National Experts in Cardiovascular Medicine Illuminate and Debate

National Experts in Cardiovascular Medicine Illuminate and Debate

National Experts in Cardiovascular Medicine Illuminate and Debate New Paradigms and Landscape Changes in Atrial Fibrillation Emerging Perspectives in Thrombosis Mitigation for the Cardiovascular SpecialistApplying Landmark Trials to the Front Lines of Cardiology Practice Program Chairman and Moderator Peter Libby, MD, FACC Chief, Cardiovascular Medicine Brigham and Womens Hospital Mallinckrodt Professor of Medicine Harvard Medical School Boston, Massachusetts Welcome and Program Overview CME-certified symposium jointly sponsored by the University of Massachusetts Medical School and CMEducation Resources, LLC Commercial Support: Sponsored by an independent educational grant from BoehringerIngelheim Faculty disclosures: Listed in program syllabus

Program Faculty Peter Libby, MD, FACC Program Chairman and Moderator Chief, Cardiovascular Medicine Brigham and Womens Hospital Mallinckrodt Professor of Medicine Harvard Medical School Boston, Massachusetts Jonathan L. Halperin, MD Mount Sinai School of Medicine Director, Clinical Cardiology Service The Zena and Michael A. Wiener Cardiovascular Institute The Marie-Jose and Henry R. Kravis Center for Cardiovascular Health New York, New York Elaine M. Hylek, MD, MPH Associate Professor of Medicine Department of Medicine Boston University Medical Center Boston, Massachusetts

Jeffrey I. Weitz, MD, FRCP, FACP Professor of Medicine and Biochemistry McMaster University Director, Henderson Research Center Canada Research Chair in Thrombosis Heart and Stroke Foundation J.F. Mustard Chair in Cardiovascular Research Ontario, Canada New Frontiers in Atrial Fibrillation Challenges in Stroke Prevention for Patients with Atrial Fibrillation Achieving Balance Between Prevention of Thromboembolism and Risk of Bleeding Risk Stratification, Current Guidelines and Therapeutic Choices Jonathan L. Halperin, MD Professor of Medicine (Cardiology) Mount Sinai School of Medicine Director, Clinical Cardiology Services The Zena and Michael A. Wiener Cardiovascular Institute

The Marie-Jose and Henry R. Kravis Center for Cardiovascular Health Atrial Fibrillation A Substantial Threat to the Brain Affects ~4% of people aged >60 years ~9% of those aged >80 years 5%/year stroke rate 12%/year for those with prior stroke $ billions annual cost for stroke care AF-related strokes have worse outcomes AF identifies millions of people with a five-fold increased risk of Natural History of Lone Atrial Fibrillation No Cardiopulmonary Disease; <60 Years Old 97 Patients

Mean Age = 44 14.8 years Follow-up 0.35%/yr Stroke 0.40%/yr Mortality Kopecky S, et al. N Engl J Med 1987; 317:669. Stroke Risk in Atrial Fibrillation Stroke Rate (% per year) Untreated Control Groups of Randomized Trials Age (years) Atrial Fibrillation Investigators. Arch Intern Med 1994;154:1449. Anticoagulation in Atrial Fibrillation Stroke Risk Reductions Warfarin Better Control Better AFASAK

SPAF BAATAF CAFA SPINAF EAFT Aggregate 100% 50% Hart R, et al. Ann Intern Med 2007;146:857. 0 -50% -100% Anticoagulation in Atrial Fibrillation The Standard of Care for Stroke Prevention Warfarin Better Control Better Unblinded AFASAK

SPAF Unblinded BAATAF Unblinded Terminated early CAFA SPINAF Double-blind; Men only 2o prevention; Unblinded EAFT Aggregate 100% 50% Hart R, et al. Ann Intern Med 2007;146:857. 0 -50% -100%

Antithrombotic Therapy for Atrial Fibrillation Stroke Risk Reduction Treatment Better Treatment Worse Warfarin vs. Placebo/Control 6 Trials n = 2,900 Antiplatelet drugs vs. Placebo 8 Trials n = 4,876 100% Hart R, et al. Ann Intern Med 2007;146:857. 50% 0

-50% Efficacy of Warfarin in Trials vs. Practice Stroke Risk Reductions Treatment Better Treatment Worse Warfarin vs. Placebo/Control 6 Trials n = 2,900 Warfarin vs. No anticoagulation Medicare cohort n = 23,657 100% Hart R, et al. Ann Intern Med 2007;146:857 Birman-Deych E. Stroke 2006; 37: 10701074

50% 0 -50% Intracerebral Hemorrhage The Most Feared Complication of Antithrombotic Therapy >10% of intracerebral hemorrhages (ICH) occur in patients on antithrombotic therapy Aspirin increases the risk by ~ 40% Warfarin (INR 23) doubles the risk to 0.30.6%/year ICH during anticoagulation is catastrophic Hart RG, et al. Stroke 2005;36:1588 Risk Stratification in AF Stroke Risk Factors High-Risk Factors Mitral stenosis

Prosthetic heart valve History of stroke or TIA Singer DE, et al. Chest 2004;126:429S. Fang MC, et al. Circulation 2005; 112: 1687. Risk Stratification in AF Stroke Risk Factors High-Risk Factors Mitral stenosis Prosthetic heart valve History of stroke or TIA Singer DE, et al. Chest 2004;126:429S. Fang MC, et al. Circulation 2005; 112: 1687. Moderate-Risk Factors Age >75 years

Hypertension Diabetes mellitus Heart failure or LV function Risk Stratification in AF Stroke Risk Factors High-Risk Factors Mitral stenosis Prosthetic heart valve History of stroke or TIA Moderate-Risk Factors Age >75 years

Hypertension Diabetes mellitus Heart failure or LV function Less Validated Risk Factors Age 6575 years Coronary artery disease Female gender Thyrotoxicosis Singer DE, et al. Chest 2004;126:429S. Fang MC, et al. Circulation 2005; 112: 1687. Risk Stratification in AF Stroke Risk Factors High-Risk Factors Mitral stenosis

Prosthetic heart valve History of stroke or TIA Moderate-Risk Factors Age >75 years Hypertension Diabetes mellitus Heart failure or LV function Less Validated Risk Factors Dubious Factors Age 6575 years Coronary artery disease Female gender Thyrotoxicosis

Singer DE, et al. Chest 2004;126:429S. Fang MC, et al. Circulation 2005; 112: 1687. Duration of AF Pattern of AF (persistent vs. paroxysmal) Left atrial diameter The CHADS2 Index Stroke Risk Score for Atrial Fibrillation Score (points) Congestive Heart failure 1 Hypertension 1 Age >75 years 1 Diabetes mellitus 1 Stroke or TIA 2 Moderate-High risk Low risk >2 0-1

VanWalraven C, et al. Arch Intern Med 2003; 163:936. * Nieuwlaat R, et al. (EuroHeart survey) Eur Heart J 2006 (E-published). Prevalence (%)* 32 65 28 18 10 50-60 40-50 Nonvalvular Atrial Fibrillation Stroke Rate (%/year) Stroke Rates Without Anticoagulation According to Isolated Risk Factors Prior Age Hypertension Female Stroke/TIA > 75 years Hart RG et al. Neurology 2007; 69: 546. Diabetes Heart Failure LVEF

The CHADS2 Index Stroke Risk Score for Atrial Fibrillation Approximate Risk threshold for Anticoagulation Score (points) 0 1 2 3 4 5 6 Van Walraven C, et al. Arch Intern Med 2003; 163:936. Go A, et al. JAMA 2003; 290: 2685. Gage BF, et al. Circulation 2004; 110: 2287. Risk of Stroke (%/year) 1.9 2.8 4.0 5.9

8.5 12.5 18.2 3%/year Risk Stratification and Anticoagulation Stroke Reduction with Warfarin Instead of Aspirin CHADS2 Score ~ 3 2 1 0 13 42 83 250 EAFT Study Group. Lancet 1993; 324:1255.

Zabalgoitia M, et al. J Am Coll Cardiol 1998; 31:1622. Number of patients Needed-to-treat to prevent 1 stroke/year Antithrombotic Therapy for Atrial Fibrillation ACC/AHA/ESC Guidelines 2006 Risk Factor No risk factors CHADS2 = 0 One moderate risk factor CHADS2 = 1 Any high risk factor or >1 moderate risk factor CHADS2 >2 or Mitral stenosis Prosthetic valve Recommended Therapy Aspirin, 81-325 mg qd

Aspirin, 81-325 mg/d or Warfarin (INR 2.0-3.0, target 2.5) Warfarin (INR 2.0-3.0, target 2.5) Warfarin (INR 2.5-3.5, target 3.0) "Actually, it's more of a guideline than a rule. Bill Murray in Ghostbusters (1984), relaxing his rule "never to get involved with possessed people" in response to Sigourney Weaver's seductive advances. Patient Selection for Anticoagulation Additional Considerations Risk of bleeding Newly anticoagulated vs. established therapy Availability of high-quality anticoagulation management program Patient preferences

The ACTIVE Trial Clopidogrel + Aspirin Atrial Fibrillation + Risk Factors ACTIVE - W Anticoagulation-eligible VKA (INR 2-3) Clopidogrel + Aspirin Open-label Non-inferiority n = 6,706 ACTIVE - A OAC Contraindications or Unwilling Aspirin + Placebo Double-blind Superiority n = 7,554 Irbesartan, 300 mg/d vs. Placebo n = 9,016

Risk Factors: Age 75, hypertension, prior stroke/ TIA, LVEF<45%, PAD, age 55-74 + CAD or diabetes Clopidogrel + Aspirin ACTIVE - I Primary outcome: Stroke, systemic embolism, MI or cardiovascular death The ACTIVE Trial Clopidogrel + Aspirin Atrial Fibrillation + Risk Factors ACTIVE W Anticoagulation-eligible VKA (INR 2-3) Clopidogrel + Aspirin Open-label Non-inferiority

n = 6,706 ACTIVE - A OAC Contraindications or Unwilling Aspirin + Placebo Clopidogrel + Aspirin Double-blind Superiority n = 7,554 Irbesartan, 300 mg/d vs. Placebo n = 9,016 ACTIVE - I Antithrombotic Therapy for Atrial Fibrillation Stroke Risk Reductions Warfarin Better Antiplatelet Rx Better ACTIVE-W

Anticoagulation vs. Aspirin + Clopidogrel n = 6,706 Anticoagulation vs. Antiplatelet drugs 7 Trials n = 4,232 100% Connolly S, et al. Lancet 2006; 367:1903. Hart R, et al. Ann Intern Med 2007;146:857. 50% 0 -50% Antithrombotic Therapy for Atrial Fibrillation Stroke Risk Reductions Warfarin Better Antiplatelet Rx Better

All patients Warfarin vs. Aspirin + Clopidogrel Prior OAC VKA-nave 100% Connolly S, et al. Lancet 2006; 367:1903. 50% 0 -50% Major Hemorrhage in Relation to Prior Anticoagulant Therapy: ACTIVE-W Event Rate (%/year) Starters Switchers

Interaction p=0.028 No Yes Anticoagulant Therapy at Entry Connolly S, et al. Lancet 2006; 367:1903. The ACTIVE Trial Clopidogrel + Aspirin Atrial Fibrillation + Risk Factors ACTIVE W Anticoagulation-eligible VKA (INR 2-3) Clopidogrel + Aspirin Open-label Non-inferiority n = 6,706 ACTIVE A OAC Contraindications or Unwilling

Aspirin + Placebo Double-blind Superiority n = 7,554 Irbesartan, 300 mg/d vs. Placebo n = 9,016 Connolly SJ, et al. N Engl J Med 2009; 360:2066. Clopidogrel + Aspirin ACTIVE - I The ACTIVE Trial Reasons for Exclusion from Anticoagulation * * * * Risk factor for bleeding* 23%

Physician judgment against anticoagulation for patient 50% Patient preference only 26% Inability to comply with INR monitoring * Severe alcohol abuse within 2 years Predisposition to falling or head trauma * Peptic Peptic ulcer ulcer disease disease Persistent hypertension >160/100 mmHg * Thrombocytopenia Thrombocytopenia * Chronic Previous serious bleeding on VKA Chronic need need for for NSAID NSAID Connolly Connolly SJ, SJ, et et al.

al. N N Engl Engl JJ Med Med 2009; 2009; 360:2066. 360:2066. ACTIVE-A Total Stroke Rates Cumulative Incidence 0.15 28% RRR 408 (3.3%/year) HR HR 0.72 0.72 (95% (95% CI, CI, 0.620.83) 0.620.83) pp <0.001 <0.001

Aspirin 0.10 296 (2.4%/year) Clopidogrel + Aspirin 0.05 0.0 0 1 2 Years Connolly Connolly SJ, SJ, et et al. al. N N Engl Engl JJ Med Med 2009; 2009; 360:2066. 360:2066.

3 4 The ACTIVE Trials Stroke Rates and Risk Reductions Treatment VKA C+A Aspirin ACTIVE W (Annual Rate) 1.4 2.4 ~ ACTIVE A (Annual Rate)

~ 2.4 3.3 RRR versus Aspirin -58% -28% ~ RRR versus C+A -42% ~ ~ VKA == oral oral anticoagulant anticoagulant C+A == clopidogrel

clopidogrel ++ aspirin aspirin Connolly Connolly SJ, SJ, et et al. al. Lancet Lancet 2006; 2006; 367:1903. 367:1903. Connolly Connolly SJ, SJ, et et al. al. N N Engl Engl JJ Med Med 2009; 2009; 360:2066. 360:2066. Investigational Anticoagulant Targets ORAL PARENTERAL TF/VIIa TTP889

TFPI (tifacogin) X IX VIIIa Rivaroxaban Apixaban Edoxaban LY517717 YM150 Betrixaban TAK 42 APC (drotrecogin alfa) sTM (ART-123) IXa Va AT Xa II (thrombin)

Dabigatran Idraparinux DX-9065a Otamixaban IIa Fibrinogen Fibrin Adapted from Weitz JI. Thromb Haemost 2007; 5 Suppl 1:65-7. APC activated protein C AT antithrombin sTM soluble thrombomodulin TF tissue factor FPI tissue factor pathway inhibitor The Ideal Anticoagulant Wide Therapeutic Margin

Safe Therapeutic Range Bleeding Bleeding Thrombosis Thrombosis Dose, Concentration, or Intensity of Anticoagulation Emerging Anticoagulants Regulatory Issues Open-label vs. blinded trial design Issues related to active-control trial design How many trials are needed? Preventing use for unapproved indications Assessing patient-oriented outcomes Alternatives to Anticoagulation Atrial Fibrillation

Current approaches Restoration and maintenance of sinus rhythm Antiarrhythmic drug therapy Catheter ablation Maze operation Emerging (investigational) approaches Obliteration of the left atrial appendage Trans-catheter occluding devices Thoracoscopic epicardial plication Amputation Strokes after Conversion to NSR Rate vs. Rhythm Control Trials n AFFIRM Rate Rhythm

control control RR (95% CI) p 4,917 5.7% 7.3% 1.28 (0.95-1.72) 0.12 RACE 522 5.5% 7.9% 1.44 (0.75-2.78) 0.44

STAF 266 1.0% 3.0% 3.01 (0.35-25.3) 0.52 PIAF 252 0.8% 0.8% 1.02 (0.73-2.16) 0.49 Total 5,957

5.0% 6.5% 1.28 (0.98-1.66) 0.08 Verheugt F, et al. J Am Coll Cardiol 2003;41(suppl):130A. AFFIRM Trial Stroke Rates 74% of all strokes were proven ischemic 44% occurred after stopping warfarin 28% in patients taking warfarin with INR <2.0 42% occurred during documented AF Wyse AG, et al. N Engl J Med 2002; 347: 1825. 1825

ATHENA Trial Dronedarone vs. Placebo in Patients with AF Stroke Rates (Secondary Analysis) Placebo (%/ Dronedarone (%/y) (95% CI) Stroke 1.79 1.19 0.66 0.027 Stroke or TIA 2.05 1.37

0.67 0.020 Fatal stroke 0.54 0.36 0.67 0.247 Event y) Hohnloser SH, et al. N Engl J Med 2009; 360: 668-78. HR P Percutaneous LAA Occlusion The WATCHMAN Device

Syed T, Halperin JL. Nature Clin Prac Cardiovasc Med 2007; 4:428 Holmes DR, et al. Lancet 2009; 374: 534 Alternatives to Anticoagulation Atrial Fibrillation Current approaches Restoration and maintenance of sinus rhythm Antiarrhythmic drug therapy Catheter ablation Maze operation Emerging (investigational) approaches Obliteration of the left atrial appendage Trans-catheter occluding devices Thoracoscopic epicardial plication Amputation

Is atrial fibrillation the cause of stroke or a marker of a population at risk? Atrial Fibrillation and Thromboembolism The Next Challenges Better tools to stratify bleeding risk Noninvasive imaging and biomarkers of inflammation and thrombosis to predict clinical events and guide therapy Confirming successful rhythm control over time Targeted therapy to prevent AF in patients at risk

Defining role and risk stratification strategies for non-monitored, oral From Fermented Sweet Clover to Molecular Targeting of Coagulation The Promise of New Approaches The Goal: To bring effective therapy to many more patients and prevent thousands of strokes. Atrial Fibrillation Case Study Atrial Fibrillation Case Study An 82-year-old man with hypertension and diabetes has permanent atrial fibrillation He has a history of spinal stenosis and walks with a walker Atrial Fibrillation Case Study Question 1: Which regimen would you prescribe for prophylaxis against thromboembolism? a. Warfarin (INR 2.0-3.0) b. Warfarin (INR 1.5-2.0)

c. Aspirin, 81 mg daily d. Aspirin, 81 mg + clopidogrel, 75 mg daily e. No antithrombotic therapy Atrial Fibrillation Case Study Assessment of Thromboembolic Risk Score (points) 0 Risk of Stroke (%/year) 1.9 1 2.8 2 3 4 5 6 4.0 5.9 8.5

12.5 18.2 Van Walraven C, et al. Arch Intern Med 2003; 163: 936. Go A, et al. JAMA 2003; 290: 2685. Gage BF, et al. Circulation 2004; 110: 2287. Atrial Fibrillation Case Study Question 2: What if you learn that he has tripped and fallen twice in the past two years? a. Warfarin (INR 2.0-3.0) b. Warfarin (INR 1.5-2.0) c. Aspirin, 81 mg daily d. Aspirin, 81 mg + clopidogrel, 75 mg daily e. No antithrombotic therapy Atrial Fibrillation Case Study Question 3: If the oral direct thrombin inhibitor dabigatran were available and FDA-approved for stroke prevention in AF, in this patient with a history of tripping you would treat with: a. Warfarin (INR 2.0-3.0) b. Warfarin (INR 1.5-2.0) c. Dabigatran 110 mg P.O. B.I.D d. Dabigatran 150 mg P.O. B.I.D. e. Aspirin, 81 mg + clopidogrel, 75 mg

daily Atrial Fibrillation Case Study Anticoagulation in Patients at Risk of Falls Atrial Fibrillation Case Study Anticoagulation in Patients at Risk of Falls persons taking warfarin must fall about 295 (535/1.81) times in 1 year for warfarin not to be the optimal therapy Atrial Fibrillation Case Study ICH in Patients with AF Prone to Falls Hazard ratios of independent predictors of intracranial hemorrhage Hazard ratio (95% CI) P value High-risk for falls 1.9 (1.03-2.9)

0.002 Prior stroke 2.2 (1.7-2.8) <0.0001 Prior bleed 1.8 (1.4-2.4) <0.0001 Neuropsychiatric impairment 1.4 (1.0-1.9) 0.055 Factor The risk of ICH was 2.8%/year in patients at high risk of falls and 1.1 in other patients. Warfarin was associated with an

increased risk of mortality among those with ICH (30 day mortality = 52 vs. 34%, p = 0.007). Gage BF, et al. Am J Med 2005; 118:612. Atrial Fibrillation Case Study Outcomes in Patients with AF Prone to Falls Hazard ratio of warfarin for composite outcomeout-ofhospital death or hospitalization for stroke, MI, or hemorrhage in 1245 patients at high risk for falls CHADS 2 score Hazard ratio (95% CI) P value Recommended antithrombotic therapy 0-1 0.98 (0.56, 1.72) 0.94

Aspirin or nil 2-6 0.75 (0.61, 0.91) 0.004 Anticoagulant Gage BF, et al. Am J Med 2005; 118:612. Summary of Case Study The risk of intracranial hemorrhage is increased in patients who fall. The use of oral anticoagulation does not predict ICH, but mortality is higher among patients on anticoagulants who develop ICH. The risk of mortality due to ICH is offset by the reduction in ischemic events achieved with anticoagulation in elderly patients with AF at high risk of thromboembolism. Better risk-stratification instruments are New Frontiers in Atrial Fibrillation

Stroke Prevention in High Risk Populations Optimizing Warfarin Therapy in Challenging Patient Populations Elaine M. Hylek, MD, MPH Associate Professor of Medicine Department of Medicine Director, Thrombosis Clinic and Anticoagulation Service Boston University Medical Center Boston, Massachusetts Prevalence of AF by Age Prevalence (%) 20 18 Framingham Study 16 Cardiovascular Health Study 14 Mayo Clinic Study

12 Western Australia Study 10 8 6 4 2 0 40 50 60 Age (years) Feinberg WM. Arch Intern Med. 1995;155(5):469473 70 80 90 Atrial Fibrillation Morbidity and Mortality

4- to 5-fold increased risk of stroke Doubling of the risk for dementia Tripling of risk for heart failure 40 to 90% increased risk for overall mortality Risk of stroke in AF patients by age group 1.5% in 50 to 59 year age group 23.5% in 80 to 89 year age group Benjamin EJ, et al. Circulation 2009;119:606-618 The graying population will slowly, radically transform society. Richard Suzman, NIA More than 37 million people are age 65. By 2030, this number will exceed 70 million.

By 2040, those aged 75 years will exceed the population 65 to 74 years old. By 2050, 12%, or 1 in 8 Americans, will be age 75 or older. Percent of Population Prevalence of CVD* in Adults by Age and Sex (NHANES: 2005-2006) 100 90 80 70 60 50 40 30 20 10 0 73.3 72.6

37.9 38.5 15.9 7.8 20-39 40-59 60-79 Age Men Women *Coronary heart disease, heart failure, stroke and hypertension Source: NCHS and NHLBI 79.3 85.9 80+ Pharmacokinetic and Pharmacodynamic Changes with Aging

Metabolism Generally, lower drug doses are required to achieve the same effect Receptor numbers, affinity, or post-receptor cellular effects may change Overall decline in metabolic capacity Decreased liver mass Decreased oxidative metabolism through P450 system decreased clearance of drugs Standard Creatine Clearance ml/min/1.73 Kidney Function and Age 140 130 120 110

100 30 40 50 60 Age (years) Andres and Tobin, 1976 70 80 Prevalence of Dementia North America: 6.9% prevalence; 63% increase 20102030; 151% increase 2010-2050 Polypharmacy in the Elderly Elderly = 12% of population; 32% of prescriptions

Average of 6 prescription medications; 1 to 3.5 over-the-counter drugs Average nursing home patient takes 7 medications Average American senior spends $670/year for pharmaceuticals Adverse Drug Reactions About 15% of hospitalizations in the elderly are related to adverse drug reactions The risk of adverse drug reactions increases with the number of prescription medications Polypharmacy and Non-adherence

Strongest predictor of non-adherence is the number of medications Non-adherence rates estimated 25-50% Intentional about 75% of the time Changes in regimen made by patients to: - Increase convenience - Reduce adverse effects or - Decrease refill expense Hazards of Anticoagulant Medications #1 in 2003 and 2004 in the number of mentions of deaths for drugs causing adverse effects in therapeutic use1

Warfarin-6% of 702,000 ADEs treated in ED per year; 17% require hospitalization1 21 million warfarin prescriptions in 1998>>>31 million in 20042 The incidence AC-related intracranial hemorrhage quintupled during this time period3 Wysowski DK, et al. Arch Intern Med. 2007;167:1414-1419. 2 Budnitz DS, et al. JAMA. 2006;296:1858-1866. 3 Flaherty ML, et al. Neurology. 2007;68:116-121. 1 Ischemic Stroke and Intracranial Bleeding Adjusted Odds in Relation to Intensity of Anticoagulation Odds Ratio 15.0 10.0 Stroke

Intracranial Bleed 5.0 1.0 0 1.0 2.0 3.0 4.0 5.0 INR Fuster et al. J Am Coll Cardiol. 2001;38:1231-1266. 6.0 7.0 8.0 Warfarin Dosing is Complex

Factors that Correlate w/ Warfarin Dose Age Body surface area (BSA) or weight Amiodarone Other drugs (e.g. acetaminophen) Race Sex Plasma vitamin K level Decompensated CHF Chemotherapy Genetic status Other Factors (up to 40%) Age, Sex, Weight (10-20%) VKORC1 (up to 25%) CYP2C9 (up to 15%) ACTIVE W Trial VKA vs dual

antiplatelet Rx Minimum threshold TTR necessary to realize benefit of warfarin: 58% Circulation 2008;118. Connolly SJ for Active W Investigators Comparison of Outcomes Among Patients Randomized to Warfarin According to Anticoagulant Control Results From SPORTIF III and V Outcome >75% TTR<60% < 60% TTR TTR 60-75% TTR>75% TTR 60-75% TTR Mortality, %

4.2 1.84 1.69 Major Bleed, % 3.85 1.96 1.58 Stroke/SEE,% 2.10 1.34 1.07 Arch Intern Med. 2007. White HD, Gruber M, Feyzi J, Kaatz S, Tse H, Husted S, Albers G Major Hemorrhage Rates Randomized Trials

INR Target ICH Major Age AFI 1.5-4.5 0.3 1.0 69 SPAF II 2.0-4.5 0.9 1.4 70

AFFIRM 2.0-3.0 ---- 2.0 70 RE-LY 2.0-3.0 0.7 3.4 72 INR Target ICH Major Age

Van der Meer, et al. (1993) 2.8-4.8 0.6 2.0 66 Palareti, et al (1996) 2.0-4.5 0.5 0.9 62 Go, et al (2003) 2.0-3.0 0.5 1.0

71 Observational Baseline Characteristics AF Trials Historical trials SPORTIF III/V ACTIVE W RE-LY 1989-1993 2003-2005 2006 2009 3,763 7,327

6,706 18,113 Age, yrs 69 71 70 72 Female 29% 31% 33% 37% Prior stroke 5%

21% 15% 20% Hypertension 45% 77% 83% 79% CHR 26% 18% 21% 32% Diabetes

13% 18% 21% 23% NA NA 2.0 2.1 Year published N CHADS2 score Cumulative Incidence of Major Bleeding 0.04 0.06 0.08 0.10 0.02 0.00

Cumulative Proportion with Major Hemorrhage First Year Among Patients Newly Starting Warfarin by Age 0 100 200 Days of Warfarin Age < 80 Hylek EM et al, Circulation 2007;115(21):2689-2696. 300 Age >=80 400 .0015 .001 .0005 0 Risk of Stopping Warfarin

.002 Risk of Stopping Therapy in the First Year Among Patients Newly Starting Warfarin by Age 0 100 200 Days of Warfarin Age < 80 Hylek EM et al, Circulation 2007;115(21):2689-2696. 300 Age >=80 400 Optimizing Benefit and Reducing Risk Hemorrhage Thrombosis

Strategies To Minimize Risk Of Hemorrhage THE FACTS: Incidence of UGIB and LGIB increases with age. 70% of acute UGIB occur > 60 years of age. Differential mucosal effect of ASA by age Incidence of LGIB increases 200-fold from the 3rd to 9th decade of life: diverticulosis, angiodysplasias, ischemic colitis, malignancy Bleeding Risk Scores for Warfarin Therapy Kuijer et al. Arch Intern Med 1999;159:457-60 Beyth et al. Am J Med 1998;105:91-9 Gage et al. Am Heart J 2006;151:713-9 Shireman et al.

Chest 2006;130:1390-6 Low Moderate High 0 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 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 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 0 0-1 1.07 1-2 2-3 >1.07 <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 >2.19 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 Warfarin Dose by Age 50

Warfarin Weekly Dose, mg Warfarin Weekly Dose, mg Derived from two independent ambulatory populations 45 40 35 30 25 20 <50 50-59 60-69 70-79 80-89 Age Female Male Garcia D, et al. Chest 2005 2005;127:2049-2056

>=90 50 45 40 35 30 25 20 <50 50-59 60-69 Age Female 70-79 80-89 Male >=90 Delay in INR Normalization with Increasing Age

1b 10 INR 6 4 3 2 Index INR 7 - 9 (n = 235) Median INR half life = 2.3 days Interquartile Range = (1.7,3.8) Median days to INR < 4: 1.5 days Interquartile Range = (1.1,2.5) 1 0.00 0.25 0.50 0.75 Hylek et al, Ann Intern Med. 2001;135:393-400

1.00 Interval (days) 1.25 1.50 1.75 2.00 Risk Factors for INR > 4.0 After Holding Two Doses of Warfarin Adjusted Odds Ratio Warfarin dose, weekly per 10 mg 0.87 (0.79 - 0.97) Age, per decade 1.18 (1.01 1.38) Decompensated heart failure 2.79 (1.30 5.98) Active malignancy

2.48 (1.11 5.57) Index INR, per unit 1.25 (1.14 1.37) Risk of UGIB with Different Combinations of Antithrombotic Agents Mean age=72 years Hallas J, et al. BMJ doi:10.1136/bmj.38947.697558.AE Evolving Role for Aspirin Meta-analysis of 10 trials that compared oral anticoagulant (OAC) therapy to ASA+OAC. 4,180 patients with either heart valve, AF, or CAD Combination therapy:

Did not benefit patients with AF (OR 0.99) or CAD (OR 0.69) nor did it influence all cause mortality. Did increase the risk of major bleeding (OR 1.43). Lower incidence of thromboembolism (OR 0.66), but the benefits were limited to patients with valves (OR 0.27). Dentali F, Douketis JD, Lim W, Crowther M. Arch Intern Med 2007; 167:117-124. Strategies to Improve Quality of VKA-Based Anticoagulant Therapy Vigilant monitoring around all transitions in care Initiate lower doses in most susceptible patient subsets Increase monitoring with medication changes

Reinforce safety points with patients and caregivers Summary Points and Conclusions Elderly patients with AF are at the highest risk of stroke and the highest risk of hemorrhage. Rates of ischemic stroke significantly exceed rates of ICH and major extracranial hemorrhage on OAC. Intensive efforts to optimize OAC will help to decrease major bleeding. Novel anticoagulants may be safer in the elderly population due to their wider therapeutic index, shorter t1/2, lack of dietary interference, and fewer drug interactions. Atrial Fibrillation Case Study Atrial Fibrillation Patient Case Study 85-year-old female with AF, HTN, HF, prior TIA,

osteoarthritis and prior diverticular GIB six months ago, on warfarin, who presents to the ED with complaints of SOB for several days and black stools. Medications: atenolol, lisinopril, lasix, warfarin, ASA Most recent INR 3 weeks ago = 3.1 Atrial Fibrillation Case Study Question 1: This patients estimated stroke risk per year without warfarin is: a)5% b)12% c)20% d)None of the above Physical Exam and Pertinent Data Exam: afebrile, HR 110-130, BP 154/90 lungs-bibasilar rales COR-irreg irreg ABD-nontender guaiac + ECG: AF with rapid VR CXR:

mild pulmonary edema Labs: Hct=21, INR=8.0, Troponin - Atrial Fibrillation Case Study Question 2: The most appropriate management strategy for this patient would be to: a)Stop both aspirin and warfarin Resume aspirin only in one week b)Stop both aspirin and warfarin Resume warfain c)Stop both aspirin and warfarin Resume both warfarin and aspirin in one week d)Stop both aspirin and warfarin permanently Atrial Fibrillation Case Study Question 3: The patients bleeding episode resolves, she is started back on warfarin, and she returns six months later with an hematocrit of 35 (her baseline). Her INR is 3.7. If dabigatran were approved by the FDA for SPAF, at this point you would: a)Stop warfarin and put the patient on clopidogrel and aspirin b)Adjust the warfarin to achieve an INR of 2.0 - 3.0 c)Transition patient to dabigatran 110mg PO BID

d)Transition patient to dabigatran 150 mg PO Bid e)Start aspirin only New Frontiers in Atrial Fibrillation The Emerging Role of New Oral Anticoagulants Landmark Trials That May Alter the Landscape of Stroke Prevention in AF Jeffrey I. Weitz, MD, FRCP, FACP Professor of Medicine and Biochemistry McMaster University Director, Henderson Research Center Canada Research Chair in Thrombosis Heart and Stroke Foundation J.F. Mustard Chair in Cardiovascular Research Overview of Presentation Limitations of warfarin New oral anticoagulants Role of new agents in AF Limitations of Warfarin Limitation

Consequence Slow onset of action Overlap with a parenteral anticoagulant Genetic variation in metabolism Variable dose requirements Multiple food and drug interactions Frequent coagulation monitoring Narrow therapeutic index Frequent coagulation monitoring New Oral Anticoagulants for Stroke Prevention in AF Direct Inhibitors of Factor Xa or Thrombin Comparison of Features of New Oral

Anticoagulants in Advanced Stages of Development Rivaroxaban Apixaban Dabigatran Etexilate Target Xa Xa IIa Molecular Weight 436 460 628 Prodrug No

No Yes Bioavailability (%) 80 50 6 Time to peak (h) 3 3 2 Half-life (h) 9 9-14 12-17

Renal excretion (%) 65 25 80 None None None Features Antidote Comparison of Features of New Anticoagulants With Those of Warfarin Features Warfarin New Agents

Onset Slow Rapid Dosing Variable Fixed Yes No Many Few Monitoring Yes No Half-life

Long Short Antidote Yes No Food effect Drug interactions Which of the Following Statements is true? 1. Oral factor Xa inhibitors have a better safety profile than oral thrombin inhibitors 2. Of the new oral anticoagulants, dabigatran etexilate is most advanced in development 3.

Oral factor Xa inhibitors can be safely given to patients with a creatinine clearance < 30 ml/min 4. The prothrombin time can be used to monitor all of the new oral anticoagulants 5. Fresh frozen plasma will reverse the anticoagulant effects of the new oral anticoagulants RE-LY: A Non-inferiority Trial Atrial Fibrillation with 1 Risk Factor Absence of Contraindications Conducted in 951 centers in 44 countries Blinded Event Adjudication R R Open Open Warfarin Adjusted

INR 2.0 3.0 N=6000 Blinded Dabigatran etexilate 110 mg BID N=6000 Dabigatran etexilate 150 mg BID N=6000 RE-LY: Baseline Characteristics Characteristic Dabigatran 110 mg Dabigatran 150 mg Warfarin Randomized

6015 6076 6022 Mean age (years) 71.4 71.5 71.6 Male (%) 64.3 63.2 63.3 CHADS2 score (mean) 0-1 (%) 2 (%) 3+ (%)

2.1 2.2 2.1 32.6 34.7 32.7 32.2 35.2 32.6 30.9 37.0 32.1 Prior stroke/TIA (%) 19.9 20.3 19.8 Prior MI (%)

16.8 16.9 16.1 CHF (%) 32.2 31.8 31.9 Baseline ASA (%) 40.0 38.7 40.6 Warfarin Nave (%) 49.9 49.8

51.4 Connolly et al., NEJM, 2009 RE-LY: Stroke or Systemic Embolism Non-inferiority Superiority p-value p-value <0.001 0.34 <0.001 <0.001 Dabigatran 110 vs. Warfarin Dabigatran 150 vs. Warfarin Margin = 1.46 0.50 0.75

Dabigatran better Connolly et al., NEJM, 2009 1.00 1.25 HR (95% CI) 1.50 Warfarin better RE-LY: Annual Rates of Bleeding Dabigatran Dabigatran Warfarin 110mg 150mg Dabigatran 110mg vs. Warfarin Dabigatran 150mg vs. Warfarin n

6015 6078 6022 RR 95% CI p 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 LifeThreatening 1.2 %

1.5 % 1.8 % 0.68 0.55-0.83 <0.001 0.81 0.66-0.99 0.04 Gastrointestinal 1.1 % 1.5 % 1.0 % 1.10 0.86-1.41 0.43

1.50 1.19-1.89 <0.001 Connolly et al., NEJM, 2009 RE-LY: Intra-cranial Bleeding Rates RR 0.31 (95% CI: 0.200.47) p<0.001 (sup) RR 0.40 (95% CI: 0.270.60) p<0.001 (sup) Number of events 0,74 % RRR 60% RRR 69% 0,30 % 0,23 % Connolly et al., NEJM, 2009

How can dabigatran be more effective than warfarin yet cause less bleeding? Targeted inhibition of thrombin Consistent and predictable anticoagulant effect RE-LY: Secondary Efficacy Outcomes According to Treatment Group Event Dabigatran 110 mg Dabigatran 150 mg Warfarin Myocardial infarction 0.7% 0.7%

0.5% Vascular death 2.4% 2.3% 2.7% All-cause mortality 3.8% 3.6% 4.1% Connolly, et al. N Engl J Med 2009;361:1139-51 Why is There More MI with Dabigatran? Chance finding? Warfarin superior to dabigatran for inhibitionof clotting at sites of plaque disruption? Other factors?

RE-LY: Outcomes in Secondary-Prevention Patients with AF by Treatment Assignment End point Warfarin Dabigatran 110 mg twice daily Stroke/ systemic embolism (%/year) 2.74 2.32 0.85 (0.591.22) 0.37 2.07 0.76

(0.531.10) 0.14 Hemorrhagic stroke (n) 18 2 0.11 (0.030.47) 0.003 5 0.27 (0.100.72) 0.009 ICH (n) 30 6

0.20 (0.080.47) 0.001 13 0.41 (0.210.79) 0.007 RR (95% CI) vs warfarin p Dabigatran 150 mg twice daily RR (95% CI) vs warfarin p Diener HC et al. American Stroke Association International Stroke Conference

2010; February 26, 2010; San Antonio, TX. 0.02 Warfarin Dabigatran 110 mg 0.01 Dabigatran 150 mg 0.0 Cumulative risk 0.03 0.04 RE-LY: Cumulative Risk of ALT or AST >3x ULN After Randomization 0 0.5 1.0

1.5 Years of follow-up Connolly, et al. N Engl J Med 2009;361:1139-51 2.0 2.5 Which Dose for Which Patient? Lower-dose regimen Elderly Renal insufficiency Lower stroke risk (CHADS2 score of 1) Higher-dose regimen Higher stroke risk (CHADS2 score 2) Meta-analysis of Ischemic Stroke or Systemic Embolism W vs placebo W vs W low dose W vs ASA W vs ASA + clopidogrel W vs dabigatran 150

0 0.3 0.6 0.9 Favours warfarin Camm J.: Oral presentation at ESC on Aug 30th 2009. 1.2 1.5 1.8 2.0 Favours other treatment What About Trials with Other New Oral Anticoagulants? ROCKET Rivaroxaban ARISTOTLE Apixaban ENGAGE - Edoxaban What about other indications? RE-COVERTM Trial Design Single-dummy

period Warfarin placebo Double-dummy period Dabigatran etexilate 150 mg bid Warfarin placebo Objective confirmation of VTE 72 h Dabigatran etexilate placebo bid Warfarin Initial parenteral therapy E E= enrolment R= randomization R Until INR 2.0 on

two consecutive measurements (8-11 days) 30 days follow up Warfarin (INR 2.03.0) 6 months End of treatment Efficacy and Safety Outcomes Outcome Dabigatran Dabigatran HR (95% CI) Recurrent VTE and VTE-related death 2.4%

2.1% 1.10 (0.65-1.84) Major bleeding 1.6% 1.9% 0.82 (0.45-1.48) Schulman et al., N Engl J Med, 2009 Is Warfarin Obsolete? New oral anticoagulants are more convenient But, warfarin effective when time in therapeutic range is high Cumulative Risk of Stroke, MI, Systemic Embolism, or Vascular Death

Patients treated at centers with a TTR below or above the study median (65%) TTR < 65% Event Rate (%) 10 RR=0.93 (0.70-1.24) p=0.61 RR=2.14 (1.61-2.85) P=0.0001 10 8 OAC 6 TTR >= 65% 12 C+A Event Rate (%)

12 4 8 C+A 6 4 2 2 0 0 0.0 0.5 Years 1.0 1.5

Connolly, S. J. et al. Circulation 2008;118:2029-2037 OAC 0.0 0.5 Years 1.0 1.5 Time in Therapeutic Range (TTR) with Warfarin in the RE-LY Trial Group Relative Risk Overall 64% VKA Experienced

61% VKA Na Na ve 67% Relative Risk of Stroke or Systemic Embolism with According to Geographical Region Dabigatran Versus Warfarin Subgroup All patients Long-term VKA therapy No Yes Patients Dabigatran Warfarin total no. 110 mg 150 mg 18,113 1.53 1.11

Hazard Ratio with P Value Dabigatran, 100 for mg (95% CI) Interaction 1.69 9,123 1.57 1.07 1.67 8,989 1.49 1.15 1.70 Region North America

6,533 1.19 1.11 1.51 South America 1,134 1.82 0.91 1.68 Western Europe 3,941 1.53 1.26 1.43

Central Europe South Asia 2,829 1,134 1.22 3.35 0.78 0.84 1.06 4.00 East Asia 1,648 1.87 1.77 2.28 Other 1,072

1.95 0.88 2.27 0.5 1.0 Dabigatran Better Connolly et al., NEJM 2009 Hazard Ratio with P Value Dabigatran, for 150 mg (95% CI) Interaction 0.72 0.81 0.91 0.11

1.5 Warfarin Better 0.5 1.0 1.5 Dabigatran Better Warfarin Better Who is Not a Candidate for Dabigatran? Stable on warfarin Renal impairment Severe hepatic disease Poor compliance Unanswered Questions Management of patients with severe coronary artery disease or recent GI bleeding? Will short half-life obviate need for

antidotes? Will elimination of monitoring adversely impact patient care? Conclusions: RE-LY and New, Oral NonMonitored Anticoagulation Dabigatran etexilate is superior to warfarin for stroke prevention and non-inferior for VTE treatment Dosing of new oral anticoagulants is critical; are the doses of factor Xa inhibitors optimal? New oral anticoagulants will replace warfarin, but transition likely to be slow Atrial Fibrillation Case Study Atrial Fibrillation Case Study Mrs. A. is a 78-year-old woman who is taking warfarin for stroke prevention on the background of atrial fibrillation. She also takes ASA 81 mg daily. Her risk factors for stroke include hypertension and type II diabetes mellitus.

Her INR control has been erratic with values ranging from 1.5 to 6.8. For the past two weeks, she has had intermittent nosebleeds lasting 5 to 20 minutes. She is anxious to stop warfarin. Atrial Fibrillation Case Study Question 1: What is the best approach for this patient? (a)Stop the warfarin and the ASA (b)Stop the ASA, but continue warfarin (c)Perform CYP2C9 and VKORC1 genotyping to better identify an appropriate warfarin dose (d)Stop the warfarin and add clopidogrel 75 mg daily (e)Continue warfarin and ASA, but monitor the INR more frequently Atrial Fibrillation Case Study The ASA was stopped, but Mrs. A. still complains of nosebleeds. Despite weekly monitoring, her INR continues to range from 1.8 to 4.8. A calculated creatinine clearance is 45 ml/min. Atrial Fibrillation Case Study Question 2: If dabigatran were approved for

stroke prevention in patients with atrial fibrillation, what would you likely do at this point? (a)Continue on warfarin (b)Continue on warfarin, but add low-dose vitamin K (c)Switch from warfarin to dabigatran etexilate 110 mg b.i.d. (d)Switch from warfarin to dabigatran etexilate 150 mg b.i.d. Atrial Fibrillation and Thromboembolism Current State of the Art and Science There is a new, quickening rhythm to the pace of research and clinical advances in atrial fibrillation Etiology of AF is multifactorial and we are just beginning to understand the inter-relationship among myriad factors Noninvasive imaging and biomarkers of

inflammation and thrombosis can predict clinical events in AF and may help guide therapy Risk stratification strategies for AF are useful but imperfect: advances and refinements are required to help define role for non-monitored, oral anticoagulants Atrial Fibrillation and Thromboembolism Current State of the Art and Science Strategies are being developed to improve the safety and efficacy of vitamin K antagonists (VKAs), but achieving acceptable TTRs remains a challenge Elderly patients with AF are at the highest risk of stroke and the highest risk of hemorrhage, and therefore demand special attention Novel anticoagulants appear to be safer in the elderly population due to their wider therapeutic index, shorter t1/2, lack of dietary interference, and fewer drug interactions.

Atrial Fibrillation and Thromboembolism Current State of the Art and Science Dabigatran etexilate is superior to warfarin for stroke prevention and non-inferior for VTE treatment Dosing strategy for new oral anticoagulants is critical: selecting the appropriate dose in the individual patient to achieve ideal balance of stroke prevention and bleeding minimization is a work in progress New oral anticoagulants will replace warfarin, and the transition will impact the landscape of Atrial Fibrillation and Thromboembolism Current State of the Art and Science At least four trials evaluating the safety and efficacy of oral, non-monitored anticoagulants for SPAF are in progress: stay tuned Thank You

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