy and whether non-coumadin systemic anticoagulation might offer the opportunity to more favorably balance the benefit-to-risk ratio, a possibility given the reduced ICH and major bleed rate with low-dose dabigatran

Issues We Will Address Will "milder, gentler" but non-inferior, and perhaps superior oral, non-monitored anticoagulation offer new opportunities and new challenges for risk stratifying subsets of patients with AF and ACS? Is warfarin on the path to extinction or will it reinvent itself with the aid of pharmacogenomic guidance, algorithm-directed care, patient self-monitoring, and a host of “let's make coumadin as good as we can” maneuvers?

Atrial Fibrillation and ACS: The Changing Antithrombotic Landscape New Dimensions and Landmark Practice Advances Atrial Fibrillation and ACS: The Changing Antithrombotic Landscape Deepak L. Bhatt, MD, MPH, FACC, FAHA, FSCAI Chief of Cardiology,VA Boston Healthcare System Director, Integrated Interventional Cardiovascular Program,   Brigham and Women’s Hospital and the VA Boston Healthcare System Associate Professor of Medicine, Harvard Medical School Senior Investigator, TIMI Group Boston, Massachusetts

Atherothrombosis: Clinical Manifestations Stroke TIA Intracranial stenosis Acute coronary syndromes STEMI NSTEMI Unstable angina Stable CAD Atrial Fibrillation Angioplasty Bare metal stent Drug eluting stent CABG Carotid artery stenosis CEA Carotid stenting Renal artery stenosis Renal artery stenting Peripheral arterial disease Acute limb ischemia Claudication Amputation Endovascular stenting Peripheral bypass Abnormal ABI Abdominal aortic aneurysm (AAA) Meadows TA, Bhatt DL. Circ Res. 2007;100:1261-1275.

Polyvascular Disease: ~15% of Patients with Stable Atherosclerosis ~25% of Patients with CAD Also Have Disease in Other Arterial Territories CAD = coronary artery disease PAD = peripheral arterial disease CVD = cerebrovascular disease CAD This slide shows the incidence of symptomatic disease in additional arterial beds in patients with documented coronary artery disease (CAD). Percentages shown are of total REACH population. The CAD population comprises 59.3% of the total REACH Registry population.1 44.6% have CAD alone 8.4 % also have cerebrovascular disease (CVD) 4.7% also have peripheral arterial disease (PAD) In total, 1.6% of the REACH Registry population have CAD, CVD and PAD.1 Reference 1. Bhatt DL et al, for the REACH Registry Investigators. International prevalence, recognition, and treatment of cardiovascular risk factors in outpatients with atherothrombosis. JAMA 2006;295:180–189. 8.4% CVD 1.6% 4.7% PAD Bhatt DL, Steg PG, Ohman EM, et al, on behalf of the REACH Investigators. JAMA 2006;295:180-189.

One-Year CV Event Rates Increase with Number of Symptomatic Disease Locations Patients (%) The risk of major adverse cardiovascular event clearly increases with increased symptomatic arterial bed involvement. This provides further support for the overlap of symptomatic locations affecting and increasing event rates, rather than only initial symptomatic bed. Asymptomatic patients with ≥3 risk factors are classified as 0; even in the presence of asymptomatic carotid plaque or reduced ankle brachial index (ABI). Indeed, only considering symptomatic polyvascular disease may have resulted in an underestimation of the impact of polyvascular disease.1 Percentage rates are adjusted for age, gender, smoking, diabetes, hypertension and hypercholesterolemia.1 Atherothrombotic events include: transient ischemic attack unstable angina other ischemic arterial events including worsening of peripheral arterial disease1 Reference 1. Steg G et al, on behalf of the REACH Registry Investigators. One Year Cardiovascular Event Rates in Outpatients with Atherothrombosis. JAMA 2007; 297 (11): 1197-1206. CV Death Non-Fatal MI Non-Fatal Stroke CV Death/ MI/Stroke CV Death/ MI/Stroke/Hosp* MI=myocardial infarction; *Such as transient ischemic attack, unstable angina, worsening of peripheral arterial disease; adjusted for age and gender Steg PG, Bhatt DL, Wilson PF, et al, on behalf of the REACH Investigators. JAMA 2007;297:1197-1206.

ATRIA: Prevalence of AF Increases with Age 12 10 8 Prevalence (%) 6 4 The Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) study was a cross-sectional analysis of 1.89 million adults aged 20 years or older enrolled in a large group-model health maintenance organization. The total prevalence of AF was 0.95%. It is estimated that there are currently 2.3 million US adults with AF. 2 <55 55-59 60-64 65-69 70-74 75-79 80-84 ≥85 Age (years) Men (n = 10,173) Women (n = 7801) AF = atrial fibrillation Go AS et al. JAMA. 2001;285:2370-5.

Atrial Fibrillation and Atherothrombosis: Risks and Management Goto S, Bhatt DL, Röther J, Alberts M, Hill MD, Ikeda Y, Uchiyama S, D’Agostino R, Ohman EM, Liau C-S, Hirsch AT, Mas J-L, Wilson PWF, Corbalán R, Aichner F, Steg Ph G, on behalf of the REACH Registry Investigators. Am Heart J 2008;156:855-863.

Atrial Fibrillation in CAD: Prevalence in the REACH Registry 37,724 stable outpatients with CAD AF, atrial fibrillation. Goto S et al, on behalf of the REACH Registry Investigators. Am Heart J 2008;156:855-863.

Atrial Fibrillation Rates by Patient Group Greater incidence of AF in patients with vascular disease compared with patients with risk factors only Goto S et al, on behalf of the REACH Registry Investigators. Am Heart J 2008;156:855-863.

CV Event Frequency in AF and non-AF Patients Combined event of CV death and/or nonfatal MI and/or nonfatal stroke in patients with vs without history of AF are shown after adjustment of age, gender, and classical risk factors Patients with a history of AF 10 Event rate of CV death/MI/Stroke (%) AF Non-AF 5 2 4 6 8 10 12 Time (months) Goto S et al, on behalf of the REACH Registry Investigators. Am Heart J 2008;156:855-863.

Atrial Fibrillation in CAD 37,724 patients with CAD: 12.5% prevalence of atrial fibrillation P < 0.0001 P < 0.0001 Patients (%) P < 0.0001 Goto S et al, on behalf of the REACH Registry Investigators. Am Heart J 2008;156:855-863.

Annual Rate of CV Death in AF and Non-AF Patients ** ** ** ** * The rates of combined end points of CV death, non fatal myocardial infarction and non fatal stroke are two times more in AF group than non AF group and results are consistent in all symptomatic patients subgroup. *p<0.05 **p<0.01 Multivariate analysis

CHADS2 Score Defined and Validated to Predict Stroke in Atrial Fibrillation Patients 1-y Stroke rate 6 13.7% 5 12.3% 4 10.9% 3 8.6% 2 4.5% 1 2.2% 0.8% points Congestive HF 1 Hypertension Age > 75 yr Diabetes Stroke 2 Sum Gage BF, JAMA 2001;285(22):2864-2870 Gage BF, Circulation 2004;110;2287-2292

Annual CV Event Risk in AF Patients by CHADS2 Score CHADS2 score classification was useful in predicting not only stroke but also CV death in stable outpatients with or at high-risk for atherothrombosis, but not as useful in the prediction of nonfatal MI Annual event rate (%) CHADS2 score Goto S et al, on behalf of the REACH Registry Investigators. Am Heart J 2008;156:855-863.

Annual Rate of Serious Bleeding in AF Patients with/without Anticoagulant 4,725 stable CAD outpatients with atrial fibrillation P = 0.0025 Goto S et al, on behalf of the REACH Registry Investigators. Am Heart J 2008;156:855-863.

Medication Use and Risk Factor Control in AF and Non-AF Patients Approximately 50% of patients with AF receive anticoagulation therapy. Oral anticoagulants are underused in patients who have a history of AF Variable, % AF + (n=6,814) AF – (n=56,775) P value Aspirin 49.51 69.44 < 0.0001 Any two antiplatelet agents 9.66 13.58 Oral anticoagulants 36.17 3.83 At least one lipid lowering agent 87.74 89.77 At least one CV agent 97.58 95.67 At least one anti-diabetic agent 81.76 86.85 Goto S et al, on behalf of the REACH Registry Investigators. Am Heart J 2008;156:855-863.

Summary High prevalence of AF among patients with or at high-risk of atherothrombosis Lower use of oral anticoagulants in AF patients even though they have risk factors for ischemic stroke, probably due to the use of antiplatelet agents for the treatment of atherothrombosis 1-year follow-up data show that the presence of AF was associated with serious and multiple CV events including a higher rate of all-cause and CV mortality, nonfatal stroke and a modest increase in the risk of nonfatal MI and unstable angina There is a need for the optimal antithrombotic therapy among AF patients to be clarified to balance the increased risk of thrombotic events and the increased risk of bleeding associated with combined anticoagulant and antiplatelet therapy Goto S et al, on behalf of the REACH Registry Investigators. Am Heart J 2008;156:855-863.

Design of ACTIVE Program Documented AF + 1 risk factor for stroke Unsuitable for VKA ACTIVE W C and ASA vs VKA ACTIVE A C and ASA vs ASA ACTIVE is a phase III, multicenter, multinational, parallel randomized controlled evaluation of clopidogrel plus ASA, with factorial evaluation of irbesartan, for the prevention of vascular events in patients with atrial fibrillation. Patients will be enrolled over 2 years and followed to common termination date (expected to be about 4 years after enrollment of the first patient). About 14,000 patients will be included in the ACTIVE W or ACTIVE A trials. Due to the partial factorial design, patients will only be randomized in ACTIVE I once first randomized into either ACTIVE A or ACTIVE W. Three separate but related trials are included in the ACTIVE study. These are known as ACTIVE W, ACTIVE A, and ACTIVE I. ACTIVE W (n= 6,500): A multicenter, prospective, randomized, non-inferiority trial of clopidogrel plus ASA versus standard care oral anticoagulation (open trial with blinded outcome evaluation). ACTIVE A (n= 7,500): A multicenter, randomized, double-blind, placebo-controlled superiority trial of clopidogrel plus ASA versus ASA alone. ACTIVE I (n= at least 10,000): A multicenter, partial factorial, randomized, double-blind, placebo-controlled superiority trial of irbesartan. No exclusion criteria for ACTIVE ACTIVE I irbesartan vs placebo 23 23

ACTIVE-W Results Stopped early because OAC was clearly superior Annual Event Rate, % ASA + Clopidogrel OAC RRR (%) P Value Primary outcome 5.6 3.9 30 0.0003 Ischemic stroke 2.15 1.0 53 <0.0001 MI 0.86 0.55 36 0.09 Major bleed 2.4 2.2 8.6 0.53 ACTIVE Writing Group of the ACTIVE Investigators et al. Lancet. 2006;367:1903.

ACTIVE A: Primary Outcome Stroke, MI, Non-CNS Systemic Embolism, Vascular Death P=0.01 Cumulative incidence ASA only Clopidogrel + ASA 1 2 3 4 Years ACTIVE Investigators et al. N Engl J Med. 2009;360:2066.

ACTIVE A: Stroke ASA only Clopidogrel + ASA Cumulative incidence Years 1 2 3 4 Years ACTIVE Investigators et al. N Engl J Med. 2009;360:2066.

ACTIVE A: Bleeding Rates ASA (%/year) Clopidogrel + ASA (%/year) P Value Major Severe Fatal 1.3 1.0 0.2 2.0 1.5 0.3 <0.001 0.07 Minor 1.4 3.5 Any 5.7 9.7 ACTIVE Investigators et al. N Engl J Med. 2009;360:2066.

Therapeutic INRs With Warfarin in Clinical Trials Annual Event Rates in Warfarin Group Trial Year Published Baseline Systolic BP INR in Therapeutic Range (%) Warfarin-Naive (%) Ischemic Stroke (%) Total Stroke (%) Hemorrhagic Stroke (%) SPAF III 1996 140 61 44 1.9 2.4 0.5 SPORTIF III 2003 139 66 27 2.3 0.4 SPORTIF V 2005 132 68 16 1.1 1.2 0.1 ACTIVE W 2006 133 64 23 1.0 1.4 Connolly et al. Circulation. 2007;116:449.

ACTIVE W: Benefit of OAC by Time in Therapeutic Range Stroke, MI, Non-CNS Systemic Embolism, Vascular Death Stroke Stroke TTR <65% TTR ≥65% TTR <65% TTR ≥65% RR = 0.93 (0.70-1.24) P=0.61 RR = 2.14 (1.61-2.85) P<0.0001 RR = 1.22 (0.75-1.97) P=0.42 C + ASA C + ASA RR = 2.25 (1.45-3.49) P=0.0003 C + ASA Event rate (%) Event rate (%) OAC C + ASA OAC OAC OAC Years Years Years Years No. at Risk C + ASA 1598 1527 1156 439 OAC 1600 1525 1152 417 1737 1625 1233 488 1771 1697 1306 507 1598 1533 1164 441 1600 1531 1156 419 1737 1635 1255 500 1771 1702 1311 511 Connolly et al. Circulation. 2008;118:2029.

RE-LY: A Noninferiority Trial •Atrial Fibrillation with ≥ 1 Risk Factor for Stroke • Absence of Contraindications • Conducted in 951 centers in 44 countries R R Blinded Event Adjudication Open Open Blinded Warfarin Adjusted INR 2.0 – 3.0 N=6000 Dabigatran etexilate 110 mg BID N=6000 Dabigatran etexilate 150 mg BID N=6000 Connolly et al. N Engl J Med. 2009;361:1139.

RE-LY: Primary Outcome Stroke or Systemic Embolism Warfarin Dabigatran 110 mga Cumulative hazard rate Dabigatran 150 mgb Months aP=0.34 vs warfarin. bP<0.001 vs warfarin. Connolly et al. N Engl J Med. 2009;361:1139.

Oral Direct Factor Xa Inhibitors Currently in Development Drug Half-life (Hours) Bioavailability Elimination (%) Dosing Renal Hepatic Apixaban 12 50 25 75 Twice Daily Betrixaban 19 47 100 Once Daily Edoxaban 6-12 100% 62 35 Rivaroxaban 5-9 80 33 67 YM150 18-20 25-82 NR Once/Twice

Novel Oral Direct Factor Xa Inhibitors for Stroke Prevention in AF Trial N Treatment Arms Primary End Point(s) ROCKET-AF 14,000 Rivaroxaban 20 mg qd vs warfarin Stroke and systemic embolism ARISTOTLE 18,000 Apixaban 5 mg bid vs warfarin AVERROES 5600 Apixaban 5 mg bid vs aspirin (in patients deemed unsuitable or inappropriate for warfarin: superiority trial) ENGAGE AF – TIMI 48 16,500 Edoxaban 30 mg qd and 60 mg qd vs warfarin www.clinicaltrials.gov. 33

Thrombosis Risk Reduction in AF Need to weigh thrombotic, ischemic, and bleeding risks in atrial fibrillation patients Anticoagulation preferred if it can be done well Antiplatelet therapy has a role in some patients Novel agents likely to provide more options, perhaps even better efficacy and safety; including in patients who are not suitable candidates for VKA

New Dimensions and Landmark Practice Advances Challenges and Emerging Dimensions of Stroke Prevention in the Setting of Atrial Fibrillation (AF) Achieving Balance Between Thromboprophylaxis and Bleeding Reduction Gregory Y.H. Lip, MD FRCP FACC FESC Professor of Cardiovascular Medicine, University of Birmingham Visiting Professor of Haemostasis Thrombosis & Vascular Sciences, University of Aston Centre for Cardiovascular Sciences City Hospital Birmingham, England UK

Independent Predictors of Stroke in AF: A Systematic Review Multivariately significant Adjusted relative risk (95% CI) Prior stroke or TIA 5 of 5 studies 2.5 (1.8–3.5) Increasing age 6 of 6 studies 1.5/decade (1.3–1.7) History of hypertension or systolic BP >160 mmHg 2.0 (1.6–2.5) Diabetes 4 of 4 studies 1.8 (1.5–22) Female gender 3 of 6 studies 1.6 (1.4–1.9) Heart failure 0 of 4 studies* Not significant Coronary artery disease 0 of 4 studies *Significant in a subgroup of AFI pooled analysis participants who underwent echocardiography The Stroke Risk in AF Working Group. Neurology 2007;69:546–554

Stroke Risk Stratification in AF Past and Present Lip and Tse. Lancet 2007 August 18;370(9587):604-18

EHS: Antithrombotic Drug Prescription per Risk Category ACC/AHA/ESC guidelines (A), ACCP (B), CHADS2 score (C), and Framingham score (D). Eur Heart J 2006 27, 3018–3026

Potentially Preventable Strokes High-Risk Patients with AF Who Are Not Adequately Anticoagulated Preadmission medications in patients with known atrial fibrillation who were admitted with acute ischemic stroke (high-risk cohort, n=597) ‘In high-risk patients with AF admitted with a stroke …. most were either not taking warfarin or were subtherapeutic at the time of ischemic stroke. …..’ Preadmission medications in patients with known atrial fibrillation and a previous ischemic stroke/TIA who were admitted with acute ischemic stroke (very high-risk cohort, n=323) Gladstone et al Stroke 2008

Published Bleeding Risk Scores Low Moderate High Kuijer et al. Arch Intern Med 1999;159:457-60 1-3 >3 1.6 x age + 1.3 x sex +2.2 x cancer with 1 point for ≥60, female or malignancy and 0 if none Beyth et al. Am J Med 1998;105:91-9 1-2 ≥3 ≥65 years old; GI bleed in last 2 weeks; previous stroke; comorbidities (recent MI, Hct < 30%, diabetes, Creat > 1.5) with 1 point for presence of each condition and 0 if absent Gage et al. Am Heart J 2006;151:713-9 0-1 2-3 ≥4 HEMORR2HAGES score: liver/renal disease, ETOH abuse, malignancy, >75 years old, low platelet count or function, rebleeding risk, uncontrolled HTN, anemia, genetic factors (CYP2C9) risk of fall or stroke, with 1 point for each risk factor present with 2 points for previous bleed Shireman et al. Chest 2006;130:1390-6 ≤1.07 >1.07 - <2.19 >2.19 (0.49 x age >70) + (0.32 x female) + (0.58 x remote bleed) + 0.62 x recent bleed) + 0.71 x ETOH/drug abuse) + (0.27 x diabetes) + (0.86 x anemia) + (0.32 x antiplatelet drug use) with 1 point for presence of each and 0 if absent Tay, Lane & Lip Thromb Haemost 2008; 100: 955–957

Major Hemorrhage and Tolerability of Warfarin First Year of Therapy Among Elderly Patients With AF Major Bleed Taken Off Therapy CHADS2 Score N Rate (per 100 person-years) 95% CI 1 3.12 0.08 to 17.38 5 15.59 5.06-36.39 4 4.28 1.17 to 10.96 16 17.12 9.79 to 27.81 2 3 2.04 0.42 to 5.96 19 12.92 7.78 to 20.18 12 19.54 10.10 to 34.13 20 32.56 19.89 to 50.29 >4 6 23.42 8.59 to 50.97 9 35.12 16.06 to 66.68 Total 26 69 Distribution of Major Hemorrhagic Events and Warfarin Terminations Due to Perceived Safety Concerns by CHADS2 Score Hylek et al Circulation. 2007;115:2689-2696

Risk Factors for Anticoagulation-Related Bleeding Complications in Patients with Atrial Fibrillation A Systematic Review Systematic review for NICE guideline [www.nice.org.uk] 9 studies identified The following patient characteristics were identified as having supporting evidence for being risk factors for anticoagulation-related bleeding complications: Advanced age Uncontrolled hypertension History of myocardial infarction or ischaemic heart disease Cerebrovascular disease Anaemia or a history of bleeding, and The concomitant use of other drugs such as antiplatelet agents The presence of diabetes mellitus, controlled hypertension and gender were not identified as significant risk factors. Some of the risk factors for anticoagulation-related bleeding are also indications for the use of anticoagulants in AF patients Hughes and Lip QJM. 2007;100(10):599-607.

Combining the CHADS2 and HEMORR2HAGES Scores for Guiding Antithrombotic Prophylaxis in AF Clinical Usefulness in Geriatrics Patients 25 20 15 10 5 N=83 Mean age 89.2+/-4.9 years Events/year (%) 0 1 2 3 4 5 Score One year stroke risk for 100 patients without anticoagulation according to CHADS2 Major hemorrhage risk for 100 patients with anticoagulation according to HEMORRH2AGES ‘The clinical usefulness of using the two scores seems poor since they indicated that two-thirds of the patients had a similar risk of hemorrhagic and ischemic events.’ Somme et al Aging Clin Exp Res. 2009 as DOI: 10.3275/6709

Choosing Antithrombotic Therapy for Elderly Patients with AF Who are at Risk for Falls A Markov decision analytic model For patients with average risks of stroke and falling … Warfarin therapy associated with 12.90 quality-adjusted life-years per patient; Aspirin therapy, 11.17 quality-adjusted life-years; and No antithrombotic therapy, 10.15 quality-adjusted life-years. ‘Elderly persons who fall have a mean of 1.81 falls per year. … Given that the risk of SDH must be 535-fold or greater for the risks of warfarin therapy to outweigh the benefits, persons taking warfarin must fall about 295 (535/1.81) times in 1 year for warfarin to not be the optimal therapy.’ Man-Son-Hing et al Arch Intern Med. 1999;159(7):677-85

Anticoagulation Control and Prediction of Adverse Events in Patients With AF A Systematic Review TTR versus adverse events (weighted by sample size) for retrospective studies. TTR versus major hemorrhage rate (n=9), correlation: r= -0.78; P=0.006; TTR versus thromboembolic rate (n=5), correlation: r= -0.88; P=0.026 8 7 6 5 4 3 2 1 Linear (major haemorrhage Linear (Thromboembolic) Outcome events rate (per 100 patient/years, %) 0 40 50 60 70 80 90 TTR (%) For retrospective studies, a 6.9% improvement in the TTR significantly reduced major hemorrhage by 1 event per 100 patient-years of treatment (95% CI, 0.29 to 1.71 events) Wan et al Circ Cardiovasc Qual Outcomes. 2008;1:84-91

Adjusted relative risk (95% CI) Annual Net Clinical Benefit of Warfarin Therapy Overall and by CHADS2 Score Using Different Weights for ICH Risk Factor Net Clinical Benefit (95% CI) Adjusted relative risk (95% CI) CHADS2 Score ICH Weight = 1.5 (Base Case) ICH Weight = 1 ICH Weight = 2 -0.11 (-0.44 to 0.20) -0.07 (0.38 to 0.20) -0.14 (-0.53 to 0.21) 1 0.19 (-0.27 to 0.45) 0.33 (-0.06 to 0.57) 0.06 (-0.50 to 0.34) 2 0.97 (0.43 to 1.41) 1.07 (0.61 to 1.45) 0.87 (0.26 to 1.35) 3 2.07 (1.21 to 2.79) 2.06 (1.26 to 2.72) 2.09 (1.12 to 2.85) 4-6 2.22 (0.58 to 3.75) 2.51 (1.04 to 4.01) 1.94 (0.19 to 3.52) The net clinical benefit of warfarin increased from essentially zero in CHADS2 stroke risk categories 0 and 1 to 2.22% per year (CI,0.58% to 3.75%) in CHADS2 categories 4 to 6. The patterns of results were preserved when weighting factors for intracranial hemorrhage of 1.0 and 2.0 were used. Singer et al Ann Intern Med. 2009;151:297-305.

Warfarin vs Aspirin for Stroke Prevention in an Elderly Community Population with AF Birmingham Atrial Fibrillation Treatment of the Aged Study, BAFTA 100 75 50 25 Aspirin Warfarin Participants without primary event (%) Yearly risk 1.8% vs 3.8%, RR 0·48, 95% CI 0·28–0·80, p=0·003; Absolute yearly risk reduction 2%, 95% CI 0·7–3·2 0 1 2 3 4 5 6 Number at risk Warfarin 488 450 383 169 77 19 Aspirin 485 447 378 146 72 14 Years since randomization Mant et al Lancet 2007; 370: 493–503

RE-LY: Time to First Stroke / SSE RR 0.91 (95% CI: 0.74–1.11) P<0.001 (NI) P=0.34 (Sup) 0.05 Warfarin Dabigatran 110 mg BID 0.04 Dabigatran 150 mg BID RRR 34% 0.03 Cumulative hazard rates RR 0.66 (95% CI: 0.53–0.82) P<0.001 (NI) P<0.001 (Sup) 0.02 0.01 0.00 0.0 0.5 1.0 1.5 2.0 2.5 Years BID = twice daily; CI = confidence interval; NI = non-inferior; RR = relative risk; RRR = relative risk reduction; Sup = superior Connolly SJ et al. N Engl J Med 2009;361:1139–51

Antithrombotic Treatment and Risk of Stroke and Death in Patients with AF and CHADS2 Score=1 Combined endpoint (death or stroke) in patients with a CHADS2 score of 1 according to their antithrombotic treatment. A total of 1,012 patients, 949 ± 777 days FU, 124 events. Gorin et al Thromb Haemostat 2010 March

Issues with Current AF Stroke Risk Assessment Schema Implications for the Future All have modest predictive value for predicting high risk for thromboembolism Low risk category needs to be truly low risk Needs to categorise low proportion in so-called ‘moderate/ intermediate risk’ category Recognise that risk factors are cumulative Simple and easy to remember, yet comprehensive Scoring system most popular Acronym Validated in multiple populations, ideally ‘real world’ cohorts rather than non-VKA arms of trial cohorts Risk schema need to evolve with new therapeutic information on thromboprophylaxis in AF Lip and Halperin Am J Med 2009; 10.1016/j.amjmed.2009.12.013

Risk for Thromboembolism (%) Comparison of Risk Stratification Schemes to Predict Thromboembolism in Nonvalvular AF Annual Thromboembolism Rate (%) Risk for Thromboembolism (%) c-Statistic Low Intermediate High All patients Subgroup* AFI 13.1 24.7 62.3 0.56 0.61 SPAF 27.7 28.5 43.8 0.60 0.65 CHADS2 18.8 61.2 20.1 0.58 0.67 Framingham 37.1 46.6 16.4 0.62 0.69 7th ACCP 11.7 7.9 80.4 Fang et al J Am Coll Cardiol 2008;51:810–5 * Subgroup of 5,588 patients not on warfarin at baseline and with continuous follow-up off of warfarin for at least 12 months

Combination risk factors Refining Clinical Risk Stratification for Predicting Stroke and Thromboembolism in AF Using A Novel Risk Factor-Based Approach The Euro Heart Survey on Atrial Fibrillation Definitive risk factors Combination risk factors Previous stroke, TIA or embolism Heart failure or moderate-severe LV dysfunction [eg. LV EF ≤40%] Female gender Age ≥ 75 y Hypertension Age 65 to 74 y Diabetes mellitus Vascular disease [previous MI, aortic or peripheral artery disease] CHA2DS2-VASc Score C ongestive heart failure/ LV dysfunction 1 H ypertension A ge≥75 2 D iabetes mellitus S troke/TIA/TE V ascular disease [prior MI, PAD, or aortic plaque] A ge 65-74 S ex category [Female] Lip et al Chest 2010 Feb;137(2):263-72. Epub 2009 Sep 17.

Risk Categorization, Incidence of Thromboembolism and Predictive Ability for Contemporary Risk Stratification Schema in the Euro Heart Survey Low Intermediate High c-statistic (95% CI) CHADS2 – classical % in risk category TE events, N (%) 20 3 (1.4) 61.9 16 (2.4) 17.7 6 (3.2) 0.561 (0.450-0.672) CHADS2 – revised 20.4 34.9 7 (1.9) 44.7 15 (3.1) 0.586 (0.477-0.695) Framingham 48.3 6 (1.2) 41.5 14 (3.2) 10.2 5 (4.6) 0.638 (0.532-0.744) NICE 2006 13.1 0 (0.0) 39.2 13 (3.1) 47.7 12 (2.3) 0.598 (0.498-0.698) ACC/AHA/ESC 2006 19.6 3 (.14) 32.6 7 (2.0) 47.8 15 (2.9) 0.571 (0.461-0.680) ACCP 2008 33.4 47.0 15 (3.0) 0.574 (0.465-0.683) Birmingham 2009 9.2 15.1 1 (0.6) 75.7 24 (3.0) 0.606 (0.513-0.699) CHA2DS2-VASc Lip et al Chest 2010 Feb;137(2):263-72. Epub 2009 Sep 17.

Recommended antithrombotic therapy Refining Clinical Risk Stratification for Predicting Stroke and Thromboembolism in AF Using a Novel Risk Factor Based Approach The Euro Heart Survey on Atrial Fibrillation Risk category CHA2DS2VASc score Recommended antithrombotic therapy One definitive risk factor or ≥2 combination risk factors >1 OAC eg.VKA (INR 2-3, target 2.5), ?dabigatran One combination risk factor 1 Antithrombotic therapy, either as OAC or aspirin 75-325mg daily We suggest OAC rather than aspirin No risk factors Aspirin 75-325mg daily or no antithrombotic therapy We suggest no antithrombotic therapy Lip et al Chest 2010 Feb;137(2):263-72. Epub 2009 Sep 17.

Achieving Balance Between Thromboprophylaxis and Bleeding Reduction Challenges and Emerging Dimensions of Stroke Prevention in the Setting of AF Achieving Balance Between Thromboprophylaxis and Bleeding Reduction AF increases the risk of stroke and thromboembolism We need to balance stroke prevention against bleeding risk New risk factors and data (eg. elderly, CHADS2=1, new drugs etc) should be considered Aspirin (and antiplatelet Rx) less useful Risk schema need to evolve with new therapeutic information on thromboprophylaxis in AF We need a paradigm shift in stroke risk assessment guidelines All schema have modest value in predicting risk We need to be better at identifying the low risk subjects, who do not need antithrombotic therapy; all others would merit anticoagulation

New Dimensions and Landmark Practice Advances The Evolving Paradigm of Warfarin-Based Therapy: Still Relevant? And for How Long? David A. Garcia, MD Associate Professor, Division of General Internal Medicine University of New Mexico Co-Director, University of New Mexico Anticoagulation Management Service President, Anticoagulation Forum Albuquerque, New Mexico USA

Long-Term Oral Anticoagulation The State of the Art

Adjusted-dose warfarin compared with placebo AFASAK I, 1989 (2); 1990 (3) SPAF I, 1991 (5) BAATAF, 1990 (4) CAFA,1991 (6) SPINAF, 1992 (7) EAFT. 1993 (8) All trials (n=6) Relative risk reduction (95% CI) Favors warfarin Favors placebo or control 100 50 -50 -100 Warfarin Protects Against Stroke Adjusted-Dose Warfarin Compared With Placebo Adjusted-dose warfarin compared with placebo Hart, et al. Ann Intern Med. 2007 Jun 19;146(12):857-67.

Timeline AC management clinics Warfarin become increasingly prevalent first used POC testing, PST, dosing algorithms, software programs, better understanding of genetics and drug interactions WHO endorses INR 1950’s 1991 1999 1983 Efficacy of VKA to prevent AF-related stroke demonstrated

Warfarin Mechanism of Action Vitamin K VII Vitamin K Utilization Impaired IX Synthesis of Dysfunctional Coagulation Factors X Warfarin: Mechanism of Action The model in this slide provides a simplified explanation for the antagonism of clotting factor biosynthesis by warfarin. The cyclic interconversion of vitamin K from its vitamin K epoxide (KO) back to its hydroquinone (KH2) form, which occurs under normal physiological and dietary conditions, is disrupted in the presence of pharmacologically effective doses of warfarin. This metabolic disruption of the cycle results in decreased availability of the active cofactor form of vitamin K, vitamin K hydroquinone (KH2). The result is decreased presence of g-carboxyglutamic acid in the vitamin K-dependent clotting factors. Warfarin inhibits the enzymatic conversion (by reductases) of KO to its active cofactor form, KH2. This inhibition decreases the amount of KH2 available to participate in the conversion of prothrombin to its biologically active form. In order for prothrombin to have normal biological activity, between 10–13 glutamic acid (glu) residues must be converted to g-carboxyglutamic acid (gla) residues. This reaction requires the addition of a second carboxyl group (–COOH) to glutamic acid residues. 46. Bovill EG, Mann KG, Lawson JH, Sadowski J. Biochemistry of vitamin K: implications of warfarin therapy. In: Ezekowitz MD, editor. Systemic cardiac embolism. New York:Marcel Dekker, 1994. p.31-54. 47. Hirsh J, Ginsberg JS, Marder VJ. Anticoagulant therapy with coumarin agents. In: Colman RW, Hirsh J, Marder VJ, Salzman EW, editors. Hemostasis and thrombosis, 3rd ed. Philadelphia: J.B. Lippincott, 1994. p.1567-81. CYP450 II Warfarin Slight genetic variation can produce significant differences in dose-response relationship

Warfarin Mechanism of Action Decarboxylated zymogen Carboxylated zymogen Vitamin KH2 Vitamin K Epoxide X Vitamin K reductase Vitamin K Vitamin K epoxide reductase NADPH Slight genetic variation can produce significant differences in dose-response relationship

Coagulation Pathway IIa (Thrombin) Initiation Vlla/TF X IX Propagation IXa VllIa This is a simplified schematic representation of the coagulation cascade. Three steps are highlighted: Initiation Propagation Fibrin Formation Xa Va II IIa (Thrombin) Fibrin Formation Fibrinogen Fibrin

Limitations of Warfarin (VKA) Anticoagulation Clinics Requires frequent monitoring ? Genotype testing Narrow Therapeutic Index & Drug/Diet Interactions Complicates management of: Bleeding patient Patient with High INR Long Half-Life Slow Onset of Action Heparin “overlap” often necessary Periprocedural Anticoagulation Difficult

Is VKA (warfarin) therapy getting safer and more “user-friendly”? Wisespread use of the INR Anticoagulation Management Services Patient Self-testing Pharmacogenomics Reversal strategies

Events per 100 Patient-Years According to International Normalized Ratio Control Poor Control Moderate Control Good Control P Value (Poor vs Good) (Moderate vs Poor) (Good vs Moderate) (n = 1190) (n = 1207) Stroke or systemic embolism 2.1 0.02 1.34 0.09 1.07 0.48 Death, all cause 4.2 < .01 1.84 1.69 0.74 Death, stroke, or systemic embolism 5.98 3.01 2.76 0.67 Major bleeding 3.85 1.96 1.58 0.38 We analyzed the relationship between INR control and the rates of death, bleeding, MI, and stroke or SEE among 3587 patients with atrial fibrillation randomized to receive warfarin treatment in the SPORTIF (Stroke Prevention Using an Oral Thrombin Inhibitor in Atrial Fibrillation) III and V trials. The mean±SD follow-up was 16.6±6.3 months. Patients were divided into 3 equal groups (those with good control [75%], those with moderate control [60%-75%], or those with poor control [60%]) according to the percentage time with an INR of 2.0 to 3.0. Outcomes were compared according to INR control. The main outcome measures were death, bleeding, MI, and stroke or SEE. White H et al. Arch Intern Med. 2007.167:239-245

Increased “Time-in-Range” = Better Outcomes “Stable” Patients N=2504 Comparator Group N=3569 P value Deceased, % 0.4 1.6 <.001 AC-related death, % 0.04 0.1 .411 AC-related thrombosis, % 0.7 AC-related bleeding, % 0.8 2.8 AC-related bleeding or thrombosis, % 1.1 3.6 Witt et al. Blood 2009. 114: 952-956.

Anticoagulation Management Service Can Increase Time-in-Range % of patients % time in range Witt et al. Chest 2005.

Anticoagulation Management Services Resource-intensive Only available to a minority of patients in many countries (including the United States)

Patient Self-testing Reduces Risk of Thromboembolic Events Similar trend for bleeding… Heneghan et al. Lancet. 2006 Feb 4;367(9508):404-11.

Patient Self-Testing Not feasible for all warfarin-treated patients Uptake in U.S. also limited by low CMS reimbursement for physician oversight

Knowledge of Genotype Allows Better Dose Prediction Primary Population † † * * * Mean Warfarin Dose (mg/day) A/A A/B B/B A/A A/B B/B A/A A/B B/B Gage B. NEJM 2005.

Anderson et al RCT (n=200) Only published high-quality RCT Incorporated both CYP2C9 and VKORC1 genotypes PG (%) Std (%) p Out-of-range INR 31 33 0.72 Therapeutic INR by Day 5 70 68 0.85 Serious Adverse Events 4 5 0.71 PG dosing: more accurate with fewer dosing changes and INR measurements (7.2 vs 8.1, p 0.06) Anderson et al, Circulation, 2007; 116: 2563-70.

Meta-analysis: % Time Therapeutic Study ID SMD 95% CI Hillman 2005 0.01 (-0.3, 0.64) Caraco 2007 0.57 (0.28, 0.86) Anderson 2007 0.05 (-0.23, 0.22) Overall (I-squared = 72.5%, p=0.026 0.24 (-0.16, 0.64) Note: weights re from random effects analysis -1 -.5 0 .5 1 Standard dose favored Pharmacogenetics favored Kangelaris, JGIM, 2009; 24(5): 656-64.

Pharmacogenetic Testing Promising science but… Clinical benefit still unproven

4-factor prothrombin complex concentrate administered Reversal Strategies 13 11 9 7 5 3 1 25 u/kg (m=20) 35 u/kg (n=12) 50 u/kg (n=10) Beriplex, a prothrombin complex concentrate (PCC), was administered to 42 patients requiring immediate reversal of their oral anticoagulant therapy. The dose administered was determined using the pretreatment International Normalized Ratio (INR). Blood samples were obtained before treatment and at 20, 60 and 120 min after treatment. The following investigations were performed on all samples - INR, clotting factors II, VII, IX and X, coagulation inhibitors protein C (PC) and antithrombin (AT), and other markers of disseminated intravascular coagulation, plasma fibrinogen, D-dimer and platelet count. Immediate reversal of the INR, the vitamin K-dependent clotting factors and PC was achieved in virtually all patients. Reduced AT levels were present in 18 patients before treatment. Further slight AT reductions occurred in four patients, but other associated abnormalities of haemostasis were observed in only one of the four patients. One patient with severe peripheral vascular disease, sepsis and renal and cardiac failure died of a thrombotic stroke following leg amputation, 48 h after receiving Beriplex. No other arterial and no venous thromboembolic events occurred within 7 d of treatment. Beriplex is effective in rapidly reversing the anticoagulant effects of warfarin, including PC deficiency, without inducing coagulation activation. Caution should continue to be exercised in the use of these products in patients with disseminated intravascular coagulation, sepsis or liver disease. Baseline 20 min 60 min 120 min13 4-factor prothrombin complex concentrate administered Preston et al. British Journal of Haematology 2002. 116: 619–624

Warfarin Reversal PO/IV vitamin K Fresh Frozen Plasma 4-factor PCC Effective but INR decrease not immediate Fresh Frozen Plasma Each unit contains limited amount of vitamin-K dependent clotting proteins Significant volume challenge 4-factor PCC Not available in U.S. ? Cost ? Risk of thrombosis

Conclusions Although warfarin treatment is safer and more practical than it was 10-15 years ago, there is certainly room for further improvement. The new agents in development may Eliminate some of the challenges unique to warfarin Allow patients for whom warfarin is not feasible to receive highly effective anti-thrombotic therapy

Questions Regarding the New Oral Anticoagulants Do they represent a significant improvement for patients who have been taking warfarin with consistently therapeutic INR values for months/years? Will the lack of an evidence-based “reversal strategy” deter their use? How long will it take clinicians and patients to become comfortable with the lack of ability to monitor? Will the elimination of regular INR measurement reduce compliance? How will their cost compare to current costs (including INR monitoring, dose adjustment, etc.)? Which (if any) will be available to patients with significantly impaired renal function?

New Dimensions and Landmark Practice Advances Emerging Role of Direct Thrombin and Factor Xa Inhibition in Atrial Fibrillation Mechanism and Applications for Thrombosis Mitigation Across the Cardiovascular Disease Spectrum Richard C. Becker, MD Professor Medicine Divisions of Cardiology and Hematology Duke University Medical Center Duke Clinical Research Institute

Emerging Role of Direct Thrombin and Factor Xa Antagonists Conditions, Dynamic Substrate and Thrombus Survival in Atrial Fibrillation Anticoagulants in Development Platelet-Thrombin Interface – A Roadmap for Future Pharmacotherapy Redefining Atrial Fibrillation at the Molecular and Proteomic Level

Increased Connective Tissue Growth Factor Expression and Fibrosis in LA of Patients with AF Adam. JACC 2010;55:469-480.

Rac1-induced CTGF Regulates Connexin 43 and N-Cadherin Expression in AF Adam. JACC 2010;55:469-480.

Stabilization of Mast Cells Infiltrating the Atrium of TAC-Operated Mice by Cromolyn Liao. JCI 2010;120:242-253

Attenuation of AF and Atrial Fibrosis by Mast Cell Stabilization by Cromolyn Liao. JCI 2010;120:242-253

Attenuation of Atrial Fibrosis and AF by Reconsitution with BM Cells from W/Wv Mice Liao. JCI 2010;120:242-253

Extracellular Matrix Degradation and Fibrosis in Atrial Fibrillation life.nctu.edu.tw/.../image006.jpg

Thrombin Generation According to Factor X Concentrations Allen. J Thromb Haemost 2004;2:402-413

Thrombin Generation According to Prothrombin Concentrations Allen. J Thromb Haemost 2004; 2:402-413

Resupply of the Synthetic Coagulation Proteome Effect of Inhibitors Targeting fXa and fXa in the Prothrombinase Complex Resupply of the synthetic coagulation proteome: the effect of inhibitors targeting fXa and fXa in the prothrombinase complex. Time courses of thrombin generation are presented for reactions initiated with 5 pm Tf reagent (♦) and then resupplied at 20 min with an equal volume of synthetic coagulation proteome, 2 μm PCPS without Tf: control resupply (⋄); 320 nm C921-78 included in the synthetic coagulation proteome, 2 μm PCPS resupply mixture (○); 0.1 mg/ml α-bfX-2 added 2 min prior to resupply with synthetic coagulation proteome, 2 μm PCPS (□); and 0.1 mg/ml α-bfX-2 added 2 min prior to resupply with 1.4 μm fII, 3.4 μm AT, 2 μm PCPS (▵). The arrow indicates the time of α-bfX-2 addition. Thrombin generation over the initial 20 min is presented as the mean ± S.D. of four determinations. Thrombin levels at each time are expressed as total moles of active thrombin to normalize for the volume change. Orfeo T et al. J. Biol. Chem. 2008;283:9776-9786

Resupply of the Synthetic Coagulation Proteome: Stability of the Response Resupply of the synthetic coagulation proteome: stability of the response. A 5 pm Tf-initiated reaction mixture was subdivided after 20 min (A), and the seven separate aliquots resupplied either immediately (20 min → t = 0, (♦)) or after an additional 15 (▪), 30 (▴), 45 (•), 60 (▾), 75 (), or 95 () min of incubation. Resupply was conducted with an equal volume of a solution consisting of 1.4 μm fII, 3.4 μm AT, 2 μm PCPS. Thrombin levels for the final 5 min of the Tf- initiated episode are also shown (⋄). Thrombin levels are expressed as total picomoles of active thrombin to normalize for the volume change. An arrow indicates the resupply time for each aliquot. Orfeo T et al. J. Biol. Chem. 2008;283:9776-9786

Traditional Paradigm of Factor Xa and Thrombin Mackman. ATVB 2008;28:698-704

Thrombin-A Pluripotent Effector Enzyme Coughlin. Nature 2000;407:258-264

Factor Xa - a Pluripotent Effector Enzyme

Trials of Antithrombotic Therapy for Stroke Prevention in Atrial Fibrillation Warfarin-Control Phase III Trial Agent Blind CHADS Size Status RE-LY Dabigatran OL >1 18,113 Complete ROCKET Rivaroxaban DB >2-3 14,000 ARISTOTLE Apixaban 15,000 BOREALIS Biotinylated Idraparinux >2 9,600 Enrolling ENGAGE Edoxaban ? Total 71,600 Historical trials: 3,763

Oral Direct Factor Xa Inhibitors Currently in Development Drug Half-Life (hours) Bioavailability Elimination (%) Renal Hepatic Dosing Apixaban 12 50 25 75 Twice daily Betrixaban 19 47 100 Once daily Endoxaban 6-12 100% 62 35 Rivaroxaban 5-9 80 33 67 YM150 intestinal 18-20 25-82 NR Once/twice

Factor Xa AF Trial Designs: Apixaban

(at least one high risk factor) RE-LY Non-valvular atrial fibrillation at moderate to high risk of stroke or systemic embolism (at least one high risk factor) R Warfarin 1 mg, 3mg, 5 mg (INR 2.0-3.0) N=6000 Dabigatran Etexilate 110 mg b.i.d. N=6000 Dabigatran Etexilate 150 mg b.i.d. N=6000 Primary objective: Noninferiority to warfarin Minimum 1 year follow-up, maximum of 3 years and mean of 2 years of follow-up. Primary end point: Stroke + systemic embolism

Hazard Ratio Primary Outcome of Stroke or Systemic Embolism Connolly, et al. N Engl J Med 2009;361:1139-51 0 6 12 18 24 30 Warfarin Dabigatran 110 mg 150 mg Warfarin 6022 5862 5718 4593 2890 1322 Dabigatran 110 mg 6015 5862 5710 4593 2945 1385 Dabigatran 150 mg 6076 5939 5779 4682 3044 1429 0 6 12 18 24 30 1.0 0.8 0.6 0.4 0.2 0.0 0.05 0.04 0.03 0.02 0.01 0.00

RE-LY: Annual Rates of Bleeding 110mg 150mg Warfarin D 110mg vs. Warfarin D 150mg vs. Warfarin n 6015 6078 6022 RR 95% CI p Total 14.6% 16.4% 18.2% 0.78 0.74-0.83 <0.001 0.91 0.86-0.97 0.002 Major 2.7 % 3.1 % 3.4 % 0.80 0.69-0.93 0.003 0.93 0.81-1.07 0.31 Life- Threatening 1.2 % 1.5 % 1.8 % 0.68 0.55-0.83 0.81 0.66-0.99 0.04 Gastro- intestinal 1.1 % 1.0 % 1.10 0.86-1.41 0.43 1.50 1.19-1.89 Connolly NEJM 2009;361:1139-1151. 99

RE-LY: Intracranial Bleeding Rates RR 0.31 (95% CI: 0.20–0.47) p<0.001 (sup) RR 0.40 (95% CI: 0.27–0.60) p<0.001 (sup) Number of events 0,74 % RRR 69% RRR 60% 0,30 % 0,23 % Connolly. NEJM 2009:361:1139-1151. 100

Oral Direct Thrombin Inhibitor AZD0837 Pharmacokinetics Lip, G. Y.H. et al. Eur Heart J 2009 30:2897-2907; doi:10.1093/eurheartj/ehp318

Oral Direct Thrombin Inhibitor AZD0837 Dynamics Lip, G. Y.H. et al. Eur Heart J 2009 30:2897-2907; doi:10.1093/eurheartj/ehp318

Platelet Polyphosphates and Factor XII Activation Muller. Cell 2009;139:1143-1156

Platelet Polyphosphates and Factor XII Activation 120 100 80 60 40 20 FXIIa [nM] 0 20 40 60 TIME (MINUTES) Muller. Cell 2009;139:1143-115614

Blood substudy program Drug administered Genome Blood Transcriptome Integrated biosignatures that predict drug response and clinical outcomes Mechanistic Data Molecular basis of drug effect on clinical phenotype Plasma Proteome Biological Phenotype (Anti-Factor Xa) Clinical Phenotype (Ischemic stroke or bleeding) Adapted from Ginsburg et al. JACC 2005;46:1615

Emerging Role of Direct Thrombin and Factor Xa Inhibition in Atrial Fibrillation Atrial fibrillation is the end-result of conditions characterized by inflammation, fibrosis and tissue remodeling. Thrombus formation represents a localized response to tissue injury and altered flow dynamics. Thrombin and factor Xa inhibitors can attenuate thrombus formation and possibly alter the natural history of disease. Never forget the platelet in thrombotic disorders. Defining atrial fibrillation at the molecular and proteomic level may inform clinical data.

Emerging Role of Direct Thrombin and Factor Xa Inhibition in Atrial Fibrillation Studies using novel anticoagulants for stroke prevention in AF are likely to change the landscape of patient management in AF. Additional trials, including those with Factor Xa inhibitors will provide a robust foundation for evaluating how the current therapeutic landscape for stroke prevention might change. Studies evaluating safety and efficacy of apixaban in patients who are not suitable candidates for VKA have the potential to identify a non-ASA strategy for a unique subset of patients.

New Dimensions and Landmark Practice Advances The Emerging Role of Factor Xa and Direct Thrombin Inhibition for the Setting of Post-ACS Secondary Prevention Shamir R. Mehta MD, MSc, FRCPC, FACC Director, Interventional Cardiology Hamilton Health Sciences Associate Professor of Medicine McMaster University Director, ACS Research Program Population Health Research Institute

CVD: A Global Epidemic 2002 World pop.: 6.12 billion Deaths: 56.6 million CVD deaths: 16.6 million Gaziano TA. Circ 2005.

Troponin elevated or not Thrombosis Non-occlusive thrombosis Occlusive thrombosis CK - MB or Troponin ↑ Troponin elevated or not Courtesy Dr. E Falk

Atherosclerotic Plaque Red Blood Cells Thrombus Platelet Aggregate Fibrin Atherosclerotic Plaque

UFH, LMWH, fondaparinux, bivalirudin Antiplatelets, Anticoagulants and their Combination in ACS: Evidence from RCT’s Short Term Long Term Antiplatelet alone ASA ASA, clopidogrel Anticoagulant alone UFH Warfarin Combination UFH, LMWH, fondaparinux, bivalirudin Under study

Randomized Trials of Aspirin in Unstable Angina: Short and Long Term Benefit ASA Treatment Length of Follow-up RRR P value Veterans Affairs Study (1983) 325 mg/d* 3 months 41% 0.004 Canadian Study (1985) 325 mg 4x daily† 18 months 30% 0.072 Montreal Heart Study (1988) 650 mg first dose, 325 mg/d* 6 days 63% 0.04 RISC (1990) 75 mg for 3 mon* 13 months 64% 0.0001 ATC meta-analysis (2002) Various regimens* Various 46% <0.0001 *comparison versus placebo, †comparison versus control Adapted from Mehta SR, J Am Coll Cardiol. 2003;41(suppl):79S NOT APPROVED-

MI, stroke, CV Death: 0–30 days Benefit of Clopidogrel Therapy: Day 0-30 and Day 30-1 year MI, stroke, CV Death: 0–30 days Proportion Event-Free 3159 3180 3929 4639 5390 5954 4004 4742 5481 5981 Months 0.90 0.92 0.94 0.96 0.98 1.00 1 4 6 8 10 12 MI, stroke, CV Death: 31 days - 1 year RRR 18% 95% CI 0.70–0.95 P=0.009 Clopidogrel + ASA Placebo + ASA 1.00 Clopidogrel + ASA 0.98 0.96 Proportion Event-Free Placebo + ASA 0.94 0.92 RRR 21% 95% CI 0.67–0.92 P=0.003 0.90 1 2 3 4 Weeks No. at Risk Clopidogrel 6259 6145 6070 6026 5990 2418 Placebo 6303 6159 6048 5993 5965 2388 Yusuf et al. Circulation. 2003;107:966 UNDERGOING REVIEW FOR E-NEWSLETTER

Early and Long Term Clopidogrel in PCI Patients Composite of MI or cardiovascular death from randomization to end of follow-up 0.15 12.6% 8.8% 31% Relative Risk Reduction Placebo + ASA* 0.10 Cumulative Hazard Rate Clopidogrel + ASA* 0.05 For the end point of MI or cardiovascular death from time of randomization to end of follow-up, treatment with clopidogrel in addition to aspirin and other standard therapies resulted in a 31% RRR (8.8% clopidogrel vs 12.6% placebo, P = 0.002). The curves diverged early and continued to separate over the course of 12 months. This end point included events that were prevented prior to PCI, in addition to those following the procedure. There were consistent reductions in MI or cardiovascular death in almost every subgroup examined. P = 0.002 N = 2658 0.0 100 200 300 400 Days of follow-up * In addition to other standard therapies. Mehta et al for the CURE Investigators. Lancet. 2001;358:527 APPROVED- CURE-PCI-CURE 10-10-01

Initial Combination Therapy with an Anticoagulant + Antiplatelet Reduces Death/MI in UA/ NSTEMI LMWH or UFH combined with ASA in ACS: Death or MI N=2,919 Eikelboom J, et al. Lancet 2000

Combination Anticoagulant + Antiplatelet Therapy Alone Reduce Mortality and MI in the Initial Management of STEMI LMWH combined with ASA in STEMI: Death LMWH combined with ASA in STEMI: MI N=16,842 Eikelboom J, et al. Circulation 2006

Longer Term Anticoagulant Therapy (8 days) + Antiplatelet Therapy Alone Superior to Short Term Therapy (48-72 hrs) OASIS 6 Investigators. JAMA 2006

Long Term Anticoagulant Therapy + ASA Reduces Death/MI/Stroke After ACS Study OR (95% CI) INR > 2.0 n=5,938 Favors Combination Favors ASA Rothberg MD, et al. Ann Intern Med 2005

Long Term Anticoagulant Therapy + ASA May Increase Bleeding After ACS Study OR (95% CI) INR > 2.0 n=5,938 Favors Combination Favors ASA Rothberg MD, et al. Ann Intern Med 2005

APC (drotrecogin alfa) Fondaparinux Idraparinux Novel Anticoagulants TF/VIIa TFPI (tifacogin) rNAPc2 TTP889 X IX Rivaroxaban Apixaban LY517717 YM150 DU-176b Betrixaban TAK 442 813893 Aptamer/antidote IXa VIIIa APC (drotrecogin alfa) sTM (ART-123) Va Xa ATIII Fondaparinux Idraparinux New generic template II ATI-5923 Otamixaban DX-9065a IIa Dabigatran AZD0837 Fibrinogen Fibrin Adapted from Turpie and Weitz & Bates, J Thromb Haemost 2007

Pure Factor Xa Inhibition with Fondaparinux Reduces Bleeding and Mortality vs Enoxaparin OASIS 5 Investigators. N Engl J Med 2006;356:1464-76

Apixaban Characteristics Oral bioavailability: 58% No food effect Low volume distribution Half-life: T1/2 ≈ 12 h Multiple elimination pathways: 25% renal No CYP inhibition / induction Highly selective for factor Xa No reactive intermediates No organ toxicity, LFT abnormalities, or QTc prolongation N O H2N OMe New generic template Pinto DJ et al. J Med Chem. 2007;50:5339-5356. He K et al. Poster presented at: 48th Annual Meeting of the American Society of Hematology; December 2006; Orlando, FL. Poster 38-I. Frost C et al. Poster presented at: 21st Congress of the International Society of Thrombosis and Haemostasis; July 2007; Geneva, Switzerland. Lassen MR et al. J Thromb Haem. 2007;5:2368-2375.

APPRAISE Steering Committee and Investigators. Apixaban, an Oral, Direct, Selective Factor Xa Inhibitor, in Combination With Antiplatelet Therapy After Acute Coronary Syndrome Results of the Apixaban for Prevention of Acute Ischemic and Safety Events (APPRAISE) Trial APPRAISE Steering Committee and Investigators. Circulation. 2009;119:2877-2885.

Study Design Recent (7 days) Acute Coronary Syndrome plus at least one additional risk factor Recent (7 days) Acute Coronary Syndrome plus at least one additional risk factor Phase A = 547 Phase A 1:1:1 Phase A 1:1:1 Randomized, double-blind. Study drug for 6 months. Aspirin 165 mg/d. Clopidogrel per MD discretion (stratified randomization) Placebo n=184 Apixaban 2.5 mg BID n=179 Apixaban 2.5 mg BID n=179 Apixaban 10 mg QD n=184 Apixaban 10 mg QD n=184 Discontinued early due to excess bleeding in patients receiving apixaban and dual antiplatelet therapy Interim analysis (DSMB review) Phase B = 1168 Phase B 3:1:1:2:2 Phase B 3:1:1:2:2 Higher rates of total and ISTH major bleeding among the apixaban 10 mg bid and 20 mg qd arms. 50% higher any bleeding and 3 x major bleeding Placebo n=427 Apixaban 2.5 mg BID n=138 Apixaban 10 mg QD n=134 Apixaban 10 mg QD n=134 Apixaban 10 mg BID n=248 Apixaban 20 mg QD n=221 Total = 1715 Primary safety outcome: ISTH major or clinically relevant non-major bleeding (ISTH) Secondary efficacy outcome: cardiovascular death, MI, severe recurrent ischemia or ischemic stroke John H. Alexander, (Circulation. 2009;119:2877-2885.)

Ischemic Outcomes John H. Alexander, (Circulation. 2009;119:2877-2885.)

Ischemic Events by Clopidogrel Status Clopidogrel subgroup tracks with PCI subgroup N 462 232 243 149 85 75 John H. Alexander, (Circulation. 2009;119:2877-2885.)

Bleeding ISTH and TIMI Scales John H. Alexander, (Circulation. 2009;119:2877-2885.)

Bleeding by Clopidogrel Status Clopidogrel subgroup tracks with PCI subgroup N 453 230 241 146 85 74 John H. Alexander, (Circulation. 2009;119:2877-2885.)

APPRAISE-2 Trial Event Driven Recent Acute Coronary Syndrome (STEMI or NSTE-ACS) Randomize 1:1 Stratified by Antiplatelet Regimen Double blind Aspirin Other antiplatelet at MD discretion N=10,800 Apixaban 5 mg BID Placebo Start study drug ASAP after acute care stabilization / parenteral anticoagulation Event Driven Primary: Death, MI, Ischemic Stroke Secondary: Death, MI, Severe Recurrent Ischemia, Ischemic stroke Safety: Major Bleeding

MD Decision to Treat with Clopidogrel ATLAS Study Design TIMI 46 Recent ACS Patients Stabilized 1-7 Days Post-Index Event Aspirin 75-100 mg MD Decision to Treat with Clopidogrel MD Decision to Treat with Clopidogrel NO YES N = 3,491 STRATUM 1 ASA Alone N=761 STRATUM 2 ASA + Clop. N=2,730 PLACEBO N=253 5 mg (77) 10 mg (98) 20 mg (78) RIVA QD N=254 5 mg (77) 10 mg (99) 20 mg (78) RIVA BID N=254 2.5 mg (77) 5 mg (97) 10 mg (80) PLACEBO N=907 5 mg (74) 10 mg (428) 15 mg (178) 20 mg (227) RIVA QD N=912 5 mg (78) 10 mg (430) 15 mg (178) 20 mg (226) RIVA BID N=911 2.5 mg (76) 5 mg (430) 7.5 mg (178) 10 mg (227 PLACEBO N=253 5 mg (77) 10 mg (98) 20 mg (78) RIVA QD N=254 5 mg (77) 10 mg (99) 20 mg (78) RIVA BID N=254 2.5 mg (77) 5 mg (97) 10 mg (80) PLACEBO N=907 5 mg (74) 10 mg (428) 15 mg (178) 20 mg (227) RIVA QD N=912 5 mg (78) 10 mg (430) 15 mg (178) 20 mg (226) Treat for 6 Months Gibson CM, AHA 2008 131

Primary Safety Endpoint Clinically Significant Bleeding TIMI 46 ATLAS Primary Safety Endpoint Clinically Significant Bleeding (= TIMI Major, TIMI Minor, Bleed Req. Med. Attn.) HR 15.3% 5.1 15 Total Daily Dose: Rivaroxaban 20 mg ---- Rivaroxaban 15 mg ---- Rivaroxaban 10 mg ---- Rivaroxaban 5 mg ---- Placebo --- (3.4-7.4) 12.7% 3.6 (2.3-5.6) 10.9% 3.4 10 (2.3-4.9) Clinically Significant Bleeding (%) 6.1% 2.2 5 (1.25-3.91) 3.3% *p<0.01 for placebo Vs Riva 5mg. p<0.001 for Riva 10,15,20mg vs placebo 30 60 90 120 150 180 Days After Start of Treatment Kaplan-Meier estimates for cumulative events, HR(CI), for bleeding rates during the 180 day period ; HR=Hazard Ratio; CI=Confidence Interval Mega, Lancet 2009; DOI:10.1016/S0140-6736(09) 132

Safety Endpoints TIMI Major, TIMI Minor and Bleeding Req. Med. Attn. P trend<0.001 Rate (%) Plac 5 10 20 Plac 5 10 20 Plac 5 10 20 TIMI Major TIMI Minor Med Attention P trend<0.0001 Rate (%) Plac 5 10 15 20 Plac 5 10 15 20 Plac 5 10 15 20 TIMI Major TIMI Minor Med Attention P trend=p value for dose response over actual dose values. Mega et. al, Lancet 2009; DOI:10.1016/S0140-6736(09)

Secondary Efficacy Endpoint: Incidence of Death / MI / Stroke TIMI 46 ATLAS Secondary Efficacy Endpoint: Incidence of Death / MI / Stroke Stratum 1: ASA Alone Stratum 2: ASA + Clop. HR 1.24 11.9 4.7 P trend = 0.01 P trend = 0.72 3.8 HR 0.67 HR 0.79 HR 0.58 HR 0.70 HR O.71 8.0 3.0 Death / MI / Stroke (%) Death / MI / Stroke (%) 7.0 2.7 2.7 HR 0.37 4.7 n=253 n=154 n=196 n=158 n=907 n=154 n=860 n=356 n=453 TDD Mega et. al, Lancet 2009; DOI:10.1016/S0140-6736(09)

APPRAISE-2 Trial Event Driven Recent Acute Coronary Syndrome (STEMI or NSTE-ACS) Randomize 1:1 Stratified by Antiplatelet Regimen Double blind Aspirin Other antiplatelet at MD discretion N=10,800 Apixaban 5 mg BID Placebo Start study drug ASAP after acute care stabilization / parenteral anticoagulation Event Driven Primary: Death, MI, Ischemic Stroke Secondary: Death, MI, Severe Recurrent Ischemia, Ischemic stroke Safety: Major Bleeding

REDEEM: Outcomes by Dabigatran Randomization Group End point Placebo (n=371) 50 mg bid (n=369) 75 mg bid (n=368) 110 mg bid (n=406) 150 mg bid (n=347) Primary end point 2.4 3.5 4.3 7.9 7.8 Major bleeding * 0.5 0.8 0.3 2.0 1.2 CV death, nonfatal MI, or stroke 3.8 4.6 4.9 3.0 * International Society of Thrombosis and Haemostasis criteria Oldgren J, American Heart Association 2009 Scientific Sessions; Nov. 18, 2009; Orlando, FL

Conclusions Short and Long term antiplatelet alone and anticoagulant therapy alone reduce major CV events after ACS Short term combination therapy reduces major CV events in ACS Long term combination therapy with new oral anticoagulants apixaban and rivaroxaban evaluated in the context of contemporary antiplatelet therapy demonstrate a reduction in ischemic events with a dose dependent increase in bleeding The widespread use of these agents as routine therapy after ACS will depend on the balance of ischemic event reduction vs bleeding currently being evaluated in large-scale phase III RCTs

Thrombosis Reduction for Heart Disease Thrombosis Risk Reduction: Summary New Frontiers in Thrombosis Reduction for Heart Disease Take Home Points and Conclusions   Deepak L. Bhatt, MD, MPH, FACC, FAHA, FSCAI Program Chairman Chief of Cardiology, VA Boston Healthcare System Director, Integrated Interventional Cardiovascular Program Brigham and Women’s Hospital and the VA Boston Healthcare System Associate Professor of Medicine, Harvard Medical School Senior Investigator, TIMI Group

Take Home Points: AF AF increases the risk of stroke and thromboembolism Need to balance stroke prevention against bleeding risk: in search of the “ideal strategy” We need a paradigm shift in stroke risk assessment guidelines: current schema have modest value in predicting risk and, therefore, best prophylactic approach Defining AF at the molecular and proteomic level may help Warfarin treatment has become safer and more practical, but limitations in achieving ideal TTR persist Newer agents inhibiting Factor Xa or thrombin offer unique opportunities in both efficacy and safety

Take Home Points: ACS Following acute coronary syndrome patients remain at high risk for: Recurrent ischemic events Bleeding (largely secondary to antithrombotic therapy) Inhibition of Factor Xa or thrombin with oral non-monitored agents has the potential to reduce ischemic events but will probably also increase in bleeding Triple therapy with DAP plus oral, non-monitored anticoagulant may be attractive if bleeding risks can be mitigated The ideal level of inhibition of Factor Xa or of thrombin to improve ACS outcomes will require further study

Take Home Points: Novel Anticoagulants Noninferiority may not suffice to alter VKA landscape, but superiority findings and/or less bleeding observed in RE-LY are very encouraging Many more trials will be forthcoming Beware of off-label use

Take Home Points: Novel Anticoagulants The RE-LY Trial represents the most compelling evidence to date for revising, reconsidering, and reshaping our current VKA-based paradigm for stroke prevention in atrial fibrillation Additional trials, including those with Factor Xa inhibitors, will provide a more robust foundation for evaluating how the current therapeutic landscape for stroke prevention might change Studies evaluating safety and efficacy Factor Xa inhibition in patients who are not suitable candidates for VKA has the potential to identify a strategy for a unique subset of patients

Take Home: Conclusions Thrombosis is critical in multiple cardiovascular syndromes, including ACS and AF Thrombosis risk reduction presents a significant unmet need in patients with atherothrombosis Novel pathways to prevent thrombosis likely to yield benefit based on number and quality of trials in progress across the arterial and venous risk spectrum 143