New Dimensions and Landmark Practice Advances National Experts

New Dimensions and Landmark Practice Advances National Experts

New Dimensions and Landmark Practice Advances National Experts in Cardiovascular Medicine Illuminate and Debate New Frontiers in Atrial Fibrillation Emerging Perspectives in Thrombosis Mitigation for the Cardiovascular SpecialistTranslating Evidence into Action Program Moderator Samuel Z. Goldhaber, MD Cardiovascular Division Brigham and Womens Hospital Professor of Medicine Harvard Medical School Welcome and Program Overview CME-accredited symposium jointly sponsored by the University of Massachusetts Medical School and CMEducation Resources, LLC Commercial Support: Sponsored by an independent educational grant from Boehringer-Ingelheim Mission statement: Improve patient care through evidence-based education, expert analysis, and case study-based management Processes: Strives for fair balance, clinical relevance, on-label indications for agents discussed, and emerging evidence and information from recent studies COI: Full faculty disclosures provided in syllabus and at the beginning of the program Program Educational Objectives As As a result of this educational educational activity, activity, participants participants will learn about:

Advances in oral anticoagulation based on new mechanisms involving inhibition of the coagulation cascade and possible implications for prophylaxis of arterial thromboembolism in the setting of atrial fibrillation. The mechanisms involved in thromboembolic prevention and the rationale for identifying agents with predictable anticoagulation, in the absence of clinical monitoring. Current ACCP, ACC, AHA, and AAN guidelines for stroke prevention in the setting of AF. Novel approaches for residual risk reduction and secondary prevention of adverse thromboembolic events (stroke) in the setting of atrial fibrillation, and related conditions. Program Faculty Program Moderator Samuel Z. Goldhaber, MD Cardiovascular Division Brigham and Womens Hospital Professor of Medicine Harvard Medical School 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 Elaine M. Hylek, MD, MPH Associate Professor of Medicine Department of Medicine Director, Thrombosis Clinic and

Anticoagulation Service 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 Faculty COI Disclosures Samuel Z. Goldhaber, MD Research Support: BMS, Boehringer-Ingelheim, Eisai, Johnson and Johnson, sanofiaventis Consultant: BMS, Boehringer-Ingelheim, Eisai, Medscape, Merck, sanofi-aventis, Vortex Jonathan L. Halperin, MD Consulting fees from the following companies involved in development of investigational drugs or devices: Astellas Pharma, U.S., Bayer HealthCare, Biotronik, Inc., Boehringer Ingelheim, Daiichi Sankyo Pharma, Johnson & Johnson, Portola Pharmaceuticals, and sanofi-aventis Elaine M. Hylek, MD, MPH Steering Committee: Bristol-Myers Squibb Advisory Board: Astellas, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, sanofiaventis Jeffrey I. Weitz, MD, FRCP, FACP Grants/Research Support: CIHR, HSFO, CFI, ORF Speakers Bureau: Bristol-Myers Squibb, Boehringer Ingelheim, sanofi-aventis, DaiichiSankyo, Bayer, Pfizer, The Medicines Company, Eisai, Takeda New Frontiers in Atrial Fibrillation ATRIAL FIBRILLATION

Current Challenges in Thrombosis Medicine for the Cardiovascular Specialist Samuel Z. Goldhaber, MD Cardiovascular Division Brigham and Womens Hospital Professor of Medicine Harvard Medical School Atrial Fibrillation: Twice as Common as Previously Suspected Incidence Incidence increased increased 13% 13% over over past past 20 20 years years In In USA, USA, 12-16 12-16 million million will will be be affected affected by by 2050 2050 Increasing Increasing obesity obesity and

and increasing increasing age age are are risk risk factors factors that that help help explain explain rise rise in in incidence incidence Miyasaka Y. Circulation 2006; 114: 119-125 AF Prevalence: Age and Gender Prevalence, percent Prevalence of atrial fibrillation with age Age, years JAMA 2001; 285: 2370 Mortality Rates in AF Double Double the the overall overall age age and and gender gender matched

matched population population No No reduction reduction in in past past two two decades decades Mortality Mortality 9-fold 9-fold higher higher during during 11stst 44 months months after after diagnosis diagnosis Miyasaka Y, et al. JACC 2007; 49: 986-992 Risk Factors for Stroke Risk Factor Relative Risk Old Stroke/TIA 2.5 Hypertension 1.6

CHF 1.4 Increased age 1.4/10 years DM 1.7 CAD 1.5 Arch Intern Med 1994; 154: 1449-1457 Atrial Fibrillation: A Risk Factor for Vascular Events RISK FACTORS for THROMBOSIS Hypertension Hyperlipidemia Age Diabetes Mellitus Smoking

Atherosclerosis/Atherothrombosis Atherosclerosis/Atherothrombosis MI MI AF Stroke, MI, Vascular Death Wolf PA et al. Arch Intern Med 1987; 147: 1561-1564 Leckey R et al. Can J Cardiol 2000; 16: 481-485 CHF CHF Thrombus in Left Atrial Appendage Associated with Stroke Thrombus Thrombus in left atrial appendage is correlated with increased thromboembolic risk in AF Chimowitz. Stroke 1993; 24: 1015 Zabalgoitia. J Am Coll Cardiol 1998; 31: 1622 Left Atrial Appendage One Sixth of all Strokes Attributable to AF Framingham Study 30

20 AF prevalence % Strokes attributable to AF 10 0 5059 6069 7079 8089 Age Range (years) Wolf et al. Stroke 1991; 22: 983-988 Problems with Established Therapy: Warfarin Delayed Delayed onset/offset onset/offset Unpredictable

Unpredictable dose dose response response Narrow Narrow therapeutic therapeutic range range Drugdrug, Drugdrug, drugfood drugfood interactions interactions Problematic Problematic monitoring monitoring High High bleeding bleeding rate rate Slow Slow reversibility reversibility First Month of Warfarin Therapy has High Bleeding Rate Bleeding Type 1st Month Warfarin

Subsequent Warfarin Head Bleed Major NonHead Bleed 0.92% (annualized) 1.2% (annualized) 0.46% per year Fang MC. J Am Geriatr Soc 2006; 54: 1231-1236 0.61% per year FDA Adds Black Box Warning/Precaution for Warfarin October 6, 2006 Warning: Bleeding Risk August 16, 2007 Precaution: Consider a lower initial warfarin dose for patients with certain genetic variations. Learning Objectives Warfarin Warfarin dosing dosing and and genetics

genetics FDA FDA warfarin warfarin labeling labeling vs. vs. NHLBI NHLBI Randomized Randomized Clinical Clinical Trial Trial Warfarin: Advantages 1. 1. 2. 2. INR INR assesses assesses anticoagulant anticoagulant level level Multiple Multiple antidotes antidotes available available 3. 3. Omitting

Omitting one one or or two two doses doses usually usually is is not not clinically clinically problematic problematic 4. 4. Introduced Introduced in in 1954. 1954. Has Has stood stood the the test test of of time. time. No No liver liver toxicity toxicity 5. 5. Ability Ability to to maintain maintain target target INR INR is is improving

improving (Now (Now >> 60% 60% in in top top facilities) facilities) 6. 6. No No anticoagulant anticoagulant has has demonstrated demonstrated superior superior efficacy efficacy or or safety safety 7. 7. Inexpensive Inexpensive Warfarin: Walking a Tightrope Excessive Excessive dose dose precipitates precipitates hemorrhage hemorrhage

Inadequate Inadequate dose dose predisposes predisposes to to stroke stroke and and pulmonary pulmonary embolism embolism Dosing Dosing nomograms nomograms are are awkward, awkward, cumbersome cumbersome Dosing Dosing by by trial trial and and error error predominates predominates

Therapeutic Range for Warfarin INR Values at Stroke or ICH Odds Ratio 15.0 Stroke Intracranial Hemorrhage 10.0 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 Hylek, EM et al. N Engl J Med. 2003;349:1019-2614 Most intracranial hemorrhages (62%) occur at INRs < 3.0 Fang MC et al. Ann Intern Med. 2004;141:745-52 Reduction of Stroke in AF Warfarin Compared with Placebo Adjusted-dose warfarin compared with placebo Relative risk reduction (95% CI) AFASAK I SPAF BAATAF CAFA SPINAF EAFT 62% (48% to 72%) All trials (n=6) 100 50 Warfarin better Hart et al. Ann Intern Med 1999; 131: 492-501

0 -50 -100 Warfarin worse ACTIVE W Trial OAC Standard Care (INR 2.0 3.0) INR at least monthly Clopidogrel plus ASA Clopidogrel 75 mg once daily ASA 75-100 mg once daily ACTIVE W: Outcome Events Primary Outcome Stroke, Non-CNS Systemic Embolism, MI, Vascular Death Safety Outcome Major Bleeding 0.10 ACTIVE W: Stroke, Non-CNS Embolism, MI and Vascular Death 0.08 RR = 1.45 P = 0.0002

0.06 Clopidogrel+ASA 0.04 3.93 %/year 0.02 OAC 0.0 Cumulative Hazard Rates 5.64 %/year # at Risk C+A OAC 0.0 3335 3371 0.5 3149 3220 Years 1.0 2387

2453 1.5 916 911 ACTIVE W: Major Bleeding RR = 1.06 0.03 P = 0.67 0.02 2.2 %/year 0.01 OAC Clopidogrel+ASA 0.0 Cumulative Hazard Rates 0.04 2.4 %/year # at Risk C+A OAC

0.0 3335 3371 Lancet. 2006;367:1903-1912, 1877-1878 0.5 3172 3212 Years 1.0 2403 2423 1.5 914 901 The Frontiers of Thrombosis: Mitigation (Stroke Reduction) in Atrial Fibrillation New oral anticoagulants, given in fixed dose without laboratory coagulation monitoring, may improve and expand on existing anticoagulation options. We will hear about these exciting development tonight. New Frontiers in Atrial Fibrillation Challenges in Stroke Prevention for Patients with Atrial Fibrillation Achieving Balance Between Prevention of Thromboembolism

and Risk of Bleeding 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 Projected U.S. Prevalence of AF Projected Number of People with AF (millions) An Expanding Epidemic 18 16 14 12 10 8 Based on Projected Incidence 6 Based on Current Incidence 4 2 0 20 00

20 05 20 10 20 15 20 20 20 25 Year Miyakasa Y, et al. Circulation 2006; 114: 119. 20 30 20 3 5 20 4

0 20 45 20 5 0 Atrial Fibrillation A Substantial Threat to the Brain Affects Affects ~~4% 4% of of people people aged aged >>60 60 years years ~9% ~9% of of those those aged aged >>80 80 years years

5%/year 5%/year stroke stroke rate rate 12%/year 12%/year for for those those with with prior prior stroke stroke $$ billions billions annual annual cost cost for for stroke stroke care care AF-related AF-related strokes strokes have have worse worse outcomes outcomes AF identifies millions of people with a five-fold increased risk of stroke

Priorities in the Management of AF The Patient Care Pathway Rhythm Control Prevention of Thromboembolism Rate Control 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% >10% of of intracerebral intracerebral hemorrhages hemorrhages (ICH) (ICH) occur occur in in patients

patients on on antithrombotic antithrombotic therapy therapy Aspirin Aspirin increases increases the the by by ~~ 40% 40% Warfarin Warfarin (INR (INR 23) 23) doubles doubles the the risk risk to to 0.3 0.3 0.6%/year 0.6%/year ICH ICH during during anticoagulation anticoagulation is is catastrophic catastrophic Hart RG, et al. Stroke 2005;36:1588 Risk Stratification in AF Stroke Risk Factors

High-Risk High-Risk Factors Factors Mitral Mitral stenosis stenosis Prosthetic Prosthetic heart heart valve valve History History of of stroke stroke or or TIA 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 High-Risk Factors Factors Mitral Mitral stenosis stenosis Prosthetic Prosthetic heart heart valve valve History History of of stroke stroke or or TIA 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 High-Risk Factors Factors Mitral Mitral stenosis stenosis Prosthetic Prosthetic heart heart valve valve History History of of stroke stroke or or TIA 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 High-Risk Factors Factors Mitral Mitral stenosis stenosis Prosthetic

Prosthetic heart heart valve valve History History of of stroke stroke or or TIA 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, "Actually, it's it's more more of of aa guideline guideline than than aa rule. rule. Bill Bill Murray Murray in in Ghostbusters Ghostbusters (1984) (1984),, relaxing relaxing his his rule rule "never

"never to to get get involved involved with with possessed possessed people" people" in in response response to to Sigourney Sigourney Weaver's Weaver's seductive seductive advances. advances. Patient Selection for Anticoagulation Additional Considerations Risk of bleeding Newly anticoagulated vs. established therapy Availability of high-quality anticoagulation management program Patient preferences INR at the Time of Stroke or Bleeding Efficacy and Safety of Warfarin 20 Odds Ratio 15

Ischemic Stroke Intracranial bleeding 10 5 1 1.0 2.0 3.0 4.0 5.0 6.0 International Normalized Ratio Fang MC, et al. Ann Intern Med 2004; 141:745. Hylek EM, et al. N Engl J Med 1996; 335:540. 7.0 8.0 Warfarin for Atrial Fibrillation Limitations Lead to Inadequate Treatment Adequacy of Anticoagulation in Patients with AF in Primary Care Practice

No warfarin 65% INR above target 6% INR in target range 15% Subtherapeutic INR 13% Samsa GP, et al. Arch Intern Med 2000;160:967. 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 ACTIVE-A 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 Incidence Cumulative 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. Warfarin Dosing and Genomics

CYP2C9 CYP2C9 Gene Gene encoding encoding cytochrome cytochrome P450 P450 hepatic hepatic enzyme enzyme responsible responsible for for primary primary clearance clearance of of S-warfarin, S-warfarin, the the active active enantiomer; enantiomer; variant variant alleles alleles are are associated associated with with sensitivity sensitivity to to warfarin. warfarin. VKORC1 VKORC1 Gene Gene encoding encoding vitamin vitamin K

K epoxide epoxide reductase reductase complex complex 1; 1; variant variant alleles alleles are are associated associated with with warfarin warfarin resistance. resistance. Warfarin Dosing and Genomics Keeping Ahead of the Data Intervention Period: Informed by genetic/clinical information Dose Initiation 1 2 3 4, 5 Dose Titration

6 7 8 Objective: To compare the effect of pharmacogenetic & clinical warfarin dosing algorithms on initial proportion of time in therapeutic range of anticoagulation intensity The Ideal Anticoagulant Wide Therapeutic Margin Thrombosis Safe Therapeutic Range Dose, Concentration, or Intensity of Anticoagulation Bleeding Bleeding Thrombosis New Anticoagulant Development The Clinical Trial Pathway DVT/VTE

Prophylaxis Orthopaedic Surgery DVT/VTE Treatment AFib/Stroke Prophylaxis Arterial Disease Other Potential Indications Investigational Anticoagulant Targets ORAL PARENTERAL TF/VIIa TTP889 TFPI (tifacogin) X IX VIIIa Rivaroxaban Apixaban

LY517717 YM150 DU-176b 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 SPORTIF III and V Stroke and Systemic Embolism Ximelagatran Better Warfarin Better -0.66 SPORTIF III p=0.10 +0.45 p=0.13 SPORTIF V -0.03 p=0.94 Pooled -4 -3

-2 -1 0 1 2 Difference in Absolute Event Rates (Ximelagatran Warfarin) SPORTIF-V Investigators. JAMA 2005; 293: 690-8. 3 4 SPORTIF III and V Secondary Stroke Prevention = 0.44%/year 95% CI 1.86, 0.98; p=0.625 Event Rate (%/year) p=NS Diener H-C, et al. Cerebrovasc Dis 2006; 21: 279 Major Bleeding Complications SPORTIF III and V

On-treatment Analysis Event Rate (%/year) p=0.054 SPORTIF III Diener H-C, et al. Cerebrovasc Dis 2006; 21: 279 SPORTIF V Pooled SPORTIF III and V Liver Enzyme Elevations Number of patients 100 Warfarin Ximelagatran 80 60 Incidence (%) ALT >3 x ULN 40 ALT >3x ULN

20 0 1 2 3 4 5 6 7 8 9 10 11 12 13 15 16 18 21 27 Months Diener H-C, et al. Cerebrovasc Dis 2006; 21: 279 Emerging Anticoagulants Potential Alternatives to Warfarin Thrombin Thrombin inhibitors inhibitors Factor Xa Direct, Direct, oral oral inhibitors

Ximelagatran Ximelagatran Dabigatran Dabigatran (RE-LY (RE-LY Trial) Trial) Indirect, parenteral Idraparinux Direct, oral Rivaroxaban Apixaban Edoxaban Oral Factor Xa Inhibitors Ongoing Phase III Trials for Prevention of Stroke and Systemic Embolism in Patients with AF Trial Acronym Drug Dose Comparator N Risk factors ROCKET-AF

Rivaroxaban 20 mg* qd Warfarin (INR 2-3) 14,000 2 ARISTOTLE Apixaban 5 mg bid Warfarin (INR 2-3) 15,000 1 ENGAGE-AF Edoxaban 30 mg bid 60 mg* qd

Warfarin (INR 2-3) 16,500 2 * Adjusted based on renal function 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 Restoration and and maintenance maintenance of of sinus sinus rhythm rhythm Antiarrhythmic Antiarrhythmic drug

drug therapy therapy Catheter Catheter ablation ablation Maze Maze operation 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% 74% of of all

all strokes strokes were were proven proven ischemic ischemic 44% 44% occurred occurred after after stopping stopping warfarin warfarin 28% 28% in in patients patients taking taking warfarin warfarin with with INR INR <2.0 <2.0 42% 42% occurred occurred during during documented documented AF 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 (%/y) Dronedarone (%/y) HR (95% CI) p 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 Stroke Hohnloser SH, et al. N Engl J Med 2009; 360: 668-78. 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 Restoration and and maintenance maintenance of of sinus sinus rhythm rhythm

Antiarrhythmic Antiarrhythmic drug drug therapy therapy Catheter Catheter ablation ablation Maze Maze operation 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 Better tools tools to to stratify stratify bleeding

bleeding risk risk Noninvasive Noninvasive imaging imaging and and biomarkers biomarkers of of inflammation inflammation and and thrombosis thrombosis to to predict predict clinical clinical events events and and guide guide therapy therapy Confirming Confirming successful successful rhythm rhythm control control over over time

time Targeted Targeted therapy therapy to to prevent prevent AF AF in in patients patients at at risk risk 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. New Frontiers in Atrial Fibrillation Stroke Prevention in High Risk Populations The Journey from Warfarin to New Options and Strategies Elaine M. Hylek, MD, MPH Associate Professor of Medicine Department of Medicine Director, Thrombosis Clinic and Anticoagulation Service

Boston University Medical Center Boston, Massachusetts Projected Number of Persons with AF (Millions) Projected Number of Persons with AF in the U.S. Between 2000 and 2050 15.2 16 15.9 13.1 14 10.2 12 7.7 10.3 6.7 8 4 11.7 8.9 10

6 15.9 5.1 5.9 8.4 12.1 9.4 7.5 6.1 5.1 11.1 11.7 6.8 5.6 2 0 2000 2005 2010 2015 2020 2025 2030 2035 2040 2045 2050 Year Assumes no further increase in age-adjusted AF incidence (blue curve) and assumes a

continued increase in incidence rate as evident in 1980 to 2000 (yellow curve) Miyasaka, Y. et al. Circulation 2006;114:119-125 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 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 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 Age Men 60-79 Women *Coronary heart disease, heart failure, stroke and hypertension Source: NCHS and NHLBI 79.3 85.9 80+

Per 1,000 Person Years Incidence of Heart Failure* by Age and Sex (Framingham Heart Study: 1980-2003) 45 40 35 30 25 20 15 10 5 0 41.9 32.7 22.3 14.8 9.2 4.7 65-74 75-84 Age Men Women * MD review of medical records using strict diagnostic criteria Source: NHLBI

85+ Prevalence of Heart Failure by Age and Sex (NHANES: 2005-2006) 16 13.8 Percent of Population 14 12.2 12 9.3 10 8 4.8 6 4 2 2.2 0.1 0.2 1.2

0 20-39 40-59 Age Men Source: NCHS and NHLBI 60-79 Women 80+ Prevalence of Dementia North America: 6.9% prevalence; 63% increase 20102030; 151% increase 2010-2050 The graying population will slowly, radically transform society. Richard Suzman, NIA More More than than 37 37 million million people people are are age

age 65. 65. By By 2030, 2030, this this number number will will exceed exceed 70 70 million. million. By By 2040, 2040, those those aged aged 75 75 years years will will exceed exceed the the population population 65 65 to to 74 74 years years old. old.

By By 2050, 2050, 12%, 12%, or or 11 in in 88 Americans, Americans, will will be be age age 75 75 or or older. older. Polypharmacy in the Elderly Elderly Elderly == 12% 12% of of population; population; 32% 32% of of prescriptions prescriptions

Average Average of of 66 prescription prescription medications; medications; 11 to to 3.5 3.5 over-the-counter over-the-counter drugs drugs Average Average nursing nursing home home patient patient takes takes 77 medications medications Average Average American American senior senior spends spends $670/year $670/year for for pharmaceuticals

pharmaceuticals Pharmacokinetic and Pharmacodynamic Changes with Aging Metabolism Metabolism Generally, Generally, lower lower drug drug doses doses are are required required to to achieve achieve the the same same effect effect Receptor Receptor numbers, numbers, affinity, affinity, or or post-receptor post-receptor cellular cellular

effects effects may may change change Overall Overall decline decline in in metabolic metabolic capacity capacity Decreased Decreased liver liver mass mass Decreased Decreased oxidative oxidative metabolism metabolism through through P450 P450 system system decreased decreased clearance clearance of of drugs 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 Adverse Drug Reactions About About 15% 15% of of hospitalizations hospitalizations in in the

the elderly elderly are are related related to to adverse adverse drug drug reactions reactions The The risk risk of of adverse adverse drug drug reactions reactions increases increases with with the the number number of of prescription prescription medications medications Adjusted Odds Ratios for Ischemic Stroke and Intracranial Bleeding in Relation to Intensity of Anticoagulation Odds Ratio 15.0 Intracranial Bleed

Stroke 10.0 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 Polypharmacy and Non-adherence Strongest

Strongest predictor predictor of of non-adherence non-adherence is is the the number number of of medications medications Non-adherence Non-adherence rates rates estimated estimated 25-50% 25-50% Intentional Intentional about about 75% 75% of of the the time time Changes Changes in in regimen regimen made made by by patients patients to: to:

-- Increase Increase convenience convenience -- Reduce Reduce adverse adverse effects effects or or -- Decrease Decrease refill refill expense expense 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 TTR <60% TTR 60-75% TTR >75%

Outcome TTR < 60% TTR 60-75% TTR>75% 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

Hazards of Anticoagulant Medications #1 #1 in in 2003 2003 and and 2004 2004 in in the the number number of of mentions mentions of of deaths deaths for for drugs drugs causing causing adverse adverse effects effects in in therapeutic therapeutic use use11 Warfarin-6% Warfarin-6% of

of 702,000 702,000 ADEs ADEs treated treated in in ED ED per per year; year; 17% 17% require require hospitalization hospitalization11 21 21 million million warfarin warfarin prescriptions prescriptions in in 1998>>>31 1998>>>31 million million in in 2004 200422 The The incidence incidence AC-related

AC-related intracranial intracranial hemorrhage hemorrhage quintupled quintupled during during this this time time period period33 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 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 Caveats Relating to Published Data on Hemorrhage Randomized trials - Enrolled few patients 80 years - Highly selected, closely monitored - Vitamin K antagonist at entry Prospective cohort studies - Predominantly non-inception cohort studies of prevalent warfarin use (survivor bias) - Enrolled few patients 80 years - Varying definitions of bleeding - Most conducted within anticoagulation clinic setting Baseline Characteristics AF Trials Year Year published published N N Age, Age, yrs yrs Female Female Historical Historical trials trials

1989-1993 1989-1993 3,763 3,763 69 69 Prior Prior stroke stroke Hypertension Hypertension CHF CHF Diabetes Diabetes CHADS CHADS22 score score 29% 29% 5% 5% 45% 45% 26% 26% 13% 13% NA NA SPORTIF

SPORTIF III/V III/V ACTIVE ACTIVE W W RE-LY RE-LY 2003-2005 2006 2009 2003-2005 2006 2009 7,327 6,706 18,113 7,327 6,706 18,113 71 70 72 71 70 72 31% 33% 37% 31% 33% 37% 21% 15% 20% 21% 15%

20% 77% 83% 79% 77% 83% 79% 18% 18% 18% 18% NA NA 21% 21% 21% 21% 2.0 2.0 32% 32% 23% 23% 2.1 2.1 0.04 0.06 0.08 0.10 0.02 0.00 Cumulative Proportion with Major Hemorrhage

Cumulative Incidence of Major Bleeding 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 .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 Major Hemorrhagic Events and Warfarin Terminations by CHADS2 Score CHADS2 Score N Major Bleed (N) Bleeding Taken Off Rates Therapy (N) % 0

42 1 3.17 5 15.84 1 121 4 4.35 16 17.39 2 181 3 2.08 19 13.16

3 94 12 19.7 20 32.84 4 34 6 23.63 9 35.44 Total 472 26 Hylek EM et al, Circulation 2007;115(21):2689-2696. 69

Taken Off Rates % How Do We Reconcile These Disparate Rates? Inception versus prevalent? Burden of hemorrhagic risk factors? Post-discharge versus outpatient? Prevalence of combination therapy? Degree of initial selection bias? Observation period? Optimizing Benefit and Reducing Risk Hemorrhage Thrombosis 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 Maintenance Warfarin Dose by Age INR Target 2-3 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 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

1.00 Interval (days) Hylek et al, Ann Intern Med. 2001;135:393-400 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) Causes of Elevated INRs Initiation Decreased vitamin K intake Potentiating Medications Decompensated heart failure Chemotherapy Warfarin dosing error Binge alcohol consumption 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 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 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 Justify use of concomitant antiplatelet therapy Promise of novel anticoagulants Incidence of Intracranial Hemorrhage Dabigatran vs Warfarin (RE-LY) Anticoagulant/Dose ICH RR P Dabigatran 110 mg BID 0.23% 0.29 <0.001 Dabigatran 150 mg BID 0.30% 0.41 <0.001 Warfarin (open label) 0.74%

REF REF Connolly Connolly et et al., al., NEJM NEJM,, 2009 2009 Risk Factors for Intracranial Hemorrhage INR intensity Age Aspirin therapy Ischemic cerebrovascular disease Hypertension Trauma Vasculopathy-Leukoaraiosis, amyloid angiopathy 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. 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 Limitations of of warfarin warfarin New New oral oral anticoagulants anticoagulants Role Role of of new new agents agents in in AF 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 Direct Inhibitors Inhibitors of of Factor Factor Xa Xa or

or Thrombin 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 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 Targeted inhibition inhibition of of thrombin thrombin Consistent Consistent and and predictable predictable anticoagulant anticoagulant effect 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 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 Lower-dose regimen regimen Elderly Elderly Renal Renal insufficiency insufficiency Lower Lower stroke stroke risk risk (CHADS (CHADS22 score score of of 1) 1) Higher-dose Higher-dose regimen regimen

Higher Higher stroke stroke risk risk (CHADS (CHADS22 score score 2) 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 ROCKET Rivaroxaban Rivaroxaban ARISTOTLE ARISTOTLE Apixaban Apixaban ENGAGE ENGAGE -- Edoxaban Edoxaban Is Warfarin Obsolete? New New oral oral anticoagulants anticoagulants are are more more convenient convenient But, But, warfarin warfarin effective effective when

when time time in in therapeutic therapeutic range range is is high high Cumulative risk of stroke, myocardial infarction, systemic embolism, or vascular death for patients treated at centers with a TTR below or above the study median (65%) 12 12 10 RR=0.93 (0.70-1.24) p=0.61 8 6 OAC C+A 4 Event Rate (%) Event Rate (%)

10 TTR >= 65% TTR < 65% RR=2.14 (1.61-2.85) P=0.0001 8 6 C+A 4 2 2 OAC 0 0 0.0 0.5 Years 1.0

1.5 Connolly, S. J. et al. Circulation 2008;118:2029-2037 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 Dabigatran Versus Warfarin According to Geographical Region 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 Stable on on warfarin warfarin Renal Renal impairment impairment Severe Severe hepatic hepatic disease disease Poor Poor compliance compliance Unanswered Questions Management Management of of patients patients with with severe

severe coronary coronary artery artery disease disease or or recent recent GI GI bleeding? bleeding? Will Will short short half-life half-life obviate obviate need need for for antidotes? antidotes? Will Will elimination elimination of of monitoring monitoring adversely adversely impact impact patient

patient care? care? Conclusions: RE-LY and New, Oral NonMonitored Anticoagulation Dabigatran Dabigatran etexilate etexilate is is superior superior to to warfarin warfarin for for stroke stroke prevention prevention Dosing Dosing of of new new oral oral anticoagulants anticoagulants is is critical: critical: are are the the doses doses of of factor factor Xa

Xa inhibitors inhibitors optimal? optimal? New New oral oral anticoagulants anticoagulants will will replace replace warfarin, warfarin, but but transition transition may may be be slow slow New Frontiers in Atrial Fibrillation Atrial Fibrillation Current Challenges in Thrombosis Medicine for the Cardiovascular Specialist Discussion, Comments, and The Way Forward Samuel Z. Goldhaber, MD Cardiovascular Division Brigham and Womens Hospital Professor of Medicine Harvard Medical School

Warfarin is Not Just Sitting Around It is fighting back with: 1) Excellent efficacy (ACTIVE) 2) Pharmacogenetics analysis 3) Point-of-care testing 4) Low cost 5) Track Record (approved in 1954) The Red Line in the Sand Can rapid turnaround genetic testing reduce the Educated Guessing Game and Play of Chance in warfarin dosing? Warfarin Pharmacogenomics 1. 1. Cytochrome Cytochrome P450 P450 2C9 2C9 genotyping genotyping identifies identifies mutations mutations associated associated with with impaired impaired warfarin warfarin metabolism. metabolism. 2. 2. Vitamin Vitamin K K receptor

receptor polymorphism polymorphism testing testing can can identify identify whether whether patients patients require require low, low, intermediate, intermediate, or or high high doses doses of of warfarin warfarin.. Schwartz UI. NEJM 2008; 358: 999 Percent with Dose Estimates within 20% of Actual Dose Pharmacogenetic Algorithm versus Clinical Algorithm versus Fixed-Dose Approach Warfarin Pharmacogenetics Consortium. NEJM 2009;360:753-764 Genotype vs Standard Warfarin Dosing (N=206) Couma-Gen Trial

Rapid Rapid turnaround turnaround CYP2C9 CYP2C9 and and VKORC1 VKORC1 testing testing vs. vs. empiric empiric Primary Primary endpoint: endpoint: TTR TTR Smaller Smaller and and fewer fewer dosing dosing changes changes with with genetic genetic testing testing No No difference difference in in TTR TTR

Circulation 2007; 116: 2563-2570 Warfarin Clinical Dosing Nomogram NEJM 2009; 360: 753-764 PHARMACOGENETIC NOMOGRAM NEJM 2009; 360: 753-764 Warfarin Pharmacogenetics Routine use of CYP2C9 and VKORC1 genotyping in patients who begin warfarin therapy is not supported by evidence currently available. Pharmacotherapy 2008; 28: 1084-1087 Genetic Testing for Warfarin Remains Unproven: NHLBI Trial About 1,200 Patients will be randomized to: 1.Genetic plus clinical guided nomogram, versus 1.Clinically-guided nomogram Results will be available in 2012 NHLBI Trial: 2009-2012 Primary Primary Endpoint: Endpoint: %

% Time Time in in Therapeutic Therapeutic Range Range (TTR) (TTR) Hypothesis: Hypothesis: 60% 60% TTR TTR in in Clinical Clinical arm arm versus versus >> 72% 72% TTR TTR in in Genetics Genetics Plus Plus Clinical Clinical Nomogram Nomogram arm arm Clinical Trials # NCT00839657 Self-Monitoring INR Meta-analysis of 14 RCTS

Reduced Reduced TE TE events events (55% (55% fewer) fewer) Reduced Reduced all-cause all-cause mortality mortality (39% (39% less) less) Reduced Reduced major major bleeds bleeds (35% (35% fewer) fewer) Benefits Benefits increase increase further further with with self-dosing self-dosing 73% 73% fewer fewer TE TE events events

63% 63% lower lower all-cause all-cause mortality mortality Heneghan C. Lancet 2006; 367: 404-411 March 19, 2008: Medicare Expanded Reimbursement for Home INR Monitoring Medicare Medicare used used to to cover cover only only mechanical mechanical heart heart valves valves Now Now will will reimburse reimburse VTE VTE (after (after 33 months months of of

warfarin) warfarin) and and permanent permanent atrial atrial fibrillation fibrillation Aetna Aetna follows follows new new Medicare Medicare guidelines guidelines (and (and surely surely others others will, will, too) too) Will Novel Anticoagulants Warrant Additional Costs? 1. 1. Does Does this this require require deconstruction, deconstruction, demobilization, demobilization, and/or

and/or reconstruction reconstruction of of anticoagulation anticoagulation management management services? services? 2. 2. Will Will patients patients require require monitoring monitoring of of renal/ renal/ hepatic hepatic function? function? Novel Oral Anticoagulants 1. 1. Noninferiority Noninferiority may may not not suffice, suffice, but but superiority superiority findings findings (150 (150 mg mg dose) dose) in in RE-LY

RE-LY are are encouraging. encouraging. 2. 2. Superiority Superiority may may be be necessary necessary to to alter alter prescribing prescribing behavior. behavior. 3. 3. More More trials trials will will be be forthcoming. forthcoming. 4. 4. Beware Beware of of off-label off-label use. use. 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: Cumulative Hazard Rates for the Primary Outcome of Stroke or Systemic Embolism 0.05

1.0 Warfarin 0.04 0.8 0.03 0.6 0.02 0.00 0.2 Warfarin Dabigatran 110 mg Dabigatran 150 mg Dabigatran 150 mg 0.01 0.4 0.0 Dabigatran 110 mg 0

6022 6015 6076 0 6 12 6 12 18 5862 5862 5939 5718 5710 5779 4593 4593 4682 Connolly, et al. N Engl J Med 2009;361:1139-51 18 24

24 2890 2945 3044 30 30 1322 1385 1429 Relative Risk of Stroke or Systemic Embolism with Dabigatran versus Warfarin: RE-LY Hazard Hazard Ratio Ratio with with Dabigatran, CI Dabigatran, 110 110 mg(95% mg(95% CI) CI) CI)) Dabigatran Dabigatran Better Better Connolly, et al. N Engl J Med 2009;361:1139-51 Warfarin Warfarin Better

Better Hazard Hazard Ratio Ratio with with Dabigatran, Dabigatran, 150 150 mg(95% mg(95% CI) CI) Dabigatran Dabigatran Better Better Warfarin Warfarin Better Better Relative Risk of Stroke or Systemic Embolism with Dabigatran versus Warfarin: RE-LY Hazard Hazard Ratio Ratio with with Dabigatran, CI Dabigatran, 110 110 mg(95% mg(95% CI) CI) CI))

Connolly, et al. N Engl J Med 2009;361:1139-51 Hazard Hazard Ratio Ratio with with Dabigatran, Dabigatran, 150 150 mg(95% mg(95% CI) CI) RE-LY: Analysis and Comments RE-LY participants who were randomly assigned to receive warfarin would have needed to have an INR time within the therapeutic range (TTR) approximately 79% of the time to have a stroke rate as low as that in the group receiving 150 mg of dabigatran. Even with diligent, patient self-monitoring or pharmacogenetic dosing, such tight control is unlikely in real world practice. Gage, B N Engl J Med 361;12 nejm.org September 17, 2009 Connolly SJ, Pogue J, Eikelboom J, et al. Circulation 2008;118:202937. Time in Therapeutic Range (TTR) in Community-Based Practice: Ranges 101 Community-Based Practices in 38 States (1) Mean TTR was 66.5%, but varies widely, with 37% having TTR above 75%, and 34% with TTR below 60% Mean TTR for new warfarin users (57.5%) lower than prevalent users for first six months TTR of patients with warfarin interruptions had TTR of 61.6% TTR rates vary widely and are affected by new warfarin use,

procedural interruptions and INR target range Meta-Analysis (2) TTR was 55% Rose, AJ Thromb Haemost. 2008 Oct;6(10):1647-54. Baker WL et al, J Manag Care Pharm. 2009 Apr;15(3):244-5 RE-LY: Analysis and Comments To prevent one nonhemorrhagic stroke, the number of patients who would need to be treated with dabigatran at a dose of 150 mg twice daily, rather than warfarin, is approximately 357. The number of patients who would need to be treated with dabigatran (rather than warfarin) to prevent one hemorrhagic stroke is approximately 370. Discussion: Novel Oral Anticoagulants Where Do We Stand, November 12, 2009? 1. 1. In In summary summary although although there there are are qualifications, qualifications, we we can can rely rely on on RE-LY. RE-LY.

Brian Brian F. F. Gage, Gage, MD MD (NEJM, (NEJM, September September 17, 17, 2009, 2009, RE-LY RE-LY Editorial) Editorial) 2. 2. The The RE-LY RE-LY Trial Trial represents represents the the most most compelling compelling evidence evidence to to date date for for revising, revising, reconsidering, reconsidering, and and reshaping reshaping our our current current VKA-based VKA-based paradigm

paradigm for for stroke stroke prevention prevention in in AF. AF. Discussion: Novel Oral Anticoagulants Discussion, Discussion, Questions, Questions, and and Comments Comments

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    Without gravity set precisely by God the universe could not exist. Yet because of gravity we can fall and skin our knee or fall off a cliff and die thus suffering the consequences. An all loving God could have set...
  • E-Learning Policy - Weebly

    E-Learning Policy - Weebly

    Duval County Public Schools, DCPS, is the school district encompassing the Jacksonville, Florida area schools. The school district is large, consisting of 151 schools including elementary, middle, and high school levels (Duval County Public Schools, 2014).
  • Powered by the Microsoft Azure Platform, Rediker Software

    Powered by the Microsoft Azure Platform, Rediker Software

    PlusPortals - ParentPlus, StudentPlus and TeacherPlus - are a family of interactive web portals for parents, students, and teachers. Seamlessly integrated with AdminPlus and the TeacherPlus Gradebook, PlusPortals enable administrators and teachers to instantly share data and engage with parents...
  • SawSafe - UMass Amherst

    SawSafe - UMass Amherst

    Currently, there are mechanical safety systems on some chainsaws such as the kick-back breaking mechanism. When using a chainsaw with this device, the operator's hand must be located on a specific area of the chainsaw in order for the kick-back...
  • Molecular Electronic Devices

    Molecular Electronic Devices

    Solids: From Bonds to Bands Levels Atom E Bond Molecule Band 1-D Solid * * Real Materials more complex Many orbitals per atom Multiple dimensions (3-D) Let us first recap the 1-D bandstructure, so we can see how to generalize...