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New Frontiers in Atrial Fibrillation

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2 New Frontiers in Atrial Fibrillation
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 Specialist—Translating Evidence into Action Program Moderator Samuel Z. Goldhaber, MD Cardiovascular Division Brigham and Women’s Hospital Professor of Medicine Harvard Medical School

3 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

4 Program Educational Objectives
As a result of this educational activity, 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.

5 Program Faculty Program Moderator Elaine M. Hylek, MD, MPH
Samuel Z. Goldhaber, MD Cardiovascular Division Brigham and Women’s 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-Josée 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

6 Faculty COI Disclosures
Samuel Z. Goldhaber, MD Research Support: BMS, Boehringer-Ingelheim, Eisai, Johnson and Johnson, sanofi-aventis 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, sanofi-aventis Jeffrey I. Weitz, MD, FRCP, FACP Grants/Research Support:  CIHR, HSFO, CFI, ORF Speakers Bureau:  Bristol-Myers Squibb, Boehringer Ingelheim, sanofi-aventis, Daiichi-Sankyo, Bayer, Pfizer, The Medicines Company, Eisai, Takeda

7 New Frontiers in Atrial Fibrillation
ATRIAL FIBRILLATION Current Challenges in Thrombosis Medicine for the Cardiovascular Specialist Samuel Z. Goldhaber, MD Cardiovascular Division Brigham and Women’s Hospital Professor of Medicine Harvard Medical School

8 Atrial Fibrillation: Twice as Common as Previously Suspected
Incidence increased 13% over past 20 years In USA, million will be affected by 2050 Increasing obesity and increasing age are risk factors that help explain rise in incidence Miyasaka Y. Circulation 2006; 114:

9 AF Prevalence: Age and Gender
Prevalence of atrial fibrillation with age Prevalence, percent Age, years JAMA 2001; 285: 2370

10 Mortality Rates in AF Double the overall age and gender matched population No reduction in past two decades Mortality 9-fold higher during 1st 4 months after diagnosis Miyasaka Y, et al. JACC 2007; 49:

11 Risk Factors for Stroke
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 An increased risk of stroke is associated with multivariate predictors of stroke in control-group patients with atrial fibrillation. This is shown from several stroke-prevention trials. These risk factors must be taken into account when deciding on the appropriate course of therapy for prevention of stroke in individual patients with AF. Arch Intern Med 1994; 154: Reference: Arch Intern Med 1994; 154(13):

12 Atrial Fibrillation: A Risk Factor for Vascular Events
RISK FACTORS for THROMBOSIS • Hypertension • Hyperlipidemia • Age • Diabetes Mellitus • Smoking Atherosclerosis/Atherothrombosis Atherosclerosis/Atherothrombosis Atrial fibrillation (AF) results when the atria of the heart contract and relax at different times, creating a seemingly chaotic, rapid and irregular rhythm. The condition can be caused by impulses which are transmitted to the ventricles in an irregular fashion or by some impulses failing to be transmitted. This makes the ventricles beat irregularly, which leads to an irregular (and usually fast) pulse in atrial fibrillation. Underlying causes of AF include dysfunction of the sinus node and a number of heart and lung disorders, including coronary artery disease, rheumatic heart disease, mitral valve disorders, pericarditis and others. Hyperthyroidism, hypertension and other diseases can cause arrhythmias, as can recent heavy alcohol use. Some cases of AF or flutter occur in the setting of a myocardial infarction or soon after cardiac surgery. One of the consequences of AF is stroke: about 15% of all strokes are directly attributable to AF, and in patients over 80 years AF is the single leading cause of major stroke.1,2 MI AF MI AF CHF CHF Stroke, MI, Vascular Death Wolf PA et al. Arch Intern Med 1987; 147: Leckey R et al. Can J Cardiol 2000; 16: References: 1. Wolf PA et al. Arch Intern Med 1987; 147: 2. Leckey R et al. Can J Cardiol 2000; 16:

13 Thrombus in Left Atrial Appendage Associated with Stroke
Thrombus in left atrial appendage is correlated with increased thromboembolic risk in AF Abnormalities detected by transesophageal echocardiography in the left atrium (LA) and appendage showed that: impaired atrial emptying associated with atrial fibrillation (AF) leads to stasis and increases the risk of thrombus formation in the left atrium and especially the left-atrial appendage (LAA).1,2 the surface of the newly formed thrombus is itself highly thrombogenic, creating a local hypercoagulable state and promoting its continued development.1,2 exposure to the dynamic circulatory forces within the cardiac chambers promotes embolization of cardiogenic thrombi and subsequent ischemic events in the different arterial beds including stroke and peripheral arterial occlusion.1,2 spontaneous echo contrast, LAA thrombi, LAA peak flow velocities 20 cm/s and complex aortic plaque are independently associated with increased risk of stroke in patients with AF.1,2 Chimowitz. Stroke 1993; 24: 1015 Zabalgoitia. J Am Coll Cardiol 1998; 31: 1622 References: 1. Chimowitz. Stroke 1993; 24: 1015. 2. Zabalgoitia. J Am Col Cardiol 1998; 31: 1622.

14 One Sixth of all Strokes Attributable to AF
% AF prevalence Strokes attributable to AF Age Range (years) Framingham Study 10 20 30 50–59 60–69 70–79 80–89 The Framingham Study examined the impact of atrial fibrillation (AF) on stroke incidence in 5,070 participants after 34 years of follow-up. Results of the study showed that the percentage of strokes attributable to AF increased dramatically with age.1 The investigators of the study concluded that AF is a major cause of stroke, particularly among elderly patients. Therefore, anticoagulation therapy should be a routine part of therapy for these patients. Wolf et al. Stroke 1991; 22: Reference: Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: The Framingham Study. Stroke 1991; 22: 14

15 Problems with Established Therapy: Warfarin
Delayed onset/offset Unpredictable dose response Narrow therapeutic range Drug–drug, drug–food interactions Problematic monitoring High bleeding rate Slow reversibility

16 First Month of Warfarin Therapy has High Bleeding Rate
Bleeding Type Head Bleed Major Non-Head Bleed 1st Month Warfarin 0.92% (annualized) 1.2% (annualized) Subsequent Warfarin 0.46% per year 0.61% per year Fang MC. J Am Geriatr Soc 2006; 54:

17 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.”

18 Learning Objectives Warfarin dosing and genetics
FDA warfarin labeling vs. NHLBI Randomized Clinical Trial

19 Warfarin: Advantages INR assesses anticoagulant level
Multiple antidotes available Omitting one or two doses usually is not clinically problematic Introduced in Has “stood the test of time.” No liver toxicity Ability to maintain target INR is improving (Now > 60% in top facilities) No anticoagulant has demonstrated superior efficacy or safety Inexpensive

20 Warfarin: Walking a Tightrope
Excessive dose precipitates hemorrhage Inadequate dose predisposes to stroke and pulmonary embolism Dosing nomograms are awkward, cumbersome Dosing by trial and error predominates

21 Therapeutic Range for Warfarin INR Values at Stroke or ICH
15.0 Stroke Intracranial Hemorrhage 10.0 Odds Ratio 5.0 1.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 INR Fuster et al. J Am Coll Cardiol. 2001;38:

22 Hylek, EM et al. N Engl J Med. 2003;349:1019-2614

23 “Most intracranial hemorrhages (62%) occur at INRs < 3.0”
Fang MC et al. Ann Intern Med. 2004;141:745-52

24 Reduction of Stroke in AF – Warfarin Compared with Placebo
Adjusted-dose warfarin compared with placebo AFASAK I SPAF BAATAF CAFA SPINAF EAFT All trials (n=6) Relative risk reduction (95% CI) Warfarin better Warfarin worse 62% (48% to 72%) 100 50 -50 -100 Five randomized trials evaluated oral anticoagulation (OAC) and two of these tested ASA for primary prevention of thromboembolism in patients with non-valvular atrial fibrillation (AF). A sixth trial focused on secondary prevention among patients who had survived non-disabling stroke or transient cerebral ischemic attack.1 Six trials in the meta-analysis: - Copenhagen AF, Aspirin and Anticoagulation Study (AFASAK I). Lancet 1989; 1: - Stroke Prevention in AF Study (SPAF I). Circulation 1991; 84: - Boston Area Anticoagulation Trial for AF (BAATAF). N Engl J Med 1990; 323: - Canadian AF Anticoagulation Study (CAFA). J Am Coll Cardiol 1991; 18: - Stroke Prevention in Non-rheumatic AF (SPINAF). N Eng J Med. 1992; 327: - European AF Trial (EAFT). Lancet 1993; 342: Meta-analysis according to the principle of intention to treat showed that adjusted-dose OAC is highly efficacious for prevention of stroke (both ischemic and hemorrhagic) with a risk reduction of 61% (95% CI, 47% to 71%) vs placebo. This reduction was similar for both primary and secondary prevention.1 Overall, warfarin is shown to be about 60% better than placebo.1 The duration of follow-up in these trials was generally between one and two years; the longest duration was 2.2 years. In clinical practice, the need for antithrombotic therapy typically extends over much longer periods. Hart et al. Ann Intern Med 1999; 131: References: 1. Hart et al. Ann Intern Med 1999; 131:

25 ACTIVE W Trial OAC Clopidogrel plus ASA Standard Care (INR 2.0 – 3.0)
INR at least monthly Clopidogrel plus ASA Clopidogrel 75 mg once daily ASA mg once daily

26 ACTIVE W: Outcome Events
Primary Outcome Stroke, Non-CNS Systemic Embolism, MI, Vascular Death Safety Outcome Major Bleeding

27 ACTIVE W: Stroke, Non-CNS Embolism, MI and Vascular Death
5.64 %/year RR = 1.45 P = 3.93 %/year Cumulative Hazard Rates Years # at Risk C+A OAC

28 ACTIVE W: Major Bleeding
2.4 %/year RR = 1.06 P = 0.67 2.2 %/year Cumulative Hazard Rates # at Risk C+A OAC Years Lancet. 2006;367: ,

29 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.

30 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-Josée and Henry R. Kravis Center for Cardiovascular Health

31 Projected U.S. Prevalence of AF An Expanding Epidemic
2 4 6 8 10 12 14 16 18 2000 2005 2010 2015 2020 2025 2030 2035 2040 2045 2050 Year Projected Number of People with AF (millions) Based on Projected Incidence Based on Current Incidence Miyakasa Y, et al. Circulation 2006; 114: 119.

32 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 Without antithrombotic prophylaxis, atrial fibrillation (AF) carries a substantial risk of ischemic stroke, even in the absence of associated rheumatic or valvular heart disease. The expense for acute and convalescent care of stroke victims, and the inestimable cost in human terms make thromboembolism associated with nonvalvular atrial fibrillation a major public health problem. It has therefore become important for all physicians to recognize atrial fibrillation as a risk factor for preventable strokes. AF identifies millions of people with a five-fold increased risk of stroke

33 Priorities in the Management of AF The Patient Care Pathway
Rhythm Control Prevention of Thromboembolism Rate Control

34 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.

35 Stroke Rate (% per year)
Stroke Risk in Atrial Fibrillation Untreated Control Groups of Randomized Trials Stroke Rate (% per year) To be replaced with a slide showing prevalence of AF-related stroke as a function of age (Framingham Study data or other). Age (years) Atrial Fibrillation Investigators. Arch Intern Med 1994;154:1449.

36 Anticoagulation in Atrial Fibrillation Stroke Risk Reductions
Warfarin Better Control Better AFASAK SPAF BAATAF CAFA SPINAF EAFT Aggregate 100% 50% -50% -100% Hart R, et al. Ann Intern Med 2007;146:857.

37 Anticoagulation in Atrial Fibrillation The Standard of Care for Stroke Prevention
Warfarin Better Control Better AFASAK Unblinded SPAF Unblinded BAATAF Unblinded CAFA Terminated early SPINAF Double-blind; Men only EAFT 2o prevention; Unblinded Aggregate 100% 50% -50% -100% Hart R, et al. Ann Intern Med 2007;146:857.

38 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% 50% -50% Hart R, et al. Ann Intern Med 2007;146:857.

39 Efficacy of Warfarin in Trials vs. Practice Stroke Risk Reductions
Treatment Better Treatment Worse 6 Trials n = 2,900 Warfarin vs. Placebo/Control Warfarin vs. No anticoagulation Medicare cohort n = 23,657 100% 50% -50% Hart R, et al. Ann Intern Med 2007;146:857 Birman-Deych E. Stroke 2006; 37: 1070–1074 39

40 Intracerebral Hemorrhage
The Most Feared Complication of Antithrombotic Therapy >10% of intracerebral hemorrhages (ICH) occur in patients on antithrombotic therapy Aspirin increases the by ~ 40% Warfarin (INR 2–3) doubles the risk to 0.3– 0.6%/year ICH during anticoagulation is catastrophic Hart RG, et al. Stroke 2005;36:1588 40

41 Risk Stratification in AF Stroke Risk Factors
High-Risk Factors Mitral stenosis Prosthetic heart valve History of stroke or TIA This slide depicts risk factors for stroke from the most recent guidelines on prevention of stroke in patients with AF from the ACCP. ACCP guidelines also suggest that women with AF who are older than 75 years may be at an increased risk of stroke compared with men of the same age. The impact of gender on risk of stroke in patients with AF has not been definitively determined. Increasing age is a risk factor for stroke in patients with AF, regardless of gender. Recently, a joint committee representing the American College of Cardiology (ACC), AHA, and European Society of Cardiology (ESC) published guidelines on the management of patients with AF. This document identifies the same risk factors for stroke in patients with AF as the ACCP guidelines, with the addition of persistent thrombus on transesophageal echocardiography (TEE) and thyrotoxicosis as risk factors. Singer DE, et al. Chest 2004;126:429S. Fang MC, et al. Circulation 2005; 112: 1687.

42 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 This slide depicts risk factors for stroke from the most recent guidelines on prevention of stroke in patients with AF from the ACCP. ACCP guidelines also suggest that women with AF who are older than 75 years may be at an increased risk of stroke compared with men of the same age. The impact of gender on risk of stroke in patients with AF has not been definitively determined. Increasing age is a risk factor for stroke in patients with AF, regardless of gender. Recently, a joint committee representing the American College of Cardiology (ACC), AHA, and European Society of Cardiology (ESC) published guidelines on the management of patients with AF. This document identifies the same risk factors for stroke in patients with AF as the ACCP guidelines, with the addition of persistent thrombus on transesophageal echocardiography (TEE) and thyrotoxicosis as risk factors. Singer DE, et al. Chest 2004;126:429S. Fang MC, et al. Circulation 2005; 112: 1687.

43 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 65–75 years Coronary artery disease Female gender Thyrotoxicosis This slide depicts risk factors for stroke from the most recent guidelines on prevention of stroke in patients with AF from the ACCP. ACCP guidelines also suggest that women with AF who are older than 75 years may be at an increased risk of stroke compared with men of the same age. The impact of gender on risk of stroke in patients with AF has not been definitively determined. Increasing age is a risk factor for stroke in patients with AF, regardless of gender. Recently, a joint committee representing the American College of Cardiology (ACC), AHA, and European Society of Cardiology (ESC) published guidelines on the management of patients with AF. This document identifies the same risk factors for stroke in patients with AF as the ACCP guidelines, with the addition of persistent thrombus on transesophageal echocardiography (TEE) and thyrotoxicosis as risk factors. Singer DE, et al. Chest 2004;126:429S. Fang MC, et al. Circulation 2005; 112: 1687.

44 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 This slide depicts risk factors for stroke from the most recent guidelines on prevention of stroke in patients with AF from the ACCP. ACCP guidelines also suggest that women with AF who are older than 75 years may be at an increased risk of stroke compared with men of the same age. The impact of gender on risk of stroke in patients with AF has not been definitively determined. Increasing age is a risk factor for stroke in patients with AF, regardless of gender. Recently, a joint committee representing the American College of Cardiology (ACC), AHA, and European Society of Cardiology (ESC) published guidelines on the management of patients with AF. This document identifies the same risk factors for stroke in patients with AF as the ACCP guidelines, with the addition of persistent thrombus on transesophageal echocardiography (TEE) and thyrotoxicosis as risk factors. Age 65–75 years Coronary artery disease Female gender Thyrotoxicosis Duration of AF Pattern of AF (persistent vs. paroxysmal) Left atrial diameter Singer DE, et al. Chest 2004;126:429S. Fang MC, et al. Circulation 2005; 112: 1687.

45 Stroke Risk Score for Atrial Fibrillation
The CHADS2 Index Stroke Risk Score for Atrial Fibrillation Score (points) Prevalence (%)* Congestive Heart failure Hypertension Age >75 years Diabetes mellitus Stroke or TIA Moderate-High risk > Low risk VanWalraven C, et al. Arch Intern Med 2003; 163:936. * Nieuwlaat R, et al. (EuroHeart survey) Eur Heart J 2006 (E-published).

46 Nonvalvular Atrial Fibrillation
Stroke Rates Without Anticoagulation According to Isolated Risk Factors Stroke Rate (%/year) Prior Stroke/TIA Age > 75 years Hypertension Female Diabetes Heart Failure  LVEF Hart RG et al. Neurology 2007; 69: 546. 46

47 Stroke Risk Score for Atrial Fibrillation
The CHADS2 Index Stroke Risk Score for Atrial Fibrillation Score (points) Risk of Stroke (%/year) Approximate Risk threshold for Anticoagulation 3%/year 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.

48 Risk Stratification and Anticoagulation
Stroke Reduction with Warfarin Instead of Aspirin CHADS2 Score ~ Number of patients Needed-to-treat to prevent 1 stroke/year 13 42 83 250 EAFT Study Group. Lancet 1993; 324:1255. Zabalgoitia M, et al. J Am Coll Cardiol 1998; 31:1622.

49 Recommended Therapy Risk Factor
Antithrombotic Therapy for Atrial Fibrillation ACC/AHA/ESC Guidelines 2006 Risk Factor Recommended Therapy No risk factors CHADS2 = 0 Aspirin, mg qd One moderate risk factor CHADS2 = 1 Aspirin, mg/d or Warfarin (INR , target 2.5) Any high risk factor or >1 moderate risk factor CHADS2 >2 or Mitral stenosis Prosthetic valve (INR , target 3.0)

50 "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.

51 Patient Selection for Anticoagulation Additional Considerations
Risk of bleeding Newly anticoagulated vs. established therapy Availability of high-quality anticoagulation management program Patient preferences

52 INR at the Time of Stroke or Bleeding Efficacy and Safety of Warfarin
20 15 Ischemic Stroke Intracranial bleeding Odds Ratio 10 5 1 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 International Normalized Ratio Fang MC, et al. Ann Intern Med 2004; 141:745. Hylek EM, et al. N Engl J Med 1996; 335:540.

53 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.

54 The ACTIVE Trial Clopidogrel + Aspirin
Atrial Fibrillation + Risk Factors ACTIVE - W ACTIVE - A Anticoagulation-eligible OAC Contraindications or Unwilling VKA (INR 2-3) Clopidogrel + Aspirin Aspirin + Placebo Clopidogrel + Aspirin Open-label Non-inferiority n = 6,706 Double-blind Superiority n = 7,554 Irbesartan, 300 mg/d vs. Placebo n = 9,016 ACTIVE - I Risk Factors: Age 75, hypertension, prior stroke/TIA, LVEF<45%, PAD, age CAD or diabetes Primary outcome: Stroke, systemic embolism, MI or cardiovascular death

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

56 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% 50% -50% Connolly S, et al. Lancet 2006; 367:1903. Hart R, et al. Ann Intern Med 2007;146:857.

57 Antithrombotic Therapy for Atrial Fibrillation Stroke Risk Reductions
Warfarin Better Antiplatelet Rx Better All patients Warfarin vs. Aspirin + Clopidogrel Prior OAC VKA-naïve 100% 50% -50% Connolly S, et al. Lancet 2006; 367:1903.

58 Major Hemorrhage in Relation to Prior Anticoagulant Therapy: ACTIVE-W
“Starters” “Switchers” Interaction p=0.028 Event Rate (%/year) No Yes Anticoagulant Therapy at Entry Connolly S, et al. Lancet 2006; 367:1903.

59 The ACTIVE Trial Clopidogrel + Aspirin
Atrial Fibrillation + Risk Factors ACTIVE – W ACTIVE - A Anticoagulation-eligible OAC Contraindications or Unwilling VKA (INR 2-3) Clopidogrel + Aspirin Aspirin + Placebo Clopidogrel + Aspirin Open-label Non-inferiority n = 6,706 Double-blind Superiority n = 7,554 Irbesartan, 300 mg/d vs. Placebo n = 9,016 ACTIVE - I Connolly SJ, et al. N Engl J Med 2009; 360:2066.

60 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 Predisposition to falling or head trauma Persistent hypertension >160/100 mmHg Previous serious bleeding on VKA Severe alcohol abuse within 2 years Peptic ulcer disease Thrombocytopenia Chronic need for NSAID Connolly SJ, et al. N Engl J Med 2009; 360:2066.

61 ACTIVE-A Total Stroke Rates
ACTIVE A Medical Advisory Board Meeting_4-09 28% RRR HR (95% CI, 0.62–0.83) p <0.001 0.15 408 (3.3%/year) Aspirin ACTIVE.N Engl J Med.May.2009/ p2070 /fig 1B(inset) 0.10 296 (2.4%/year) Cumulative Incidence 0.05 Clopidogrel + Aspirin Note: This slide contains off-label information regarding PLAVIX, and should not be used in promotional presentations except in response to unsolicited questions from the audience. In the ACTIVE A trial, stroke was a component of the composite outcome and occurred in 3.3% of patients per year treated with ASA compared with 2.4% of patients per year treated with PLAVIX plus ASA. This represents a 28% RRR in patients treated with PLAVIX plus ASA vs ASA alone (HR 0.72; 95% CI, 0.62 to 0.83; P<0.001). 0.0 ACTIVE.N Engl J Med.May.2009/ p2070/table 2, p2071/fig 1B 1 2 3 4 Years Connolly SJ, et al. N Engl J Med 2009; 360:2066. The ACTIVE trial is sponsored by the Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership. ACTIVE Investigators. Effect of clopidogrel added to aspirin in patients with atrial fibrillation. N Engl J Med. 2009;360:

62 The ACTIVE Trials Stroke Rates and Risk Reductions
New Treatment VKA C+A Aspirin ACTIVE W (Annual Rate) 1.4 2.4 ~ ACTIVE A 3.3 RRR versus Aspirin -58% -28% versus C+A -42% Connolly.ACTIVE A.ACC.OrlandoFL.Mar.2009[Presentation]/slide 27 Speaker will refer to slide for presentation. VKA = oral anticoagulant C+A = clopidogrel + aspirin Connolly SJ, et al. Lancet 2006; 367:1903. Connolly SJ, et al. N Engl J Med 2009; 360:2066. The ACTIVE trial is sponsored by the Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership. Connolly SJ. ACTIVE A: Effects of addition of clopidogrel to aspirin in patients with atrial fibrillation who are unsuitable for vitamin K antagonists. Presented at: ACC 58th Annual Scientific Session; March 29-31, 2009; Orlando, FL. Available at:

63 Warfarin Dosing and Genomics
CYP2C9 – Gene encoding cytochrome P450 hepatic enzyme responsible for primary clearance of S-warfarin, the active enantiomer; variant alleles are associated with sensitivity to warfarin. VKORC1 – Gene encoding vitamin K epoxide reductase complex 1; variant alleles are associated with warfarin resistance.

64 Warfarin Dosing and Genomics Keeping Ahead of the Data

65 Dose Initiation Dose Titration 1 2 3 4, 5 6 7 8 …
Intervention Period: Informed by genetic/clinical information Dose Initiation Dose Titration 1 2 3 4, 5 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

66 The Ideal Anticoagulant Wide Therapeutic Margin
Thrombosis Safe Therapeutic Range Bleeding Thrombosis Bleeding Dose, Concentration, or Intensity of Anticoagulation

67 New Anticoagulant Development The Clinical Trial Pathway
DVT/VTE Prophylaxis Orthopaedic Surgery DVT/VTE Treatment Arterial Disease Other Potential Indications AFib/Stroke Prophylaxis

68 Investigational Anticoagulant Targets
ORAL PARENTERAL TF/VIIa TFPI (tifacogin) TTP889 X IX APC (drotrecogin alfa) sTM (ART-123) IXa VIIIa Rivaroxaban Apixaban LY YM150 DU-176b Betrixaban TAK 42 Va AT Xa Idraparinux Source: Turpie State of the art presentation EFORT-08 (rivaroxaban, apixaban and dabigatran highlighted and all the others greyed out) Reference Weitz JI, Bates SM. New anticoagulants. J Thromb Haemost 2005;3:1843–1853 All of the drugs in the above figure are to be found in Weitz and Bates (2005) in Figure 2, apart from: Apixaban – this was called BMS in the original figure Betrixaban and YM150 – see Graham Turpie’s review paper: Turpie AGG. New oral anticoagulants in atrial fibrillation. Eur Heart J 2008;29:155–165 Otamixaban – Guertin KR, Choi YM. The discovery of the Factor Xa inhibitor otamixaban: from lead identification to clinical development. Curr Med Chem 2007;14:2471–2481 II (thrombin) DX-9065a Otamixaban IIa Dabigatran APC activated protein C AT antithrombin sTM soluble thrombomodulin TF tissue factor FPI tissue factor pathway inhibitor Fibrinogen Fibrin Adapted from Weitz JI. Thromb Haemost 2007; 5 Suppl 1:65-7. 68

69 SPORTIF III and V Stroke and Systemic Embolism
Ximelagatran Better Warfarin Better -0.66 SPORTIF III p=0.10 +0.45 SPORTIF V p=0.13 Pooled -0.03 p=0.94 -4 -3 -2 -1 1 2 3 4 Difference in Absolute Event Rates (Ximelagatran – Warfarin) SPORTIF-V Investigators. JAMA 2005; 293:

70 SPORTIF III and V Secondary Stroke Prevention
Δ = –0.44%/year 95% CI –1.86, 0.98; p=0.625 p=NS Event Rate (%/year) Diener H-C, et al. Cerebrovasc Dis 2006; 21: 279

71 Major Bleeding Complications SPORTIF III and V
On-treatment Analysis p=0.054 Event Rate (%/year) SPORTIF III SPORTIF V Pooled Diener H-C, et al. Cerebrovasc Dis 2006; 21: 279

72 SPORTIF III and V Liver Enzyme Elevations
ALT >3 x ULN 100 Warfarin Ximelagatran 80 Incidence (%) 60 Number of patients 40 ALT >3x ULN 20 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

73 Emerging Anticoagulants Potential Alternatives to Warfarin
Thrombin inhibitors Direct, oral Ximelagatran Dabigatran (RE-LY Trial) Factor Xa inhibitors Indirect, parenteral Idraparinux Direct, oral Rivaroxaban Apixaban Edoxaban others

74 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 15,000 ≥ 1 ENGAGE-AF Edoxaban 30 mg bid 60 mg* qd 16,500 * Adjusted based on renal function

75 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

76 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

77 Strokes after Conversion to NSR Rate vs. Rhythm Control Trials
Rate control Rhythm control RR (95% CI) p AFFIRM 4,917 5.7% 7.3% 1.28 ( ) 0.12 RACE 522 5.5% 7.9% 1.44 ( ) 0.44 STAF 266 1.0% 3.0% 3.01 ( ) 0.52 PIAF 252 0.8% 1.02 ( ) 0.49 Total 5,957 5.0% 6.5% 1.28 ( ) 0.08 Take home point: Stroke risk persists even in patients in SR. Verheugt F, et al. J Am Coll Cardiol 2003;41(suppl):130A.

78 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 Take home point: Nearly ¾ of all strokes were related to discontinuation or inadequate anticoagulation. Background: The percentage of patients receiving warfarin therapy was not as high in the AFFIRM study compared with RACE. The use of anticoagulants remained high in the rate-control group at each assessment (85%). However, there was a decrease in warfarin use in the rhythm-control group following the first 4 months of the study. However, the overall number of patients averaged approximately 70% throughout the trial in the rhythm-control group. The majority of patients taking warfarin therapy, regardless of randomization, fell into the recommended INR range of 2.0 to 3.0. Although the rate of ischemic stroke across both groups was low, approximately 1% per year, 74% of all strokes were ischemic. However, strokes tended to occur most often in patients who had ceased to take warfarin or who had a subtherapeutic INR. As the slide illustrates, 44% of ischemic strokes occurred following termination of warfarin therapy and 28% with an INR of less than 2.0. Only 42% of ischemic strokes occurred while a patient was still in AF. There was no significant difference between the 2 groups in rate of ischemic stroke: 5.5% in the rate-control arm and 7.1% in the rhythm-control arm. There was also no significant difference in the percentage of patients with ischemic stroke, primary intracerebral hemorrhage, subdural or subarachnoid hemorrhage, or disabling anoxic encephalopathy. Wyse AG, et al. N Engl J Med 2002; 347: 1825.

79 ATHENA Trial Dronedarone vs
ATHENA Trial Dronedarone vs. Placebo in Patients with AF Stroke Rates (Secondary Analysis) Event Placebo (%/y) Dronedarone (%/y) HR (95% CI) p 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 0.247 Hohnloser SH, et al. N Engl J Med 2009; 360:

80 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

81 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?

82 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

83 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.

84 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

85 Projected Number of Persons with AF in the U.S. Between 2000 and 2050
15.9 15.2 16 14 12 10 8 6 4 2 15.9 13.1 11.7 10.2 12.1 8.9 11.7 Projected Number of Persons with AF (Millions) 11.1 7.7 10.3 6.7 9.4 5.9 8.4 5.1 7.5 6.8 6.1 5.6 5.1 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:

86 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: 86

87 Prevalence of AF by Age 20 18 16 14 12 10 8 Prevalence (%) 6 4 2
Framingham Study Cardiovascular Health Study Mayo Clinic Study Western Australia Study Prevalence (%) Age (years) Feinberg WM. Arch Intern Med. 1995;155(5):469–473 87

88 Prevalence of CVD* in Adults by Age and Sex (NHANES: 2005-2006)
*Coronary heart disease, heart failure, stroke and hypertension Source: NCHS and NHLBI

89 Incidence of Heart Failure
Incidence of Heart Failure* by Age and Sex (Framingham Heart Study: ) * MD review of medical records using strict diagnostic criteria Source: NHLBI

90 Prevalence of Heart Failure by Age and Sex (NHANES: 2005-2006)
Source: NCHS and NHLBI

91 Prevalence of Dementia
North America: 6.9% prevalence; 63% increase ; 151% increase

92 “The graying population will slowly, radically transform society
“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.

93 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

94 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

95 Kidney Function and Age
140 130 120 110 100 Standard Creatine Clearance ml/min/1.73 Age (years) Andres and Tobin, 1976

96 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

97 Intracranial Bleed Stroke INR
Adjusted Odds Ratios for Ischemic Stroke and Intracranial Bleeding in Relation to Intensity of Anticoagulation 15.0 Intracranial Bleed Stroke 10.0 Odds Ratio 5.0 1.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 INR Fuster et al. J Am Coll Cardiol. 2001;38:

98 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

99 ≥ 58% 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

100 Results From SPORTIF III and V
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

101 Hazards of Anticoagulant Medications
#1 in 2003 and 2004 in the number of mentions of “deaths for drugs causing adverse effects in therapeutic use”1 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 1 Wysowski DK, et al. Arch Intern Med. 2007;167: Budnitz DS, et al. JAMA. 2006;296: Flaherty ML, et al. Neurology. 2007;68:

102 Major Hemorrhage Rates
Randomized Trials INR Target ICH Major Age AFI 0.3 1.0 69 SPAF II 0.9 1.4 70 AFFIRM ---- 2.0 RE-LY 0.7 3.4 72 Observational INR Target ICH Major Age Van der Meer, et al. (1993) 0.6 2.0 66 Palareti, et al (1996) 0.5 0.9 62 Go, et al (2003) 1.0 71 102

103 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) - Varying definitions of bleeding - Most conducted within anticoagulation clinic setting 103

104 Baseline Characteristics AF Trials
Historical trials SPORTIF III/V ACTIVE W RE-LY Year published N 3, , , ,113 Age, yrs Female 29% % % % Prior stroke 5% % % % Hypertension 45% % % % CHF 26% % % % Diabetes 13% % % % CHADS2 score NA NA 104

105 Hylek EM et al, Circulation 2007;115(21):2689-2696.
Cumulative Incidence of Major Bleeding in the First Year Among Patients Newly Starting Warfarin by Age Cumulative Proportion with Major Hemorrhage Days of Warfarin Age < 80 Age >=80 Hylek EM et al, Circulation 2007;115(21):

106 Risk of Stopping Therapy in the First Year Among
Patients Newly Starting Warfarin by Age Risk of Stopping Warfarin Days of Warfarin Age < 80 Age >=80 Hylek EM et al, Circulation 2007;115(21):

107 Major Hemorrhagic Events and Warfarin Terminations by CHADS2 Score
Major Bleed (N) Bleeding Rates % Taken Off Therapy (N) Taken Off Rates 42 1 3.17 5 15.84 121 4 4.35 16 17.39 2 181 3 2.08 19 13.16 94 12 19.7 20 32.84 ≥4 34 6 23.63 9 35.44 Total 472 26 69 Hylek EM et al, Circulation 2007;115(21):

108 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?

109 Optimizing Benefit and Reducing Risk
Hemorrhage Thrombosis

110 Bleeding Risk Scores for Warfarin Therapy
Low Moderate High Kuijer et al. Arch Intern Med 1999;159:457-60 1-3 >3 1.6 x age x sex +2.2 x cancer with 1 point for ≥60, female or malignancy and 0 if none Beyth et al. Am J Med 1998;105:91-9 1-2 ≥3 ≥65 years old; GI bleed in last 2 weeks; previous stroke; comorbidities (recent MI, Hct < 30%, diabetes, Creat > 1.5) with 1 point for presence of each condition and 0 if absent Gage et al. Am Heart J 2006;151:713-9 0-1 2-3 ≥4 HEMORR2HAGES score: liver/renal disease, ETOH abuse, malignancy, >75 years old, low platelet count or function, rebleeding risk, uncontrolled HTN, anemia, genetic factors (CYP2C9) risk of fall or stroke, with 1 point for each risk factor present with 2 points for previous bleed Shireman et al. Chest 2006;130:1390-6 ≤1.07 > <2.19 >2.19 (0.49 x age >70) + (0.32 x female) + (0.58 x remote bleed) x recent bleed) x ETOH/drug abuse) + (0.27 x diabetes) + (0.86 x anemia) + (0.32 x antiplatelet drug use) with 1 point for presence of each and 0 if absent 110

111 Maintenance Warfarin Dose by Age INR Target 2-3
Derived from two independent ambulatory populations 50 45 40 35 30 25 20 50 45 40 35 30 25 20 Warfarin Weekly Dose, mg Warfarin Weekly Dose, mg ACTION on left, ATU on right < >=90 < >=90 Age Age Female Male Female Male Garcia D, et al. Chest ;127: 111

112 Hylek et al, Ann Intern Med. 2001;135:393-400
In this study, outpatients were identified with an INR greater than All patients were instructed to hold two doses of warfarin and return on Day 2 for a repeat INR measurement. The Figure displays the INR decay curves of these patients over the 48-hour period. On Day 2, 63% of patients had an INR less that 4.0 and 37% of patients had an INR of 4.0 or higher. Twelve percent of patients with an index INR between 6-9 had a subtherapeutic INR (less than 2.0) after holding two doses of warfarin. Hylek et al, Ann Intern Med. 2001;135: 112

113 Risk Factors for INR > 4.0 After Holding Two Doses of Warfarin
Adjusted Odds Ratio Warfarin dose, weekly per 10 mg 0.87 ( ) 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 factors associated with prolonged return to the therapeutic range following an INR of 6.0 or greater included older age, lower warfarin dose requirements, decompensated heart failure, an actively treated malignancy, and degree of elevation of the index INR. For each decade of age, the risk of having an INR greater than 4.0 on Day 2 increased by 18%. The clinical implications of this study are that elderly patients, especially those who require lower doses of warfarin to attain an INR of , are at highest risk for prolonged exposure to risk-laden levels of anticoagulation. 113

114 Causes of Elevated INRs
Initiation Decreased vitamin K intake Potentiating Medications Decompensated heart failure Chemotherapy Warfarin dosing error Binge alcohol consumption

115 Risk of UGIB with Different Combinations of Antithrombotic Agents
Mean age=72 years Hallas J, et al. BMJ doi: /bmj AE 115 115

116 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 Revised Guidelines for the Management of Patients with Atrial Fibrillation were published in August 2006. 116

117 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 117

118 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 Warfarin (open label) 0.74% REF Connolly et al., NEJM, 2009 118

119 Risk Factors for Intracranial Hemorrhage
INR intensity Age Aspirin therapy Ischemic cerebrovascular disease Hypertension Trauma Vasculopathy-Leukoaraiosis, amyloid angiopathy 119

120 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. . 120

121 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

122 Overview of Presentation
Limitations of warfarin New oral anticoagulants Role of new agents in AF

123 Limitations of Warfarin
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

124 New Oral Anticoagulants for Stroke Prevention in AF
Direct Inhibitors of Factor Xa or Thrombin

125 Comparison of Features of New Oral
Anticoagulants in Advanced Stages of Development Features Rivaroxaban Apixaban Dabigatran Etexilate Target Xa IIa Molecular Weight 436 460 628 Prodrug No Yes Bioavailability (%) 80 50 6 Time to peak (h) 3 2 Half-life (h) 9 9-14 12-17 Renal excretion (%) 65 25 Antidote None

126 Comparison of Features of New Anticoagulants With Those of Warfarin
New Agents Onset Slow Rapid Dosing Variable Fixed Food effect Yes No Drug interactions Many Few Monitoring Half-life Long Short Antidote

127 RE-LY: A Non-inferiority Trial
•Atrial Fibrillation with ≥ 1 Risk Factor • Absence of Contraindications • Conducted in 951 centers in 44 countries R R Blinded Event Adjudication Open Open Blinded Statistical testing in the RE-LY Study: Primary endpoint: Non-inferiority design allowing for statistical analysis of superiority once non-inferiority is achieved All other endpoints: Superiority testing. P < 0.05  superior (95% CI is below 1) P > 0.05  comparable (if 95% CI includes 1) Warfarin Adjusted INR 2.0 – 3.0 N=6000 Dabigatran etexilate mg BID N=6000 Dabigatran etexilate mg BID N=6000

128 RE-LY: Baseline Characteristics
Dabigatran mg Dabigatran 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 (%) (%) 3+ (%) 2.1 32.6 34.7 32.7 2.2 32.2 35.2 30.9 37.0 32.1 Prior stroke/TIA (%) 19.9 20.3 19.8 Prior MI (%) 16.8 16.9 16.1 CHF (%) 31.8 31.9 Baseline ASA (%) 40.0 38.7 40.6 Warfarin Naïve (%) 49.9 49.8 51.4 Connolly et al., NEJM, 2009

129 RE-LY: Stroke or Systemic Embolism
0.50 0.75 1.00 1.25 1.50 Dabigatran 110 vs. Warfarin Dabigatran 150 vs. Warfarin Non-inferiority p-value <0.001 Superiority 0.34 Margin = 1.46 HR (95% CI) Dabigatran better Warfarin better Connolly et al., NEJM, 2009

130 RE-LY: Annual Rates of Bleeding
Dabigatran 110mg 150mg Warfarin Dabigatran 110mg vs. Warfarin Dabigatran 150mg vs. Warfarin n 6015 6078 6022 RR 95% CI p Total 14.6% 16.4% 18.2% 0.78 <0.001 0.91 0.002 Major 2.7 % 3.1 % 3.4 % 0.80 0.003 0.93 0.31 Life- Threatening 1.2 % 1.5 % 1.8 % 0.68 0.81 0.04 Gastro- intestinal 1.1 % 1.0 % 1.10 0.43 1.50 Connolly et al., NEJM, 2009

131 RE-LY: Intra-cranial Bleeding Rates
RR 0.31 (95% CI: 0.20–0.47) p<0.001 (sup) RR 0.40 (95% CI: 0.27–0.60) p<0.001 (sup) Number of events 0,74 % RRR 69% RRR 60% 0,30 % 0,23 % Connolly et al., NEJM, 2009

132 Targeted inhibition of thrombin
How can dabigatran be more effective than warfarin yet cause less bleeding? Targeted inhibition of thrombin Consistent and predictable anticoagulant effect

133 RE-LY: Secondary Efficacy Outcomes According to Treatment Group
Event Dabigatran 110 mg Dabigatran 150 mg Warfarin Myocardial infarction 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:

134 RE-LY: Cumulative risk of ALT or AST >3x ULN after randomization
0.04 0.03 Warfarin Cumulative risk 0.02 Dabigatran 110 mg Dabigatran 150 mg 0.01 0.0 0.5 1.0 1.5 2.0 2.5 Years of follow-up Connolly, et al. N Engl J Med 2009;361: 134

135 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)

136 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 0.3 0.6 0.9 1.2 1.5 1.8 2.0 Favours warfarin Favours other treatment Camm J.: Oral presentation at ESC on Aug 30th 2009.

137 What About Trials with Other New Oral Anticoagulants?
ROCKET – Rivaroxaban ARISTOTLE – Apixaban ENGAGE - Edoxaban

138 Is Warfarin Obsolete? New oral anticoagulants are more convenient But, warfarin effective when time in therapeutic range is high

139 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 10 8 6 4 2 12 10 8 6 4 2 TTR < 65% TTR >= 65% RR=0.93 ( ) p=0.61 RR=2.14 ( ) P=0.0001 Event Rate (%) Event Rate (%) C+A OAC C+A OAC Years Years Connolly, S. J. et al. Circulation 2008;118:

140 Time in Therapeutic Range (TTR) with Warfarin in the RE-LY Trial
Group Relative Risk Overall 64% VKA Experienced 61% VKA Naïve 67%

141 Relative Risk of Stroke or Systemic Embolism with Dabigatran Versus Warfarin According to Geographical Region Hazard Ratio with Dabigatran, 100 mg (95% CI) P Value for Interaction Hazard Ratio with Dabigatran, 150 mg (95% CI) P Value for Interaction Patients total no. Dabigatran Warfarin Subgroup 110 mg 150 mg All patients 18, Long-term VKA therapy 0.72 0.81 No 9, Yes 8, Region 0.91 0.11 North America 6, South America 1, Western Europe 3, Central Europe 2, South Asia 1, East Asia 1, Other 1, 0.5 1.0 1.5 0.5 1.0 1.5 Dabigatran Better Warfarin Better Dabigatran Better Warfarin Better Connolly et al., NEJM 2009

142 Who is Not a Candidate for Dabigatran?
Stable on warfarin Renal impairment Severe hepatic disease Poor compliance

143 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?

144 Conclusions: RE-LY and New, Oral Non-Monitored Anticoagulation
Dabigatran etexilate is superior to warfarin for stroke prevention Dosing of new oral anticoagulants is critical: are the doses of factor Xa inhibitors optimal? New oral anticoagulants will replace warfarin, but transition may be slow

145 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 Women’s Hospital Professor of Medicine Harvard Medical School

146 Warfarin is Not Just Sitting Around
It is fighting back with: Excellent efficacy (ACTIVE) Pharmacogenetics analysis Point-of-care testing Low cost Track Record (approved in 1954)

147 The “Red Line” in the Sand
Can rapid turnaround genetic testing reduce the “Educated Guessing Game” and “Play of Chance” in warfarin dosing?

148 Warfarin Pharmacogenomics
Cytochrome P450 2C9 genotyping identifies mutations associated with impaired warfarin metabolism. Vitamin K receptor polymorphism testing can identify whether patients require low, intermediate, or high doses of warfarin. Schwartz UI. NEJM 2008; 358: 999

149 Percent with Dose Estimates within 20% of Actual Dose
Pharmacogenetic Algorithm versus Clinical Algorithm versus Fixed-Dose Approach Figure 2. Percentage of Patients with Dose Estimates within 20% of the Actual Dose, as Derived with the Use of a Pharmacogenetic Algorithm, a Clinical Algorithm, and a Fixed-Dose Approach. The dose estimates are shown according to three actual-dose groups: low-dose (<=21 mg per week), intermediate-dose (>21 to <49 mg per week), and high-dose (>=49 mg per week). The fixed dose was 35 mg per week. With the fixed-dose approach, none of the estimates for the patients in the low-dose and high-dose groups were within 20% of the actual dose. Panel A shows data for the validation cohort (1009 patients), and Panel B for the derivation-plus-validation cohorts (5052 patients). Warfarin Pharmacogenetics Consortium. NEJM 2009;360:

150 Genotype vs Standard Warfarin
Dosing (N=206) Couma-Gen Trial Rapid turnaround CYP2C9 and VKORC1 testing vs. “empiric” Primary endpoint: TTR Smaller and fewer dosing changes with genetic testing No difference in TTR Circulation 2007; 116:

151 Warfarin Clinical Dosing Nomogram
NEJM 2009; 360:

152 PHARMACO- GENETIC NOMOGRAM
NEJM 2009; 360:

153 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:

154 Genetic Testing for Warfarin Remains Unproven: NHLBI Trial
About 1,200 Patients will be randomized to: Genetic plus clinical guided nomogram, versus Clinically-guided nomogram Results will be available in 2012

155 NHLBI Trial: Primary Endpoint: % Time in Therapeutic Range (TTR) Hypothesis: 60% TTR in Clinical arm versus > 72% TTR in Genetics Plus Clinical Nomogram arm Clinical Trials # NCT

156 Self-Monitoring INR Meta-analysis of 14 RCTS
Reduced TE events (55% fewer) Reduced all-cause mortality (39% less) Reduced major bleeds (35% fewer) Benefits increase further with self-dosing 73% fewer TE events 63% lower all-cause mortality Heneghan C. Lancet 2006; 367:

157 Medicare used to cover only mechanical heart valves
March 19, 2008: Medicare Expanded Reimbursement for Home INR Monitoring Medicare used to cover only mechanical heart valves Now will reimburse VTE (after 3 months of warfarin) and permanent atrial fibrillation Aetna follows new Medicare guidelines (and surely others will, too)

158 Will Novel Anticoagulants Warrant Additional Costs?
Does this require deconstruction, demobilization, and/or reconstruction of anticoagulation management services? Will patients require monitoring of renal/ hepatic function?

159 Novel Oral Anticoagulants
Noninferiority may not suffice, but superiority findings (150 mg dose) in RE-LY are encouraging. Superiority may be necessary to alter prescribing behavior. More trials will be forthcoming. Beware of off-label use.

160 RE-LY: Stroke or Systemic Embolism
0.50 0.75 1.00 1.25 1.50 Dabigatran 110 vs. Warfarin Dabigatran 150 vs. Warfarin Non-inferiority p-value <0.001 Superiority 0.34 Margin = 1.46 HR (95% CI) Dabigatran better Warfarin better Connolly et al., NEJM, 2009 160

161 RE-LY: Cumulative Hazard Rates for the Primary Outcome of Stroke or Systemic Embolism
0.05 0.04 0.03 0.02 0.01 0.00 1.0 0.8 0.6 0.4 0.2 0.0 Warfarin Dabigatran 110 mg Dabigatran 150 mg Warfarin Dabigatran 110 mg Dabigatran 150 mg Connolly, et al. N Engl J Med 2009;361: 161

162 Relative Risk of Stroke or Systemic Embolism with Dabigatran versus Warfarin: RE-LY
Hazard Ratio with Dabigatran, 110 mg(95% CI) Hazard Ratio with Dabigatran, 150 mg(95% CI) Dabigatran Better Warfarin Better Dabigatran Better Warfarin Better Connolly, et al. N Engl J Med 2009;361: 162

163 Relative Risk of Stroke or Systemic Embolism with Dabigatran versus Warfarin: RE-LY
Hazard Ratio with Dabigatran, 110 mg(95% CI) Hazard Ratio with Dabigatran, 150 mg(95% CI) Connolly, et al. N Engl J Med 2009;361: 163

164 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.  164

165 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): Baker WL et al, J Manag Care Pharm. 2009 Apr;15(3):244-5 165

166 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. 166

167 Discussion: Novel Oral Anticoagulants
Where Do We Stand, November 12, 2009? 1. “In summary although there are qualifications, we can rely on RE-LY.” Brian F. Gage, MD (NEJM, September 17, 2009, RE-LY Editorial) 2. The RE-LY Trial represents the most compelling evidence to date for revising, reconsidering, and reshaping our current VKA-based paradigm for stroke prevention in AF.

168 Discussion: Novel Oral Anticoagulants
Discussion, Questions, and Comments


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