National Experts in Cardiovascular Medicine Illuminate and Debate

National Experts in Cardiovascular Medicine Illuminate and Debate
New Paradigms and Landscape Changes in Atrial Fibrillation Emerging Perspectives in Thrombosis Mitigation for the Cardiovascular Specialist—Applying Landmark Trials to the Front Lines of Cardiology Practice Program Chairman and Moderator Peter Libby, MD, FACC Chief, Cardiovascular Medicine Brigham and Women’s Hospital Mallinckrodt Professor of Medicine Harvard Medical School Boston, Massachusetts

Welcome and Program Overview
CME-certified symposium jointly sponsored by the University of Massachusetts Medical School and CMEducation Resources, LLC Commercial Support: Sponsored by an independent educational grant from Boehringer-Ingelheim Faculty disclosures: Listed in program syllabus

Program Faculty Peter Libby, MD, FACC Elaine M. Hylek, MD, MPH
Program Chairman and Moderator Chief, Cardiovascular Medicine Brigham and Women’s Hospital Mallinckrodt Professor of Medicine Harvard Medical School Boston, Massachusetts Jonathan L. Halperin, MD Mount Sinai School of Medicine Director, Clinical Cardiology Service The Zena and Michael A. Wiener Cardiovascular Institute The Marie-Josée and Henry R. Kravis Center for Cardiovascular Health New York, New York Elaine M. Hylek, MD, MPH Associate Professor of Medicine Department of Medicine Boston University Medical Center Boston, Massachusetts Jeffrey I. Weitz, MD, FRCP, FACP Professor of Medicine and Biochemistry McMaster University Director, Henderson Research Center Canada Research Chair in Thrombosis Heart and Stroke Foundation J.F. Mustard Chair in Cardiovascular Research Ontario, Canada

New Frontiers in Atrial Fibrillation
Challenges in Stroke Prevention for Patients with Atrial Fibrillation Achieving Balance Between Prevention of Thromboembolism and Risk of Bleeding Risk Stratification, Current Guidelines and Therapeutic Choices Jonathan L. Halperin, MD Professor of Medicine (Cardiology) Mount Sinai School of Medicine Director, Clinical Cardiology Services The Zena and Michael A. Wiener Cardiovascular Institute The Marie-Josée and Henry R. Kravis Center for Cardiovascular Health

Atrial Fibrillation A Substantial Threat to the Brain
Affects ~4% of people aged >60 years ~9% of those aged >80 years 5%/year stroke rate 12%/year for those with prior stroke $ billions annual cost for stroke care AF-related strokes have worse outcomes 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

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 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.

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.

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.

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.

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 12

Intracerebral Hemorrhage
The Most Feared Complication of Antithrombotic Therapy >10% of intracerebral hemorrhages (ICH) occur in patients on antithrombotic therapy Aspirin increases the risk by ~ 40% Warfarin (INR 2–3) doubles the risk to 0.3– 0.6%/year ICH during anticoagulation is catastrophic Hart RG, et al. Stroke 2005;36:1588 13

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.

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.

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.

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.

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).

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. 19

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.

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.

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)

guideline than a rule.” "Actually, it's more of a
Bill Murray in GhostbustersⒸ (1984), relaxing his rule "never to get involved with possessed people" in response to Sigourney Weaver's seductive advances.

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

The ACTIVE Trial Clopidogrel + Aspirin
Atrial Fibrillation + Risk Factors ACTIVE - W 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

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

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.

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.

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.

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.

The ACTIVE Trial Reasons for Exclusion from Anticoagulation
Risk factor for bleeding* 23% Physician judgment against anticoagulation for patient 50% Patient preference only 26% Inability to comply with INR monitoring 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.

ACTIVE-A Total Stroke Rates
ACTIVE A Medical Advisory Board Meeting_4-09 296 (2.4%/year) 408 (3.3%/year) Cumulative Incidence 28% RRR HR (95% CI, 0.62–0.83) p <0.001 0.0 0.05 0.10 0.15 1 2 3 4 Aspirin Clopidogrel + Aspirin Years ACTIVE.N Engl J Med.May.2009/ p2070 /fig 1B(inset) 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). ACTIVE.N Engl J Med.May.2009/ p2070/table 2, p2071/fig 1B 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:

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:

Investigational Anticoagulant Targets
ORAL PARENTERAL TF/VIIa TFPI (tifacogin) TTP889 X IX APC (drotrecogin alfa) sTM (ART-123) IXa VIIIa Rivaroxaban Apixaban Edoxaban LY YM150 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. 34

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

Emerging Anticoagulants Regulatory Issues
Open-label vs. blinded trial design Issues related to active-control trial design How many trials are needed? Preventing use for unapproved indications Assessing patient-oriented outcomes

Alternatives to Anticoagulation Atrial Fibrillation
Current approaches Restoration and maintenance of sinus rhythm Antiarrhythmic drug therapy Catheter ablation Maze operation Emerging (investigational) approaches Obliteration of the left atrial appendage Trans-catheter occluding devices Thoracoscopic epicardial plication Amputation

Strokes after Conversion to NSR Rate vs. Rhythm Control Trials
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.

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.

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:

Percutaneous LAA Occlusion The WATCHMAN® Device
Syed T, Halperin JL. Nature Clin Prac Cardiovasc Med 2007; 4:428 Holmes DR, et al. Lancet 2009; 374: 534

Alternatives to Anticoagulation Atrial Fibrillation
Current approaches Restoration and maintenance of sinus rhythm Antiarrhythmic drug therapy Catheter ablation Maze operation Emerging (investigational) approaches Obliteration of the left atrial appendage Trans-catheter occluding devices Thoracoscopic epicardial plication Amputation Is atrial fibrillation the cause of stroke or a marker of a population at risk?

Atrial Fibrillation and Thromboembolism The Next Challenges
Better tools to stratify bleeding risk Noninvasive imaging and biomarkers of inflammation and thrombosis to predict clinical events and guide therapy Confirming successful rhythm control over time Targeted therapy to prevent AF in patients at risk Defining role and risk stratification strategies for non-monitored, oral anticoagulants

From Fermented Sweet Clover to Molecular Targeting of Coagulation The Promise of New Approaches
The Goal: To bring effective therapy to many more patients and prevent thousands of strokes.

Atrial Fibrillation Case Study

An 82-year-old man with hypertension and diabetes has permanent atrial fibrillation He has a history of spinal stenosis and walks with a walker

Question 1: Which regimen would you prescribe for prophylaxis against thromboembolism? Warfarin (INR ) Warfarin (INR ) Aspirin, 81 mg daily Aspirin, 81 mg + clopidogrel, 75 mg daily No antithrombotic therapy

Atrial Fibrillation Case Study Assessment of Thromboembolic Risk
Score (points) Risk of Stroke (%/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.

Question 2: What if you learn that he has tripped and fallen twice in the past two years? Warfarin (INR ) Warfarin (INR ) Aspirin, 81 mg daily Aspirin, 81 mg + clopidogrel, 75 mg daily No antithrombotic therapy

Question 3: If the oral direct thrombin inhibitor dabigatran were available and FDA-approved for stroke prevention in AF, in this patient with a history of tripping you would treat with: Warfarin (INR ) Warfarin (INR ) Dabigatran 110 mg P.O. B.I.D Dabigatran 150 mg P.O. B.I.D. Aspirin, 81 mg + clopidogrel, 75 mg daily No antithrombotic therapy 50

Atrial Fibrillation Case Study Anticoagulation in Patients at Risk of Falls

Atrial Fibrillation Case Study Anticoagulation in Patients at Risk of Falls
“…persons taking warfarin must fall about 295 (535/1.81) times in 1 year for warfarin not to be the optimal therapy…”

Atrial Fibrillation Case Study ICH in Patients with AF Prone to Falls
Hazard ratios of independent predictors of intracranial hemorrhage Factor Hazard ratio (95% CI) P value High-risk for falls 1.9 ( ) 0.002 Prior stroke 2.2 ( ) <0.0001 Prior bleed 1.8 ( ) Neuropsychiatric impairment 1.4 ( ) 0.055 The risk of ICH was 2.8%/year in patients at high risk of falls and 1.1 in other patients. Warfarin was associated with an increased risk of mortality among those with ICH (30 day mortality = 52 vs. 34%, p = 0.007). Gage BF, et al. Am J Med 2005; 118:612.

Recommended antithrombotic therapy
Atrial Fibrillation Case Study Outcomes in Patients with AF Prone to Falls Hazard ratio of warfarin for composite outcome—out-of-hospital death or hospitalization for stroke, MI, or hemorrhage—in 1245 patients at high risk for falls CHADS 2 score Hazard ratio (95% CI) P value Recommended antithrombotic therapy 0-1 0.98 (0.56, 1.72) 0.94 Aspirin or nil 2-6 0.75 (0.61, 0.91) 0.004 Anticoagulant Gage BF, et al. Am J Med 2005; 118:612.

Summary of Case Study The risk of intracranial hemorrhage is increased in patients who fall. The use of oral anticoagulation does not predict ICH, but mortality is higher among patients on anticoagulants who develop ICH. The risk of mortality due to ICH is offset by the reduction in ischemic events achieved with anticoagulation in elderly patients with AF at high risk of thromboembolism. Better risk-stratification instruments are needed.

New Frontiers in Atrial Fibrillation
Stroke Prevention in High Risk Populations Optimizing Warfarin Therapy in Challenging Patient Populations Elaine M. Hylek, MD, MPH Associate Professor of Medicine Department of Medicine Director, Thrombosis Clinic and Anticoagulation Service Boston University Medical Center Boston, Massachusetts

Prevalence of AF by Age 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 57

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: 58

“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.

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

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

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

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

Polypharmacy in the Elderly
Elderly = 12% of population; 32% of prescriptions Average of 6 prescription medications; 1 to 3.5 over-the-counter drugs Average nursing home patient takes 7 medications Average American senior spends $670/year for pharmaceuticals

Adverse Drug Reactions
About 15% of hospitalizations in the elderly are related to adverse drug reactions The risk of adverse drug reactions increases with the number of prescription medications

Polypharmacy and Non-adherence
Strongest predictor of non-adherence is the number of medications Non-adherence rates estimated 25-50% Intentional about 75% of the time Changes in regimen made by patients to: - Increase convenience - Reduce adverse effects or - Decrease refill expense

Hazards of Anticoagulant Medications
#1 in 2003 and 2004 in the number of mentions of “deaths for drugs causing adverse effects in therapeutic 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:

Intracranial Bleeding
Ischemic Stroke and Intracranial Bleeding Adjusted Odds in Relation to Intensity of Anticoagulation 15.0 10.0 Stroke Intracranial Bleed 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:

Warfarin Dosing is Complex Factors that Correlate w/ Warfarin Dose
Age Body surface area (BSA) or weight Amiodarone Other drugs (e.g. acetaminophen) Race Sex Plasma vitamin K level Decompensated CHF Chemotherapy Genetic status Other Factors (up to 40%) Age, Sex, Weight (10-20%) CYP2C (up to 15%) VKORC1 (up to 25%) Pie chart adapted from AMA brochure 69 69

≥ 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

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

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 72

Baseline Characteristics AF Trials
Historical trials SPORTIF III/V ACTIVE W RE-LY Year published 2006 2009 N 3,763 7,327 6,706 18,113 Age, yrs 69 71 70 72 Female 29% 31% 33% 37% Prior stroke 5% 21% 15% 20% Hypertension 45% 77% 83% 79% CHR 26% 18% 32% Diabetes 13% 23% CHADS2 score NA 2.0 2.1 73

Cumulative Incidence of Major Bleeding
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):

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):

Optimizing Benefit and Reducing Risk
Hemorrhage Thrombosis

Strategies To Minimize
Risk Of Hemorrhage THE FACTS: Incidence of UGIB and LGIB increases with age. 70% of acute UGIB occur > 60 years of age. Differential mucosal effect of ASA by age Incidence of LGIB increases 200-fold from the 3rd to 9th decade of life: diverticulosis, angiodysplasias, ischemic colitis, malignancy Revised Guidelines for the Management of Patients with Atrial Fibrillation were published in August 2006. 77

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 78

Warfarin Dose by Age 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: 79

Delay in INR Normalization with Increasing Age
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: 80

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. 81

Risk of UGIB with Different Combinations of Antithrombotic Agents
Mean age=72 years Hallas J, et al. BMJ doi: /bmj AE 82 82

Evolving Role for Aspirin
Meta-analysis of 10 trials that compared oral anticoagulant (OAC) therapy to ASA+OAC. 4,180 patients with either heart valve, AF, or CAD Combination therapy: Lower incidence of thromboembolism (OR 0.66), but the benefits were limited to patients with valves (OR 0.27). Did not benefit patients with AF (OR 0.99) or CAD (OR 0.69) nor did it influence all cause mortality. Did increase the risk of major bleeding (OR 1.43). This recently published meta-analysis suggests that the combination of aspirin with oral anticoagulant therapy is associated with significant bleeding risk and is of benefit only for patients with mechanical heart valves. There appears to be emerging consensus that combination therapy is associated with more harm than benefit. Combination therapy continues to be a pressing concern particularly for elderly patients following stent placement. Further research is needed to better clarify hemorrhagic risks. Dentali F, Douketis JD, Lim W, Crowther M. Arch Intern Med 2007; 167: Dentali F, Douketis JD, Lim W, Crowther M. Arch Intern Med 2007; 167:

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 84

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. . 85

Atrial Fibrillation Patient Case Study
85-year-old female with AF, HTN, HF, prior TIA, osteoarthritis and prior diverticular GIB six months ago, on warfarin, who presents to the ED with complaints of SOB for several days and black stools. Medications: atenolol, lisinopril, lasix, warfarin, ASA Most recent INR 3 weeks ago = 3.1

Question 1: This patient’s estimated stroke risk per year without warfarin is: 5% 12% 20% None of the above

Physical Exam and Pertinent Data
Exam: afebrile, HR , BP 154/90 lungs-bibasilar rales COR-irreg irreg ABD-nontender guaiac + ECG: AF with rapid VR CXR: mild pulmonary edema Labs: Hct=21, INR=8.0, Troponin -

Question 2: The most appropriate management strategy for this patient would be to: Stop both aspirin and warfarin – Resume aspirin only in one week Stop both aspirin and warfarin – Resume warfain Stop both aspirin and warfarin – Resume both warfarin and aspirin in one week Stop both aspirin and warfarin permanently

Question 3: The patient’s bleeding episode resolves, she is started back on warfarin, and she returns six months later with an hematocrit of 35 (her baseline). Her INR is 3.7. If dabigatran were approved by the FDA for SPAF, at this point you would: Stop warfarin and put the patient on clopidogrel and aspirin Adjust the warfarin to achieve an INR of Transition patient to dabigatran 110mg PO BID Transition patient to dabigatran 150 mg PO Bid Start aspirin only Stop all anticoagulation

New Oral Anticoagulants
New Frontiers in Atrial Fibrillation The Emerging Role of New Oral Anticoagulants Landmark Trials That May Alter the Landscape of Stroke Prevention in AF Jeffrey I. Weitz, MD, FRCP, FACP Professor of Medicine and Biochemistry McMaster University Director, Henderson Research Center Canada Research Chair in Thrombosis Heart and Stroke Foundation J.F. Mustard Chair in Cardiovascular Research

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

Limitations of Warfarin
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

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

Comparison of Features of New Oral
Anticoagulants in Advanced Stages of Development 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

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

Which of the Following Statements is true?
Oral factor Xa inhibitors have a better safety profile than oral thrombin inhibitors Of the new oral anticoagulants, dabigatran etexilate is most advanced in development Oral factor Xa inhibitors can be safely given to patients with a creatinine clearance < 30 ml/min The prothrombin time can be used to monitor all of the new oral anticoagulants Fresh frozen plasma will reverse the anticoagulant effects of the new oral anticoagulants

RE-LY: A Non-inferiority Trial
•Atrial Fibrillation with ≥ 1 Risk Factor • Absence of Contraindications • Conducted in 951 centers in 44 countries 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

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

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

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

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

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

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:

Why is There More MI with Dabigatran?
Chance finding? Warfarin superior to dabigatran for inhibitionof clotting at sites of plaque disruption? Other factors?

RE-LY: Outcomes in Secondary-Prevention Patients with AF by Treatment Assignment
End point Warfarin Dabigatran 110 mg twice daily RR (95% CI) vs warfarin p Dabigatran 150 mg Stroke/ systemic embolism (%/year) 2.74 2.32 0.85 (0.59–1.22) 0.37 2.07 0.76 (0.53–1.10) 0.14 Hemorrhagic stroke (n) 18 2 0.11 (0.03–0.47) 0.003 5 0.27 (0.10–0.72) 0.009 ICH (n) 30 6 0.20 (0.08–0.47) 0.001 13 0.41 (0.21–0.79) 0.007 Diener HC et al. American Stroke Association International Stroke Conference 2010; February 26, 2010; San Antonio, TX.

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: 108

Which Dose for Which Patient?
Lower-dose regimen Elderly Renal insufficiency Lower stroke risk (CHADS2 score of 1) Higher-dose regimen Higher stroke risk (CHADS2 score ≥ 2)

Meta-analysis of Ischemic Stroke or Systemic Embolism
W vs placebo W vs W low dose W vs ASA W vs ASA + clopidogrel W vs dabigatran 150 0.3 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.

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

What about other indications?

RE-COVERTM Trial Design
Objective confirmation of VTE E R 30 days follow up Initial parenteral therapy Single-dummy period Double-dummy period 72 h 6 months End of treatment Until INR 2.0 on two consecutive measurements (8-11 days) Warfarin (INR 2.0–3.0) Dabigatran etexilate placebo bid Warfarin placebo Dabigatran etexilate 150 mg bid placebo E= enrolment R= randomization

Efficacy and Safety Outcomes
Dabigatran HR (95% CI) Recurrent VTE and VTE-related death 2.4% 2.1% 1.10 ( ) Major bleeding 1.6% 1.9% 0.82 ( ) Schulman et al., N Engl J Med, 2009

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

Cumulative Risk of Stroke, MI, Systemic Embolism, or Vascular Death
Patients treated at centers with a TTR below or above the study median (65%) 12 10 8 6 4 2 TTR < 65% TTR >= 65% 12 10 8 6 4 2 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:

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

Relative Risk of Stroke or Systemic Embolism with According to Geographical Region
Dabigatran Versus Warfarin 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

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

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

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

Mrs. A. is a 78-year-old woman who is taking warfarin for stroke prevention on the background of atrial fibrillation. She also takes ASA 81 mg daily. Her risk factors for stroke include hypertension and type II diabetes mellitus. Her INR control has been erratic with values ranging from 1.5 to 6.8. For the past two weeks, she has had intermittent nosebleeds lasting 5 to 20 minutes. She is anxious to stop warfarin.

Question 1: What is the best approach for this patient? Stop the warfarin and the ASA Stop the ASA, but continue warfarin Perform CYP2C9 and VKORC1 genotyping to better identify an appropriate warfarin dose Stop the warfarin and add clopidogrel 75 mg daily Continue warfarin and ASA, but monitor the INR more frequently

The ASA was stopped, but Mrs. A. still complains of nosebleeds. Despite weekly monitoring, her INR continues to range from 1.8 to A calculated creatinine clearance is 45 ml/min.

Question 2: If dabigatran were approved for stroke prevention in patients with atrial fibrillation, what would you likely do at this point? Continue on warfarin Continue on warfarin, but add low-dose vitamin K Switch from warfarin to dabigatran etexilate 110 mg b.i.d. Switch from warfarin to dabigatran etexilate 150 mg b.i.d. Switch from warfarin to ASA and clopidogrel

Atrial Fibrillation and Thromboembolism Current State of the Art and Science
There is a new, quickening rhythm to the pace of research and clinical advances in atrial fibrillation Etiology of AF is multifactorial and we are just beginning to understand the inter-relationship among myriad factors Noninvasive imaging and biomarkers of inflammation and thrombosis can predict clinical events in AF and may help guide therapy Risk stratification strategies for AF are useful but imperfect: advances and refinements are required to help define role for non-monitored, oral anticoagulants

Strategies are being developed to improve the safety and efficacy of vitamin K antagonists (VKAs), but achieving acceptable TTRs remains a challenge Elderly patients with AF are at the highest risk of stroke and the highest risk of hemorrhage, and therefore demand special attention Novel anticoagulants appear to be safer in the elderly population due to their wider therapeutic index, shorter t1/2, lack of dietary interference, and fewer drug interactions. 128

Dabigatran etexilate is superior to warfarin for stroke
Atrial Fibrillation and Thromboembolism Current State of the Art and Science Dabigatran etexilate is superior to warfarin for stroke prevention and non-inferior for VTE treatment Dosing strategy for new oral anticoagulants is critical: selecting the appropriate dose in the individual patient to achieve ideal balance of stroke prevention and bleeding minimization is a work in progress New oral anticoagulants will replace warfarin, and the transition will impact the landscape of anticoagulation management 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 . 129

At least four trials evaluating the safety and efficacy of oral, non-monitored anticoagulants for SPAF are in progress: stay tuned Thank You QUESTIONS

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