1.

Stroke Prevention in Atrial Fibrillation
New Frontiers and Treatment Paradigms for Stroke Prevention in Atrial Fibrillation Evidence- and Guideline-Based Strategies for Optimizing Clinical Outcomes and Anticoagulation-Based Management for SPAF Program Chairman Samuel Z. Goldhaber, MD Cardiovascular Division Brigham and Women’s Hospital Professor of Medicine Harvard Medical School

Welcome and Program Overview
CME-certified symposium jointly sponsored by the University of Massachusetts Medical School and CMEducation Resources, LLC Commercial Support: This National Initiative is Sponsored by an Independent Educational Grant from the Bristol-Myers Squibb/Pfizer Cardiovascular Partnership.

Program Faculty PROGRAM CHAIRMAN SAMUEL Z. GOLDHABER, MD
Cardiovascular Division Brigham and Women’s Hospital Professor of Medicine Harvard Medical School CHRISTIAN T. RUFF, MD, MPH TIMI Study Group Boston, MA ELAINE M. HYLEK, MD, MPH Professor of Medicine Department of Medicine Boston University Medical Center Boston, Massachusetts

Conflict of Interest Disclosures
Program Chairman SAMUEL Z. GOLDHABER, MD Research Support: Eisai, EKOS, Johnson & Johnson, sanofi-aventis Consultant: Baxter, Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi, Eisai, Janssen, Merck, Pfizer, Portola, sanofi-aventis CHRISTIAN T. RUFF, MD, MPH Research Support: Daiichi Sankyo, AstraZeneca, Bristol-Meyers Squibb, sanofi-aventis Consultant: Alere and Beckman Coulter ELAINE M. HYLEK, MD, MPH Research Support: Bristol-Myers Squibb, Ortho-McNeil Consultant: Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Johnson & Johnson, Pfizer

New Paradigms in the Science and Medicine of Stroke Prevention for Atrial Fibrillation
Epidemiology and Overview Risk, Disease Burden, and Deciphering the Maze of Risk-Specific Interventions for AF Focus on Non-Monitored Oral Anticoagulation and the Unmet Need for Safer and More Effective Stroke Prevention in NVAF Samuel Z. Goldhaber, MD Program Chairman Director, VTE Research Group Cardiovascular Division Brigham and Women’s Hospital Professor of Medicine Harvard Medical School

Faculty COI Disclosures
Research Support Eisai, EKOS, Johnson & Johnson, sanofi-aventis Consultant Baxter, Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi, Eisai, Janssen, Merck, Pfizer, Portola, sanofi-aventis

Formal Definition: Atrial Fibrillation
AF is an arrhythmia characterized by uncoordinated atrial activation, with consequent deterioration of atrial mechanical function Circulation 2011; 121: e269-e367

The ECG of Atrial Fibrillation
Normal sinus rhythm Atrial fibrillation Loss of coordinated atrial activation Loss of atrial mechanical function EKG-replacement of P waves with fibrillatory waves Irregular and frequently rapid ventricular response 9 9

Cardioversion Failed or Not Attempted
The “3 Ps” and Natural History of Atrial Fibrillation Paroxysmal Self-Terminating Persistent Lasts > 7 Days Permanent Cardioversion Failed or Not Attempted Inexorable progression: Paroxysmal – terminates spontaneously Persistent – sustained beyond 7 days Permanent – CV failed or has been forgone Paroxysmal AF is as likely to cause stroke as persistent or permanent AF Normal Sinus Rhythm Atrial Fibrillation

Atrial Fibrillation: Epidemiology
The No. 1 preventable cause of stroke In the United States, up to 16 million individuals will be affected by the year 2050 Increasing survival from heart attack and increasing age (“the ‘graying’ of America”) help explain rise in incidence of AF 11

Atrial Fibrillation Risk Factors
Magnani JW et al. Circulation 2011; 124:

Atrial Fibrillation: An Epidemic
18 US Prevalence 16 million 16 14 12 1 in 4 lifetime risk in men and women ≥ 40 years old 10 Projected Number of People with AF (millions) 8 6 It has been estimated that 2.2 million people in the US and 4.5 million people in European Union suffer from AF with a prevalence that is estimated to at least double within the next 50 years. 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 (red curve). Most common sustained cardiac arrhythmia Currently affects > 2.3 million Americans, or 1% of population In USA, million will be affected by 2050 (2.5 fold) Increasing obesity and increasing age are risk factors that help explain rise in incidence Lifetime risk of developing AF: 1 in 4 for men and women ≥ 40 years of age1 4 2 2000 2005 2010 2015 2020 2025 2030 2035 2040 2045 2050 Year Miyakasa Y, et al. Circulation. 2006; 114: 13

Atrial Fibrillation and Age
Relationship Between Atrial Fibrillation and Age Prevalence, percent Prevalence of AF is rapidly increasing as the population ages, 8% of individuals older than 80. Age, years Go AS, et al. JAMA. 2001; 285:

Atrial Fibrillation Causes Stroke
Left Atrial Appendage Thrombus 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.

Stroke and Atrial Fibrillation Burden
Approximately 5-fold increased risk of stroke Quantify stroke risk: CHADS2/ CHA2DS2-VASc AF strokes have worse outcomes Costly health care ~ $16 billion/year 30 Framingham 20 AF prevalence % Mortality Mortality is doubled independent of other known predictors of mortality. No reduction in past two decades Mortality 9-fold higher during 1st 4 months after diagnosis 1/5th of all strokes attributed to AF 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 Strokes attributable to AF 10 50–59 60–69 70–79 80–89 Age Range (years) Wolf PA, et al. Stroke 1991; 22:

Framingham Heart Study
Ischemic Strokes in Atrial Fibrillation More Likely to be Severely Disabling Framingham Heart Study 73 33 58 16 36 30 11 Strokes in patients with AF are more severe than in those without AF The findings of many studies have suggested that strokes related to AF are more severe than strokes in patients without AF In a long-term (40-year) prospective follow-up of the Framingham Heart Study cohort (n=5,070), 501 initial ischaemic strokes, including 103 strokes in patients with AF, were analysed for stroke severity1 Stroke severity was rated as none, mild, moderate, severe, or fatal as follows: None: no deficit or impairment Mild: deficit present in visual, communication, motor and/or sensory realms, but the impairment was not sufficient to interfere with functional independence Moderate: deficit was severe enough that the patient required assistance in any one of the domains Severe: the patient was functionally dependent on others in two or more domains Strokes in subjects with AF were more frequently classed as ‘severe’ compared with strokes in patients without AF not only in the acute phase but also at the 3-month, 6-month, and 12-month post-stroke time points: In the acute phase 73% of AF stroke patients had severe disability vs 33% of patients with non-AF strokes At 3 months post-stroke 58% of AF stroke patients had severe disability compared with 16% of patients with non-AF strokes At 6 months post-stroke, 36% of AF stroke patients had severe disability compared with 16% of patients with non-AF strokes At 12 months post-stroke, 30% of AF stroke patients had severe disability compared with 11% of patients with non-AF strokes Abbreviation AF, atrial fibrillation Reference Lin et al. Stroke severity in atrial fibrillation. The Framingham Study. Stroke 1996;27:1760–1764. Lin HJ, et al. Stroke. 1996;27:

Fuster V. Circulation 2012; epubl April 18
AF PIE: FUTURE AF PIE: PAST Fuster V. Circulation 2012; epubl April 18

ESC 2012 AF Update Guidelines
Important New Developments Assess stroke risk exclusively with CHA2DS2- VASc and no longer use CHADS2 ESC Guidelines recommend anticoagulation for stroke prevention with CHA2DS2-VASc score of 1 or greater Preference given to novel, non-monitored anticoagulants: apixaban, rivaroxaban, and dabigatran

RRR All-cause mortality:
Anticoagulation in Atrial Fibrillation Effects on Stroke Risk Reduction Warfarin better Control better AFASAK SPAF BAATAF CAFA SPINAF EAFT 100% 50% -50% -100% Aggregate RRR of stroke: 62% RRR All-cause mortality: 26% This slide illustrates risk reductions for warfarin versus control in stroke across several AF trials. Overall RRR was 62%, which was statistically significant in 4 of the trials, SPAF, BAATAF, SPINAF, and EAFT. Of the primary-prevention trials, the combined reduction was 59%. EAFT, the only secondary-prevention trial, had a 68% risk reduction. The RRR of all-cause mortality was 26%. RRR, relative risk reduction. Hart RG, et al. Ann Intern Med. 1999;131: Hart RG, Benavente O, McBride R, Pearce LA. Antithrombotic therapy to prevent stroke in patients with atrial fibrillation: a meta-analysis. Ann Intern Med. 1999;131:

ESC 2012 Update Guidelines HAS-BLED for Evaluation of Bleeding Risk
Clinical Characteristic Points Hypertension (systolic BP > 160 mm Hg) 1 Abnormal renal or liver function 1 + 1 Stroke Bleeding Labile INRs Elderly (age > 65 years) Drugs or alcohol Maximum score 9 Pisters R, et al. Chest. 2010;138: 21

Swedish AF Cohort; Circulation 2011; 125: 2298-2307

Known Problems With Warfarin
Delayed onset/offset Unpredictable dose response Narrow therapeutic index Drug-drug, drug-food interactions Problematic monitoring High bleeding rate Slow reversibility

Warfarin Will Likely Survive: Why?
Established efficacy Low cost ($4/month; $10/3 mos) Long track record (1954) Centralized anticoagulation clinics that maintain TTRs > 60% Rapid, turnaround genetic testing Point-of-care self-testing INR testing q 12 weeks if stable CoumaGen-II. Circ 2012; March 19 ACCP Chest Guidelines 2012

Pharmacogenetic Dosing Achieves TTR of 71%
COUMAGEN-II Pharmacogenetic Dosing Achieves TTR of 71% Circulation 2012; epub March 19

Comparison Overview of New Anticoagulants with Warfarin
Features Warfarin New Agents Onset Slow Rapid Dosing Variable Fixed Food effect Yes No Drug interactions Many Few Monitoring Half-life Long Short Antidote 26

Sites of Action in Coagulation System Novel Factor Xa and DT Inhibitors
Steps in Coagulation Pathway Drugs TF/VIIa Initiation X IX IXa VIIIa Va Rivaroxaban Apixaban Edoxaban Betrixaban Xa Propagation II Fibrin formation IIa Dabigatran Fibrinogen Fibrin Hankey GJ and Eikelboom JW. Circulation 2011;123:

Novel Oral Anticoagulants Important Comparative Features
Oral direct thrombin inhibitor Twice daily dosing Renal clearance Dabigatran Direct factor Xa inhibitor Once daily (maintenance), twice daily (loading) Rivaroxaban Hepatic clearance Apixaban Once daily dosing Edoxaban Circulation 2010;121:1523

Comparison of Phase 3 SPAF Trials for NOACs: A Robust Trial Base
Novel Anticoagulants FIIa Inhibitor Fxa Inhibitor Rivaroxaban Apixaban Edoxaban Dabigatran Open Label Two Doses Twice Daily RE-LY Double Blind Two Doses Once Daily ROCKET-AF Double Blind Two Doses Twice Daily ARISTOTLE Double Blind Two Doses Once Daily ENGAGE Four large trials with novel oral anticoagulants in AF are compared. Note the two doses, both of which are adjusted in patients with decreased drug clearance. ENGAGE AF-TIMI 48 is the largest of the 4 trials. Open label introduces bias. More likely to report AEs or order tests. But hard end points such as mortality and ICH difficult to affect by bias. 29

“Best Options” for Anticoagulation
The Consensus is Shifting Despite continued use of warfarin, NOACs are considered by many professional medical organizations to be the “best option” for anticoagulation of SPAF patients: ESC 2012 AF Update Guidelines ACCP 2012 Guidelines Canadian AF Guidelines

ESC 2012 UPDATE GUIDELINES For ATRIAL FIBRILLATION

The Rationale for AF Registries
Registries provide a “real life” perspective on patient populations, management “in the field,” and outcomes in settings that do not have the special resources and monitoring capabilities of pivotal randomized clinical trials. Information from registries complements clinical trial data. Registries can highlight the disconnect between evidence/guidelines and clinical practice.

The GARFIELD Registry Novel approach to outcomes research
Planned to be conducted in 50 countries 50,000 prospective and 5000 retrospective patients Patients newly diagnosed with non-valvular AF Five sequential cohorts Random site selection Sites representative of national AF care settings Consecutive patients Minimum follow-up period of 2 years

Summary of Garfield Data Cohort One: ESC 2012
10,537 were available for this analysis 5075 retrospective and 5462 prospective Newly diagnosed patients carry high risk for stroke 57% with CHADS2 score >2 83% with CHA2DS2-VASc score >2 VKAs not prescribed in: 38% of patients with CHADS2 score >2 40% of patients with CHA2DS2-VASc score >2 34

Modest Use of Vitamin K Antagonists Even in High-Risk Patients
European Heart Survey 100 5333 AF patients in 35 countries: 2003–2004 80 64 61 58 59 60 OAC therapy (%) 40 20 Abbreviations AF, atrial fibrillation; VKAs, vitamin K antagonists References Nieuwlaat R, Capucci A, Lip GY, et al. Euro Heart Survey Investigators. Antithrombotic treatment in real-life atrial fibrillation patients: a report from the Euro Heart Survey on Atrial Fibrillation. Eur Heart J 2006;27:3018–3026 Gage BF, Waterman AD, Shannon AW, et al. Validation of clinical classification schemes for predicting stroke results from the National Registry of Atrial Fibrillation. JAMA 2001;285:2864–2870 Note: Although the data on oral anticoagulant therapy by CHADS2 score has been used before the values cannot be verified from the paper Nieuwlaat et al The paper represents the data graphically therefore we may be able to use this instead (See slide 32 in back ups). 1 2 3 4 CHADS2 score OAC, oral anticoagulant Nieuwlaat et al. Eur Heart J 2006; Gage et al. JAMA 2001 35 35

A “Failure to Prophylax” Syndrome
Over the past decade, about 40% of patients with atrial fibrillation are unprotected from stroke because of failure to prescribe anticoagulation. Because criteria for anticoagulation have expanded in 2012, the problem has intensified. Heightened awareness of the disconnect between guidelines/evidence and suboptimal intervention for SPAF. Anticoagulation is necessary as a first step.

The SPAF Landscape 2012: Conclusions
The frequency of atrial fibrillation is increasing, so risk of devastating stroke is increasing as well. Anticoagulants can effectively reduce stroke risk, but they are underutilized. NOACs have less ICH bleeding risk than warfarin and are superior—or at least noninferior—for stroke prevention. We must overcome the failure-to-prophylax syndrome. 37

New Paradigms in the Science and Medicine of Heart Disease State-of-the-Art Risk Stratification of Patients with Atrial Fibrillation Anticoagulation Strategies Based on Established and Evolving Atrial Fibrillation Scoring Systems for Thrombosis and Hemorrhagic Risk Elaine M. Hylek, MD, MPH Professor of Medicine Department of Medicine Boston University Medical Center Boston, Massachusetts 38

Independent Predictors of Stroke in AF Systematic Review
Significant by Multivariate Analysis Adjusted Relative Risk (95% CI) Prior stroke or TIA 5 of 5 studies 2.5 (1.8–3.5) Increasing age 6 of 6 studies 1.5/decade (1.3–1.7) History of hypertension or systolic BP > 160 mm Hg 2.0 (1.6–2.5) Diabetes 4 of 4 studies 1.8 (1.5–22) Female gender 3 of 6 studies 1.6 (1.4–1.9) Heart failure 0 of 4 studies* Not significant Coronary artery disease 0 of 4 studies * Significant in a subgroup of participants undergoing echocardiography in trials included AFI pooled analysis Hart RG et al. Neurology 2007; 69: 546.

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. 40

Less Validated Risk Factors
Risk Stratification in Atrial Fibrillation Established 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.

Stroke Risk Threshold Favoring Anticoagulation
The CHADS2 Score Stroke Risk Threshold Favoring Anticoagulation 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.

Stroke Risk Score for Atrial Fibrillation
The CHADS2 Score 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).

CV Event Rates in Patients with Atrial Fibrillation Related to CHADS2 Score
REACH Registry Goto S, et al. Am Heart J 2008; 156: 855.

Stroke Risk Score for Atrial Fibrillation
The CHA2DS2-VASc Score Stroke Risk Score for Atrial Fibrillation Weight (points) Congestive heart failure or LVEF < 35% Hypertension Age > 75 years Diabetes mellitus Stroke/TIA/systemic embolism Vascular Disease (MI/PAD/Aortic plaque) Age years Sex category (female) Moderate-High risk > 2 Low risk Lip GYH, Halperin JL. Am J Med 2010; 123: 484.

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

Tay, Lane & Lip. Thromb Haemost 2008; 100: 955.
Published Bleeding Risk Scores Patients on Oral Vitamin K Antagonist Anticoagulant Therapy Low Moderate High Kuijer et al. Arch Intern Med 1999;159:457. 1-3 > 3 1.6 x age x sex +2.2 x cancer; 1 point for ≥ 60 years old, female or malignancy; 0 if none Beyth et al. Am J Med 1998;105:91. 1-2 ≥ 3 ≥ 65 years old; GI bleed within 2 weeks; prior stroke; comorbidities (recent MI, Hct < 30%, diabetes, Cr > 1.5 mg/dL) ;1 point for each condition; 0 if absent Gage et al. Am Heart J 2006;151:713. < 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; 1 point for each factor; 2 points for previous bleeding Shireman et al. Chest 2006;130:1390. ≤ 1.07 > 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); 1 point for each; 0 if none Tay, Lane & Lip. Thromb Haemost 2008; 100: 955.

Science and Medicine of SPAF
Advances in the Science and Medicine of SPAF

Importance of the HAS-BLED Score
Risk Score for Predicting Bleeding in Anticoagulated Patients with Atrial Fibrillation Weight (points) Hypertension (> 160 mm Hg systolic) Abnormal renal or hepatic function Stroke Bleeding history or anemia Labile INR (TTR < 60%) Elderly (age > 75 years) Drugs (antiplatelet, NSAID) or alcohol High risk (> 4%/year) > 4 Moderate risk (2-4%/year) Low risk (< 2%.year) Pisters R, et al. Chest 2010; 138: 1093. Lip GYH, et al. J Am Coll Cardiol 2010; 57: 173.

Canadian Cardiovascular Society AF Guidelines 2012 Update
Assess Thromboembolic Risk (CHADS2) CHADS2 = 0 CHADS2 = 1 CHADS2 > 2 Increasing stroke risk No anti-thrombotic ASA OAC* OAC* OAC No additional risk factors of stroke Either female sex or vascular disease Age > 65 y or combination of female sex and vascular disease *Aspirin is a reasonable alternative in some as indicated by risk/benefit

Canadian Cardiovascular Society AF Guidelines 2012 Update
All patients with atrial fibrillation or atrial flutter (paroxysmal, persistent, or permanent), should be stratified using a predictive index for stroke (eg, CHADS2) and for the risk of bleeding (eg, HAS-BLED), and that most patients should receive either an oral anticoagulant or aspirin. (Strong recommendation, high quality evidence) When oral anticoagulation therapy is indicated, most patients should receive dabigatran, rivaroxaban, or apixaban* in preference to warfarin. (Conditional recommendation. high-quality evidence). *Once approved by Health Canada.

ESC 2012 AF Update Guidelines
2012 focused update of the ESC Guidelines for the management of atrial fibrillation: Europace Aug 24

ESC 2012 Guidelines: Identifying “Truly Low-Risk” Patients with AF
Thus, this guideline strongly recommends a practice shift toward greater focus on identification of ‘truly low-risk’ patients with AF (ie,‘age <65 and lone FL’ who do not need any antithrombotic therapy), instead of trying to focus on identifying ‘high-risk’ patients. To achieve this, it is necessary to be more inclusive (rather than exclusive) of common stroke risk factors as part of any comprehensive stroke risk assessment. Indeed, patients with AF who have stroke risk factor(s) > 1 are recommended to receive effective stroke prevention therapy, which is essentially OAC with either well-controlled VKA therapy [INR 2-3, with a high percentage of time in the therapeutic range (TTR), for example, at least 70%] or one of the NOACs 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: Europace Aug 24

CHA2DS2-VASc vs. CHADS2 Is More Information Better?
The new scoring systems have been adopted in Europe but not in the United States, even in the latest practice guideline updates. The components of the CHA2DS2-VASc score are less well validated than those of the CHADS2 score. The C-statistic used to validate the CHA2DS2-VASc score is only marginally superior to those of other schema. There is no consensus about how to combine stroke risk and bleeding risk scores into a composite instrument.

Current AF Stroke Risk Stratification Schemes Limitations, Challenges, and Opportunities
All have modest predictive value for thromboembolism Patients classified as low risk must truly be at low risk to safely avoid anticoagulation Should classify small proportion into the intermediate risk category, for which optimum therapy is less clear Incorporate risk factors as cumulative Should be comprehensive yet easy to apply Scoring systems are the most popular method Acronym for easy recall Should be validated in multiple populations, ideally clinical practice populations, rather than in the control arms of trial cohorts Risk schemes must evolve to address the wider therapeutic margin offered by new oral anticoagulants Lip GYH, Halperin JL. Am J Med 2010;123:484

Atrial Fibrillation and Thromboembolism The Next Challenges
Better risk-stratification that balances stroke and bleeding and addresses new anticoagulants Noninvasive methods to better predict events and guide therapy Safer treatments for the highest risk patients Achieving and confirming successful rhythm control over time Targeted atrial fibrillation prevention

New Paradigms in the Science and Medicine of Heart Disease Deciphering the Maze of Evidence from Landmark Trials Evaluating Non-Monitored, Oral Anticoagulants (NOACs) for SPAF Christian T. Ruff, MD, MPH TIMI Study Group Brigham and Women’s Hospital Harvard Medical School Boston, MA 57

Research Support Daiichi Sankyo, AstraZeneca, Bristol-Meyers Squibb, sanofi-aventis Consultant Alere and Beckman Coulter 58

Properties of an Ideal Anticoagulant
Benefit Oral, once-daily dosing Ease of administration Rapid onset of action No need for overlapping parenteral anticoagulant Minimal food or drug interactions Simplified dosing Predictable anticoagulant effect No coagulation monitoring Extra renal clearance Safe in patients with renal disease Rapid offset in action Simplifies management in case of bleeding or intervention Antidote For emergencies 59

Oral Anticoagulation for SPAF
Major Advances In Oral Anticoagulation for SPAF ROCKET AF (Rivaroxaban) 2010 ENGAGE AF (Edoxaban) 2013 6 Trials of Warfarin vs Placebo RE-LY (Dabigatran) 2009 ARISTOTLE (Apixaban) 2011

Comparative Pharmacokinetics/ Pharmacodynamics of Novel Agents
Dabigatran Apixaban Rivaroxaban Edoxaban Target IIa (thrombin) Xa Hrs to Cmax 2 1-3 2-4 1-2 CYP metabolism None 15% 32% NR Bioavailability 7% 66% 80% > 45% Transporters P-gp P-gp/BCRP Protein binding 35% 87% >90% 55% Half-life 12-14h 8-15h 9-13h 8-10h Renal elimination 25% 33% Linear PK Yes No BCRP = breast cancer resistance protein; CYP = cytochrome P450; NR = not reported; P-gp = P-glycoprotein Ruff CR and Giugliano RP. Hot Topics in Cardiology 2010;4:7-14 Ericksson BI, et al. Clin Pharmacokinet 2009;48:1-22 61

The RE-LY Trial: Dabigatran
Recommendations for the prevention of stroke in patients with atrial fibrillation. The inner circle represents treatment recommendations based on the use of the CHADS2 score, as in US guidelines.1 The outer circle represents recommendations based on the CHA2DS2-VASc model, as outlined in the European guidelines,4 which advise anticoagulant therapy in a larger proportion of patients with atrial fibrillation. Bleeding risk assessment is recommended for patients at intermediate stroke risk (yellow-shaded area), with particular caution and regular patient review for those on warfarin therapy when the HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly, drugs/alcohol concomitantly) score is ≥3. For patients at very high risk of bleeding (eg, those with malignant hypertension or prior episodes of major bleeding), conservative monitoring without treatment should be considered. OAC indicates oral anticoagulation.

Absence of contra-indications
RE-LY Atrial fibrillation ≥1 Risk Factor Absence of contra-indications 951 centers in 44 countries PROBE=Prospective Randomized Open Trial with Blinded Adjudication of Events R open Blinded Warfarin (INR ) N = 6022 Dabigatran Etexilate 110 mg bid N = 6015 Dabigatran Etexilate 150 mg bid N = 6076 The Phase 3, RE-LY trial was a Prospective Randomized Open Blinded Endpoint (PROBE) design that compared two dose strategies of dabigatran (110 mg and 150 mg twice daily) with open-label warfarin in 18,113 patients with atrial fibrillation (AF). 10 efficacy outcome = stroke or systemic embolism 10 safety outcome = major bleeding Non-inferiority margin 1.46

RE-LY Efficacy (Dabigatran)
Stroke/Systemic Embolic Event 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) Connolly, et al. N Engl J Med 2009;361: 64

RE-LY Efficacy (Dabigatran)
Dabigatran 110 mg Dabigatran 150 mg 0.91 ( ) Stroke/SEE 0.66 ( ) 1.11 ( ) Ischemic Stroke 0.76 ( ) Review of the efficacy data from RE-LY: Dabigatran 150 mg twice daily was superior to warfarin in reducing the composite primary endpoint of stroke and systemic embolism. Dabigatran 110 mg twice daily was non-inferior to warfarin. These results were largely driven by the substantial reductions in hemorrhagic stroke with both dabigatran dose groups compared to warfarin. There was a more modest reduction in ischemic stroke with dabigatran 150 mg twice daily compared to warfarin and similar rates for dabigatran 110 mg twice daily compared to warfarin. No significant difference in mortality. 0.31 ( ) Hemorrhagic Stroke 0.26 ( ) 0.1 0.3 0.5 1.0 2.0 Connolly, et al. N Engl J Med 2009;361: Dabigatran Better Warfarin Better

RE-LY Safety Results (Dabigatran)
Dabigatran 110 mg Dabigatran 150 mg 0.80 ( ) Major Bleed 0.93 ( ) 0.31 ( ) ICH 0.40 ( ) 1.10 ( ) GI Bleed Review of the safety data from RE-LY: The risk of major bleeding was similar in the dabigatran 150 mg and warfarin groups and significantly lower in the dabigatran 110 mg group. Substantial reductions in intracranial hemorrhage (ICH) were seen for both dabigatran dose groups compared to warfarin. The rate of gastrointestinal bleeding was significantly higher with dabigatran 150 mg twice daily compared to warfarin and numerically increased for the lower dose. Higher rates of dyspepsia: 150 mg 11.3%, 110 mg 11.8%, warfarin 5.8% There were non-significant increases in the rates of myocardial infarction in both dabigatran dose groups compared to warfarin. 1.50 ( ) 1.29 ( ) MI 1.27 ( ) Connolly, et al. N Engl J Med 2009;361: 0.1 0.3 0.5 1.0 2.0 Dabigatran Better Warfarin Better

RE-LY Efficacy Stratified by CHADS2
D110mg D150mg Annualized Rate Stroke/SEE (%) P = 0.44 0.50 1.00 1.50 Dabigatran better Warfarin P = 0.82 0.50 1.00 1.50 Dabigatran better Warfarin CHADS2 D110 D150 WARF 0-1 1.06 0.65 1.05 2 1.43 0.84 1.38 3-6 2.12 1.88 2.68 Oldgren J, et al. ACC 2010 67

RE-LY Efficacy Stratified by Prior Vitamin K Anatagonist
Comparisons of primary end points by treatment group for the overall population and VKA-naive and -experienced cohorts. VKA naive is defined as a total lifetime use of a VKA of ≤62 days. Interaction P values are for the interaction between treatment group and VKA status. Ezekowitz MD, et al. Circulation 2010;122: 68

RE-LY Cardioversion (Dabigatran)
# Strokes 110 : 5, 150:2, Warf: 4 Methods and Results—Cardioversion on randomized treatment was permitted. Precardioversion transesophageal echocardiography was encouraged, particularly in dabigatran-assigned patients. Data from before, during, and 30 days after cardioversion were analyzed. A total of 1983 cardioversions were performed in 1270 patients: 647, 672, and 664 in the D110, D150, and warfarin groups, respectively. For D110, D150, and warfarin, transesophageal echocardiography was performed before 25.5%, 24.1%, and 13.3% of cardioversions, of which 1.8%, 1.2%, and 1.1% were positive for left atrial thrombi. Continuous treatment with study drug for 3 weeks before cardioversion was lower in D110 (76.4%) and D150 (79.2%) compared with warfarin (85.5%; P0.01 for both). Stroke and systemic embolism rates at 30 days were 0.8%, 0.3%, and 0.6% (D110 versus warfarin, P0.71; D150 versus warfarin, P0.40) and similar in patients with and without transesophageal echocardiography. Major bleeding rates were 1.7%, 0.6%, and 0.6% (D110 versus warfarin, P0.06; D150 versus warfarin, P0.99). Conclusions—This study is the largest cardioversion experience to date and the first to evaluate a novel anticoagulant in this setting. The frequencies of stroke and major bleeding within 30 days of cardioversion on the 2 doses of dabigatran were low and comparable to those on warfarin with or without transesophageal echocardiography guidance. Dabigatran is a reasonable alternative to warfarin in patients requiring cardioversion. (N = 647) (N = 672) (N = 664) Nagarakanti R, et al. Circulation 2011;123: 69

Dabigatran Approval Prevention of stroke in AF
Available in 75 mg and 150 mg (twice daily) Dose of 75 mg if CrCl mL/min Data in favor of 110 mg were “suggestive, but not entirely convincing” October 2010 FDA approved dabigatran No approval for 110 mg because more ischemic strokes and inferior to high dose (although approved in Canada, Brazil, Europe) 70 70

ROCKET AF: Rivaroxaban
Recommendations for the prevention of stroke in patients with atrial fibrillation. The inner circle represents treatment recommendations based on the use of the CHADS2 score, as in US guidelines.1 The outer circle represents recommendations based on the CHA2DS2-VASc model, as outlined in the European guidelines,4 which advise anticoagulant therapy in a larger proportion of patients with atrial fibrillation. Bleeding risk assessment is recommended for patients at intermediate stroke risk (yellow-shaded area), with particular caution and regular patient review for those on warfarin therapy when the HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly, drugs/alcohol concomitantly) score is ≥3. For patients at very high risk of bleeding (eg, those with malignant hypertension or prior episodes of major bleeding), conservative monitoring without treatment should be considered. OAC indicates oral anticoagulation.

Atrial Fibrillation Rivaroxaban Warfarin
Risk Factors CHF Hypertension Age  75 Diabetes OR Stroke, TIA or Systemic embolus At least 2 required Atrial Fibrillation Rivaroxaban Randomize Double blind / Double Dummy (n = 14,266) Warfarin 20 mg daily 15 mg for Cr Cl 30-49 INR target - 2.5 ( inclusive) Monthly Monitoring and adherence to standard of care guidelines The ROCKET AF trial will be the first Phase 3 trial to report results of a factor Xa inhibitor in AF. ROCKET AF is a randomized, double blind, double dummy, event driven trial comparing the safety and efficacy of rivaroxaban 20 mg once daily with warfarin (titrated to INR 2-3). Blinded treatment is maintained through the use of sham INRs in patients receiving rivaroxaban. Patients with moderate renal dysfunction receive a dose reduction (15 mg) and patients with severe renal dysfunction are excluded. 14,266 subjects who had at least two episodes of AF documented in the previous 6 months and a CHADS2 risk score of ≥2 have been enrolled. The primary efficacy endpoint is a non-inferiority analysis of the composite endpoint of stroke and systemic embolism. The primary safety endpoint is the composite of major and non-major clinically relevant bleeding. Primary End point: Stroke or non-CNS Systemic Embolism Statistics: non-inferiority, > 95% power, 2.3% warfarin event rate 72

Event Rates are per 100 patient-years
ROCKET AF Efficacy Stroke/Systemic Embolic Event Rivaroxaban Warfarin Event Rate HR (95% CI) P-value On Treatment N = 14,143 1.70 2.15 (0.65, 0.95) 0.015 ITT N = 14,171 2.12 2.42 (0.74, 1.03) 0.117 Rivaroxaban better Warfarin better Event Rates are per 100 patient-years Based on Safety on Treatment or Intention-to-Treat through Site Notification populations Patel, et al. N Engl J Med 2011;365(10);

ROCKET AF Key Secondary Efficacy
Event Rivaroxaban (%/yr) Warfarin Hazard Ratio (95% CI) P-value Ischemic Stroke 1.34 1.42 0.94 ( ) 0.581 Hemorrhagic Stroke 0.26 0.44 0.59 ( ) 0.024 MI 0.91 1.12 0.81 ( ) 0.121 Total Mortality 1.87 2.21 0.85 ( ) 0.073 Vascular Mortality 1.53 1.71 0.89 ( ) 0.289 Patel, et al. N Engl J Med 2011; 365(10); 74

ROCKET AF Safety (Rivaroxaban)
Event Rivaroxaban (%/yr) Warfarin Hazard Ratio (95% CI) P-value Major and Clinically Relevant Bleed 14.9 14.5 1.03 ( ) 0.44 Major Bleed 3.6 3.4 1.04 ( ) 0.58 Fatal Bleed 0.2 0.5 0.50 ( ) 0.003 ICH 0.7 0.67 ( ) 0.02 Patel, et al. N Engl J Med 2011; 365(10); 75

ROCKET AF Efficacy (Rivaroxaban)
Moderate Renal Impairment Methods and results We randomized patients with AF in a double-blind trial to rivaroxaban 20 mg/day [15 mg/day if creatinine clearance (CrCl) 30–49 mL/min] or dose-adjusted warfarin (target international normalized ratio 2.0–3.0). Compared with patients with CrCl .50 mL/min (mean age 73 years), the 2950 (20.7%) patients with CrCl 30–49 mL/ min were older (79 years) and had higher event rates irrespective of study treatment. Among those with CrCl 30–49 mL/min, the primary endpoint of stroke or systemic embolism occurred in 2.32 per 100 patient-years with rivaroxaban 15 mg/day vs per 100 patient-years with warfarin [hazard ratio (HR) 0.84; 95% confidence interval (CI) 0.57–1.23] in the per-protocol population. Intention-to-treat analysis yielded similar results (HR 0.86; 95% CI 0.63–1.17) to the per-protocol results. Rates of the principal safety endpoint (major and clinically relevant non-major bleeding: vs per 100 patient-years; P ¼ 0.76) and intracranial bleeding (0.71 vs per 100 patient-years; P ¼ 0.54) were similar with rivaroxaban or warfarin. Fatal bleeding (0.28 vs. 0.74% per 100 patient-years; P ¼ 0.047) occurred less often with rivaroxaban. Conclusion Patients with AF and moderate renal insufficiency have higher rates of stroke and bleeding than those with normal renal function. There was no evidence of heterogeneity in treatment effect across dosing groups. Dose adjustment in ROCKET-AF yielded results consistent with the overall trial in comparison with dose-adjusted warfarin. Fox KA, et al. Eur Heart J 2011;32(19):

Moderate Renal Impairment
G w_script.ppt ROCKET AF Safety Moderate Renal Impairment 3/27/2017 Methods and results We randomized patients with AF in a double-blind trial to rivaroxaban 20 mg/day [15 mg/day if creatinine clearance (CrCl) 30–49 mL/min] or dose-adjusted warfarin (target international normalized ratio 2.0–3.0). Compared with patients with CrCl .50 mL/min (mean age 73 years), the 2950 (20.7%) patients with CrCl 30–49 mL/ min were older (79 years) and had higher event rates irrespective of study treatment. Among those with CrCl 30–49 mL/min, the primary endpoint of stroke or systemic embolism occurred in 2.32 per 100 patient-years with rivaroxaban 15 mg/day vs per 100 patient-years with warfarin [hazard ratio (HR) 0.84; 95% confidence interval (CI) 0.57–1.23] in the per-protocol population. Intention-to-treat analysis yielded similar results (HR 0.86; 95% CI 0.63–1.17) to the per-protocol results. Rates of the principal safety endpoint (major and clinically relevant non-major bleeding: vs per 100 patient-years; P ¼ 0.76) and intracranial bleeding (0.71 vs per 100 patient-years; P ¼ 0.54) were similar with rivaroxaban or warfarin. Fatal bleeding (0.28 vs. 0.74% per 100 patient-years; P ¼ 0.047) occurred less often with rivaroxaban. Conclusion Patients with AF and moderate renal insufficiency have higher rates of stroke and bleeding than those with normal renal function. There was no evidence of heterogeneity in treatment effect across dosing groups. Dose adjustment in ROCKET-AF yielded results consistent with the overall trial in comparison with dose-adjusted warfarin. Fox KA, et al. Eur Heart J 2011;32(19): 77

Rivaroxaban Approval Prevention of stroke in AF
Dose 20 mg if CrCl > 50 mL/min Dose of 15 mg if CrCl mL/min November 2011 FDA approved rivaroxaban 78 78

AVERROES Recommendations for the prevention of stroke in patients with atrial fibrillation. The inner circle represents treatment recommendations based on the use of the CHADS2 score, as in US guidelines.1 The outer circle represents recommendations based on the CHA2DS2-VASc model, as outlined in the European guidelines,4 which advise anticoagulant therapy in a larger proportion of patients with atrial fibrillation. Bleeding risk assessment is recommended for patients at intermediate stroke risk (yellow-shaded area), with particular caution and regular patient review for those on warfarin therapy when the HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly, drugs/alcohol concomitantly) score is ≥3. For patients at very high risk of bleeding (eg, those with malignant hypertension or prior episodes of major bleeding), conservative monitoring without treatment should be considered. OAC indicates oral anticoagulation.

AVERROES Trial Design: Apixaban
36 countries, 522 centers Apixaban 5 mg bid 2 mg bid in selected patients AF and >1 risk factor, and demonstrated or unexpected unsuitable of VKA R 5600 patients Double-blind ASA ( mg/d) Primary Outcome: Stroke or Systemic Embolic Event (SEE) 80

Stroke or Systemic Embolic Event
AVERROES: Apixaban Stroke or Systemic Embolic Event Major Bleeding Aspirin Apixaban P < 0.001 0.020 0.015 0.010 0.005 0.000 Aspirin Apixaban P < 0.001 0.05 0.04 0.03 0.02 0.01 0.00 Presented at ESC and recently published. 5,600 subjects with AF and at least one risk factor for stroke who have failed or were unsuitable for anticoagulation. Randomized to apixaban 5 mg bid (2.5 in select patients) compared with ASA Trial stopped by DSMB at prespecified interim analysis. 55% reduction in stroke/SEE and nonsignificant 13% increase in major bleeding with no increased risk of fatal bleeding or ICH. HR 0.45 ( ) HR 1.13 ( ) Connolly SJ, et al. N Engl J Med 2011 (epub) 81

ARISTOTLE: Apixaban Recommendations for the prevention of stroke in patients with atrial fibrillation. The inner circle represents treatment recommendations based on the use of the CHADS2 score, as in US guidelines.1 The outer circle represents recommendations based on the CHA2DS2-VASc model, as outlined in the European guidelines,4 which advise anticoagulant therapy in a larger proportion of patients with atrial fibrillation. Bleeding risk assessment is recommended for patients at intermediate stroke risk (yellow-shaded area), with particular caution and regular patient review for those on warfarin therapy when the HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly, drugs/alcohol concomitantly) score is ≥3. For patients at very high risk of bleeding (eg, those with malignant hypertension or prior episodes of major bleeding), conservative monitoring without treatment should be considered. OAC indicates oral anticoagulation.

ARISTOTLE Trial Design: Apixaban
Inclusion risk factors Age ≥ 75 years Prior stroke, TIA, or SE HF or LVEF ≤ 40% Diabetes mellitus Hypertension Randomize double blind, double dummy (n = 18,201) Exclusion Mechanical prosthetic valve Severe renal insufficiency Need for aspirin plus thienopyridine Apixaban 5 mg oral twice daily (2.5 mg bid in selected patients) Warfarin (target INR 2-3) Warfarin/warfarin placebo adjusted by INR/sham INR based on encrypted point-of-care testing device Primary outcome: stroke or systemic embolism Hierarchical testing: non-inferiority for primary outcome, superiority for primary outcome, major bleeding, death

P (non-inferiority) < 0.001
ARISTOTLE Efficacy: Apixaban (1.60 %/yr) HR 0.79 (0.66–0.95) 21% RRR (1.27 %/yr ) P (non-inferiority) < 0.001 P (superiority) = 0.011 Granger CB, et al. NEJM 2011; 365:

ARISTOTLE Efficacy Outcomes
Apixaban (N = 9120) Warfarin (N = 9081) HR (95% CI) P Value Event Rate (%/yr) Stroke or systemic embolism* 1.27 1.60 0.79 (0.66, 0.95) 0.011 Stroke 1.19 1.51 0.79 (0.65, 0.95) 0.012 Ischemic or uncertain 0.97 1.05 0.92 (0.74, 1.13) 0.42 Hemorrhagic 0.24 0.47 0.51 (0.35, 0.75) < 0.001 Systemic embolism (SE) 0.09 0.10 0.87 (0.44, 1.75) 0.70 All-cause death* 3.52 3.94 0.89 (0.80, 0.998) 0.047 Stroke, SE, or all-cause death 4.49 5.04 0.89 (0.81, 0.98) 0.019 Myocardial infarction 0.53 0.61 0.88 (0.66, 1.17) 0.37 Granger CB, et al. NEJM 2011; 365:

ARISTOTLE Safety End Points
Event Apixaban (%/yr) Warfarin Hazard Ratio (95% CI) P-value ISTH Major Bleeding 2.13 3.09 0.69 ( ) < 0.001 ICH 0.33 0.80 0.42 ( ) GUSTO Severe 0.52 1.13 0.46 ( ) Gastrointestinal 0.76 0.86 0.89 ( ) 0.37 Granger CB, et al. NEJM 2011; 365: 86

ARISTOTLE: Apixaban Renal Function Stroke or SEE Major Bleeding
Annualized Event Rate Results based on renal function: Stroke, systemic embolism, and bleeding rates all trended higher in both arms as renal function declined. The efficacy of apixaban as compared with warfarin appeared to be similar irrespective of renal function. However, a significant reduction in major bleeding was noted in patients with impaired renal function with apixaban as compared with warfarin. Annual bleeding rates were 1.46% vs. 1.84% for glomerular filtration rate (GFR) ≥80, 2.45% vs. 3.21% for GFR 50-80, and 3.21% vs. 6.44% for GFR ≤50, respectively (p for interaction = 0.03). Baseline Cockcroft-Gault eGFR mL/min Hohnloser SH, et al. EHJ 2012 (epub August 29)

Phase III: Protocol Schema
AF on Electrical Recording < 12 mo Intended oral A/C CHADS2 >2 N = 21,105 Randomization Stratified By 1. CHADS2 2-3 vs 4-6 2. Drug Clearance DOUBLE BLIND DOUBLE DUMMY R Low dose regimen Edoxaban 30 mg qd (n ≈ 7000) High dose regimen Edoxaban 60 mg qd (n ≈ 7000) Active Control Warfarin (n ≈ 7000) Median Duration of Follow-up 24 Months As a reminder: the ENGAGE AF-TIMI 48 trial is a double blind, double dummy, non-inferiority designed trial comparing two exposure strategies (high and low) with warfarin for the prevention of stroke and systemic embolism in patients with atrial fibrillation. The trial is event driven. Primary Objective Edoxaban: Therapeutically as Good as Warfarin 1º EP = Stroke or SEE (Noninferiority Boundary HR 1.38) 2º EP = Stroke or SEE or CV mortality Safety EP’s = Major Bleeding, Hepatic Function EVENT DRIVEN SEE = systemic embolic event Ruff CR et al. Am Heart J 2010; 160:635-41 88

Pivotal Atrial Fibrillation Trials
Baseline Characteristics RE-LY (Dabigatran) ARISTOTLE (Apixaban) ENGAGE AF-TIMI 48* (Edoxaban) ROCKET-AF (Rivaroxaban) # Enrolled 18,113 18,201 21,105 14,264 Age (yrs) 72 ± 9 70 [63-76] 72 [64-77] 73 [65-78] Female 36% 35% 38% 40% CHADS2 score ≥3 32% 30% 52% 87% VKA naive 50% 43% 41% Paroxysmal AF 33% 15% 25% 18% Prior stroke/TIA 20% 19% 18% / 12% 55%** Diabetes 23% Prior CHF 56% 62% Hypertension 79% 90% 91% Connolly SJ et al. N Engl J Med 2009; 361: Patel MR et al. N Engl J Med 2011; 365:883-91 Granger CB et al. N Engl J Med 2011; 365:981-92 Ruff CR et al. Am Heart J 2010; 160:635-41 *Preliminary data **includes prior systemic embolism

Pivotal Atrial Fibrillation Trials
Dose Comparison RE-LY ROCKET-AF ARISTOTLE ENGAGE AF-TIMI 48 Drug Dabigatran Rivaroxaban Apixaban Edoxaban N 18,113 14,266 18,201 21,105 Dose (mg) Frequency 150, 110 bid 20 qd 5 bid 60, 30 qd Initial Dose adj* No 20 → 15 mg 5 → 2.5 mg 60 → 30 mg 30 → 15 mg Dose adj (%) 21 4.7 > 25 Dose adj* after randomization Yes Design PROBE 2 x blind *Dose adjusted in patients with ↓drug clearance. PROBE = prospective, randomized, open-label, blinded end point evaluation Connolly SJ et al. N Engl J Med 2009; 361: Patel MR et al. N Engl J Med 2011; 365:883-91 Granger CB et al. N Engl J Med 2011; 365:981-92 Ruff CR et al. Am Heart J 2010; 160:635-41

ITT cohort: non-infer. On Rx cohort: Superior
Pivotal Atrial Fibrillation Trials Results to Date Drug Dose (mg) RE-LY ROCKET-AF ARISTOTLE Dabigatran 110 bid BID Rivaroxaban 20 mg qd Apixaban 5 mg bid Stroke + SEE non-infer Superior ITT cohort: non-infer. On Rx cohort: Superior ICH Bleeding Lower similar Mortality P = 0.051 Superior: P = 0.047 Ischemic stroke Mean TTR 64% 55% 62% Stopped drug 21% 23% WD consent 2.3% 8.7% 1.1% TTR = time in therapeutic range WD consent = withdrawal of consent, no further data available

Efficacy of New Oral Anticoagulants
Stroke & SEE Ischemic & Unsp. Stroke 13% Hemorraghic Stroke 55% Favors NOACs Favors Warfarin Miller CS, et al. Am J Cardiol 2012;110(3):

51% Safety of New Oral Anticoagulants Bleeding Major ICH GI
Favors NOACs Favors Warfarin Miller CS, et al. Am J Cardiol 2012;110(3):

Does INR (TTR) Matter? ARISTOTLE - Apixaban TTR (%) Apixaban (%/yr)
Warfarin HR (95% CI) < 58.0 1.75 2.28 0.77 ( ) 58.0–65.7 1.30 1.61 0.80 ( ) 65.7–72.2 1.21 1.55 0.79 ( ) > 72.2 0.83 1.02 0.81 ( ) P-interaction 0.29 Granger CB, et al. NEJM 2011; 365:

Does INR Matter? 0.2 1 2 5 Hazard Ratio (95% CI) Treatment Group
Study Drug Warfarin Favors Treatment Group Event Rate / Year Warfarin P-value (interaction) ROCKET AF 0.74 % 1.77 2.53 % 1.94 2.18 % 1.90 2.14 % 1.33 1.80 RE-LY (Dabigatran 150 mg) 0.20 < 57.1% 1.1 1.92 57.1–65.5% 1.04 2.06 65.5–72.6% 1.51 > 72.6% 1.27 1.34 Outcome events—instantaneous incidence rates of deaths or thrombo-embolisms during treatment and interruption of warfarin. A retrospective, nationwide cohort study of all patients in Denmark treated with warfarin after a first hospitalization with AF in the period 1997–2008. Incidence rate ratios (IRRs) of thrombo-embolic events and all-cause mortality were calculated using the Poisson regression analyses. In total, AF patients receiving warfarin treatment were included. In patients with AF, an interruption of warfarin treatment is associated with a significantly increased short-term risk of death or thrombo-embolic events within the first 90 days of treatment interruption. ARISTOTLE 0.29 < 58.0% 1.75 2.28 58.0–65.7% 1.30 1.61 65.7–72.2 % 1.21 1.55 > 72.2 % 0.83 1.02 0.2 1 2 5 Wallentin L, et al. Lancet 2010;376: Patel, et al. NEJM 2011;365(10); Granger CB, et al. NEJM 2011; 365:

Warfarin Treatment Interruption
All-Cause Death & Thromboembolism Outcome events—instantaneous incidence rates of deaths or thrombo-embolisms during treatment and interruption of warfarin. A retrospective, nationwide cohort study of all patients in Denmark treated with warfarin after a first hospitalization with AF in the period 1997–2008. Incidence rate ratios (IRRs) of thrombo-embolic events and all-cause mortality were calculated using the Poisson regression analyses. In total, AF patients receiving warfarin treatment were included. In patients with AF, an interruption of warfarin treatment is associated with a significantly increased short-term risk of death or thrombo-embolic events within the first 90 days of treatment interruption. Raunsø J, et al. Eur Heart J 2012; 33:

Novel Oral Anticoagulants
More Events “Off-Drug” 13% 25% %/yr If we look more closely at the data there is a significant difference in the increase in events rates between on treatment and ITT when we compare warfarin to rivaroxaban. For warfarin, there was a 13% increase in the rate of stroke and systemic embolism when you compare the event rate in the on treatment group compared to the ITT. However, for rivaroxaban there is 25% increase (almost double that of warfarin) in the rate of stroke and systemic embolism when you compare the event rate in the on treatment group compared to the ITT. P = 0.015 P = 0.117

ROCKET AF Rivaroxaban Increased Events at End of Trial P = 0.008
# Primary Events 81.3 Warfarin P = 0.008 48.8 # Primary Events during first 30 days of transition Rivaroxaban Rivaroxaban Warfarin Safety/Days 3 to 30 after the last dose Patel MR, et al. NEJM 2011; 365: Piccini JP, AHA Emerging Science Series, April 25, 2012 webinar. Abstract 114

Apixaban Increased Events at End of Trial
ARISTOTLE Apixaban Increased Events at End of Trial Days after last dose Apixaban to VKA group Warfarin to VKA group n/N %/year Stroke or systemic embolism 1–30 21/6791 4.02 5/6569 0.99 1–2 1/6791 2.69 1/6569 2.78 3–7 4/6787 4.31 0/6566 8–14 5/6780 3.85 1/6559 0.80 15–30 11/6771 4.18 3/6548 1.18 Pattern mirrored the first 30 days of the trial where warfarin-naïve patients starting warfarin had a higher rate of stroke or systemic embolism (5.41%/year) than warfarin-experienced patients (1.41%/year). Granger CB, et al. European Heart Journal 2012; 23 (Supplement):

Translating Trials into Practice and Guidelines: 2012 Update
“After the Deluge” of SPAF Trials Translating Trials into Practice and Guidelines: 2012 Update Post-Trial, Real World Concerns, Guidelines, and Actions—Where Have Landmark SPAF Trials Taken Us? How Have Recent Guidelines Made Sense of These Data? Recommendations for the prevention of stroke in patients with atrial fibrillation. The inner circle represents treatment recommendations based on the use of the CHADS2 score, as in US guidelines.1 The outer circle represents recommendations based on the CHA2DS2-VASc model, as outlined in the European guidelines,4 which advise anticoagulant therapy in a larger proportion of patients with atrial fibrillation. Bleeding risk assessment is recommended for patients at intermediate stroke risk (yellow-shaded area), with particular caution and regular patient review for those on warfarin therapy when the HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly, drugs/alcohol concomitantly) score is ≥3. For patients at very high risk of bleeding (eg, those with malignant hypertension or prior episodes of major bleeding), conservative monitoring without treatment should be considered. OAC indicates oral anticoagulation.

NOACs Elevated to "Favored" Status by ESC 2012 Update Guidelines for Management of AF
The net clinical benefit of VKAs, balancing ischaemic stroke against ICH in patients with non-valvular AF, has been modeled on to stroke and bleeding rates from the Danish nationwide cohort study for dabigatran, rivaroxaban, and apixaban, on the basis of recent clinical trial outcome data for these NOACs. At a CHA2DS2-VASc score of 1, apixaban and both doses of dabigatran (110 mg bid and 150 mg bid) had a positive net clinical benefit while, in patients with CHA2DS2-VASc score ≥ 2, all three NOACs were superior to warfarin, with a positive net clinical benefit, irrespective of bleeding risk. Recommendations for the prevention of stroke in patients with atrial fibrillation. The inner circle represents treatment recommendations based on the use of the CHADS2 score, as in US guidelines.1 The outer circle represents recommendations based on the CHA2DS2-VASc model, as outlined in the European guidelines,4 which advise anticoagulant therapy in a larger proportion of patients with atrial fibrillation. Bleeding risk assessment is recommended for patients at intermediate stroke risk (yellow-shaded area), with particular caution and regular patient review for those on warfarin therapy when the HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly, drugs/alcohol concomitantly) score is ≥3. For patients at very high risk of bleeding (eg, those with malignant hypertension or prior episodes of major bleeding), conservative monitoring without treatment should be considered. OAC indicates oral anticoagulation. 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: Europace Aug 24

Consider patient values and preferences
NOAC VKA Assess bleeding risk (HAS-BLED score) Consider patient values and preferences LINE SOLID = BEST OPTION DASHED = ALTERNATIVE OPTION 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: Europace Aug 24

Bleeding Risk with Dabigatran
Fact vs Fiction Recommendations for the prevention of stroke in patients with atrial fibrillation. The inner circle represents treatment recommendations based on the use of the CHADS2 score, as in US guidelines.1 The outer circle represents recommendations based on the CHA2DS2-VASc model, as outlined in the European guidelines,4 which advise anticoagulant therapy in a larger proportion of patients with atrial fibrillation. Bleeding risk assessment is recommended for patients at intermediate stroke risk (yellow-shaded area), with particular caution and regular patient review for those on warfarin therapy when the HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly, drugs/alcohol concomitantly) score is ≥3. For patients at very high risk of bleeding (eg, those with malignant hypertension or prior episodes of major bleeding), conservative monitoring without treatment should be considered. OAC indicates oral anticoagulation.

Bleeding Risk with Dabigatran
Fact vs Fiction: What Do Regulators Conclude? Disconnect Between Clinical Trials and Post-Marketing Surveillance Bias: A Case Study EMA Report on Dabigatran: May 24, 2012 "What are the conclusions of the CHMP? The CHMP concluded that the latest available data are consistent with the known risk of bleeding and that the risk profile of dabigatran was unchanged. The Committee found that frequency of reported fatal bleedings with dabigatran was significantly lower than what had been observed in clinical trials at the time of authorisation, but considered that the risks should nonetheless continue to be kept under close review." Recommendations for the prevention of stroke in patients with atrial fibrillation. The inner circle represents treatment recommendations based on the use of the CHADS2 score, as in US guidelines.1 The outer circle represents recommendations based on the CHA2DS2-VASc model, as outlined in the European guidelines,4 which advise anticoagulant therapy in a larger proportion of patients with atrial fibrillation. Bleeding risk assessment is recommended for patients at intermediate stroke risk (yellow-shaded area), with particular caution and regular patient review for those on warfarin therapy when the HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly, drugs/alcohol concomitantly) score is ≥3. For patients at very high risk of bleeding (eg, those with malignant hypertension or prior episodes of major bleeding), conservative monitoring without treatment should be considered. OAC indicates oral anticoagulation.

EMA Report on Dabigatran May 24, 2012
What is the updated advice for prescribers? Prescribers are reminded of the need to follow all the necessary precautions with regard to the risk of bleeding with dabigatran, including the assessment of kidney function before treatment in all patients and during treatment if a deterioration is suspected, as well as dose reductions in certain patients. Dabigatran must not be used in patients with a lesion or condition putting them at significant risk of major bleeding (see the revised product information for details). Dabigatran must not be used in patients using any other anticoagulant, unless the patient is being switched to or from dabigatran (see the revised product information for details). A European Commission decision on this opinion will be issued in due course. Recommendations for the prevention of stroke in patients with atrial fibrillation. The inner circle represents treatment recommendations based on the use of the CHADS2 score, as in US guidelines.1 The outer circle represents recommendations based on the CHA2DS2-VASc model, as outlined in the European guidelines,4 which advise anticoagulant therapy in a larger proportion of patients with atrial fibrillation. Bleeding risk assessment is recommended for patients at intermediate stroke risk (yellow-shaded area), with particular caution and regular patient review for those on warfarin therapy when the HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly, drugs/alcohol concomitantly) score is ≥3. For patients at very high risk of bleeding (eg, those with malignant hypertension or prior episodes of major bleeding), conservative monitoring without treatment should be considered. OAC indicates oral anticoagulation.

Dabigatran vs. Warfarin: Surgical Bleeding
Compared with warfarin, dabigatran is associated with similar rates of perioperative bleeding and thrombotic complications, even among patients having major or urgent surgery. Patients receiving dabigatran were 4 times more likely to have their procedure or surgery within 48 hours of withholding anticoagulation Recommendations for the prevention of stroke in patients with atrial fibrillation. The inner circle represents treatment recommendations based on the use of the CHADS2 score, as in US guidelines.1 The outer circle represents recommendations based on the CHA2DS2-VASc model, as outlined in the European guidelines,4 which advise anticoagulant therapy in a larger proportion of patients with atrial fibrillation. Bleeding risk assessment is recommended for patients at intermediate stroke risk (yellow-shaded area), with particular caution and regular patient review for those on warfarin therapy when the HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly, drugs/alcohol concomitantly) score is ≥3. For patients at very high risk of bleeding (eg, those with malignant hypertension or prior episodes of major bleeding), conservative monitoring without treatment should be considered. OAC indicates oral anticoagulation. Circulation, Healey et al., 2012

No antithrombotic therapy Dabigatran / Rivaroxaban / Apixaban
ESC 2012 Atrial Fibrillation Guidelines Update: Risk Assessment Risk Profile Class / Level CHA2DS2-VASc = 0 No antithrombotic therapy I B CHA2DS2-VASc = 1 VKA (INR 2-3) Or Dabigatran / Rivaroxaban / Apixaban IIa A (Favored) CHA2DS2-VASc ≥ 2 I A (Favored)

Conclusions: From Trials and Evidence to Strategy and Practice
New therapies provide the promise of providing safer, more effective, and more convenient anticoagulation. Trials are consistent in reduction of intracranial hemorrhage and bleeding mortality. SPAF trials are consistent in demonstrating that NOACs are at least as good as, and in some cases, superior to warfarin in preventing stroke in patients with AF. There are important differences in the PK/PD of these agents (half-life, metabolism, renal elimination) that will alter the risk/benefit profile in specific populations; in particular, careful monitoring of renal function is a precondition for optimizing safety and efficacy of these agents. 108 108

Conclusions No reversal agent is currently available but whether the lack of such agents lead to increased bleeding or mortality risk has not been substantiated. New ESC 2012 Update Guidelines for AF have refined and incorporated a new suite of risk prediction strategies (CHA2DS2-VASc, HAS-BLED) that will result in a greater proportion of patients being eligible for oral anticoagulation. New ESC 2012 Update Guidelines for AF have elevated NOACs to "favored" status over VKA for patients who meet risk stratification criteria for requiring oral anticoagulation for AF. 109 109

New Paradigms in the Science and Medicine of Heart Disease Stroke Prevention in Atrial Fibrillation Megatrends, Challenges, and Clinical Dilemmas Samuel Z. Goldhaber, MD, Program Chairman Director, VTE Research Group Cardiovascular Division Brigham and Women’s Hospital Professor of Medicine Harvard Medical School 110

Research Support Eisai, EKOS, Johnson & Johnson, sanofi-aventis Consultant Baxter, Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi, Eisai, Janssen, Merck, Pfizer, Portola, sanofi-aventis

Risk Assessment Megatrend
CHA2DS2-VASc has replaced CHADS2 as the predominant assessment tool to predict stroke risk (ESC 2012 AF Guidelines Update). HAS-BLED has gained dominance as the most predictive bleeding index. It is best used as a cautionary “yellow flag” rather than as a reason to withhold anticoagulation (ESC 2012).

Clinical Dilemma and Challenge— Stroke Risk Underestimated
Paroxysmal AF is difficult to detect. 24h Holter is often insufficient. Long-term noninvasive or invasive monitoring may be necessary. Many strokes are misclassified as “cryptogenic” and are treated with aspirin or other antiplatelet agents, with questionable efficacy for AF. The misclassified strokes are really thromboembolic and warrant anticoagulants.

Stroke or Systemic Embolism
Subclinical AF and Risk of Stroke Atrial tachyarrhythmia > 6 min ≤ 3 months after pacemaker or defibrillator implantation Stroke or Systemic Embolism The risk of ischemic stroke or systemic embolism after 3-month visit, according to whether subclinical atrial tachyarrhythmias were or were not detected between enrollment and the 3-month visit. We enrolled 2580 patients, 65 years of age or older, with hypertension and no history of atrial fibrillation, in whom a pacemaker or defibrillator had recently been im- planted. We monitored the patients for 3 months to detect subclinical atrial tachyarrhythmias (episodes of atrial rate >190 beats per minute for more than 6 minutes) and followed them for a mean of 2.5 years for the primary outcome of ischemic stroke or systemic embolism. Patients with pacemakers were randomly assigned to receive or not to receive continuous atrial overdrive pacing. The population attributable risk of stroke or systemic embolism associated with subclinical atrial tachyarrhythmias was 13%. Subclinical atrial tachyarrhythmias remained predictive of the primary outcome after adjustment for predictors of stroke (hazard ratio, 2.50; 95% CI, 1.28 to 4.89; P=0.008). Continuous atrial overdrive pacing did not prevent atrial fibrillation. Conclusions Subclinical atrial tachyarrhythmias, without clinical atrial fibrillation, occurred frequently in patients with pacemakers and were associated with a significantly increased risk of ischemic stroke or systemic embolism. Years Healey JS, et al. NEJM 2012; 366: 114

Clinical Characteristic
Redefining Risk vs Benefit for OAC HAS-BLED Letter Clinical Characteristic Points H Hypertension 1 A Abnormal Liver or Renal Function 1 or 2 S Stroke B Bleeding L Labile INR E Elderly (age > 65) D Drugs or Alcohol Maximum Score 9 HAS-BLED Score Stroke (% / yr) 1.1 % 1 1.0 % 2 1.9 % 3 3.7 % 4 8.7 % >5 ?? % Using a ‘real-world’ cohort of 3978 European patients with AF from the EuroHeart Survey, a new simple bleeding risk score, HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile INR, elderly [>65 years], drugs/alcohol concomitantly), has been derived. It would seem reasonable to use the HAS-BLED score to assess bleeding risk in AF patients, whereby a score of ≥3 indicates high risk, and some caution and regular review of the patient is needed following the initiation of antithrombotic therapy, whether with VKA or aspirin. Lip GYH. Am J Med. 2011;124: ESC Guidelines: Eur Heart J ;31: 115 115

Clinical Dilemma: Bleeding Risk Correlates With Stroke Risk
The higher the bleeding risk, as assessed by the HAS-BLED Index, the higher the stroke risk—A “Catch 22” when considering and/or deploying oral anticoagulation. Based on observational and trial evidence, we must be especially vigilant to prescribe anticoagulation to AF patients at high risk of bleeding, when the thrombosis risk assessment justifies this course of action.

Action Plan When OAC is Indicated and Patient Has High HAS-BLED Index
Modify bleeding risk factors. Intensify surveillance for bleeding and for triggers that cause bleeding. Consider “renal dose” for NOAC, especially in the presence of some renal dysfunction or frailty or age ≥ 80 years. Monitor renal function with vigilance. Prescribe PPI when indicated.

Stroke and Bleeding in Atrial Fibrillation with Chronic Kidney Disease
Danish Registry 146,251 patients were discharged with nonvalvular atrial fibrillation ( ) 13,879 were excluded 127,884 (96.6%) did not have renal disease 3587 (2.7%) received a diagnosis of non-end-stage chronic kidney disease 901 (0.7%) underwent renal-replacement therapy 4538 (3.5%) received a diagnosis of non-end-stage chronic kidney disease 228 (6.4%) underwent renal-replacement therapy during follow-up Olesen JB. NEJM 2012; 367:

Stroke Risk and Renal Disease
Aspirin does not prevent stroke Characteristic Total Population (n = 132,372) No Renal Disease (n = 127,884) Hazard Ratio (95% CI) P Value All participants 1.00 Antithrombotic Therapy None Warfarin 0.59 ( ) < 0.001 1.10 ( ) Aspirin 1.11 ( ) 1.10( ) Warfarin and aspirin 0.70( ) 0.69( ) Olesen JB. NEJM 2012; 367:

Bleeding Risk and Renal Disease
Aspirin and warfarin/aspirin increase bleeding Characteristic Total Population (n = 132,372) No Renal Disease (n = 127,884) Hazard Ratio (95% CI) P Value All participants 1.00 Antithrombotic Therapy None Warfarin 1.28( ) < 0.001 Aspirin 1.21( ) Warfarin and aspirin 2.15( ) 2.18( ) Olesen JB. NEJM 2012; 367:

Megatrend: Recognizing Overuse of Aspirin
Role of aspirin in the setting of SPAF is called into question. Aspirin is often prescribed for “CAD prevention,” without a clear evidence-based rationale, thus increasing bleeding risk when combined with OACs used for SPAF. Evaluate necessity for ASA.

Dosing Options for Renal Dysfunction
Consider also for age ≥80, weight ≤ 60 KG (frailty) Dabigatran 75 mg bid (USA) 50% Dabigatran 110 mg bid (non-USA) Rivaroxaban 15 mg daily 25% Apixaban 2.5 mg bid 50% ESC 2012

Dilemmas in “Under-Anticoagulation”
Anticoagulants clearly prevent stroke in AF patients but are markedly underutilized Failure to prophylax in the setting of non-valvular AF is characterized by fear of: Bleeding Older age Renal dysfunction Lack of medication adherence

Dilemmas: NOACs vs Warfarin
By most metrics, NOACs are the “best option” for SPAF (ESC 2012 Update for AF) Failure to prescribe NOACs is characterized by: Lack of familiarity Lack of reversal agent Inability to measure NOAC level Inertia, fear of change, “preapprovals”

NOACs vs Warfarin— A View From 30,000 Feet
NOACs generally more effective than warfarin for stroke prevention NOACs are generally safer (less bleeding, with some exceptions, but NOACs uniformly cause less intracranial hemorrhage, most devastating and mortality-inducing bleeding complication of OAC) NOACs, overall, reduce mortality NOACs are more convenient for patient/clinician

New Anticoagulant Therapies Compared to Warfarin: All-cause Mortality
Connolly S et al NEJM 2009; Patel M et al NEJM 2011; Granger CB et al NEJM 2011

Limitations of Novel Agents are Exaggerated
No antidote when bleeding Best treatment is prevention Warfarin has no great antidote Time is a great antidote No antidote for urgent procedures RELY analysis 2012 shows no increase in bleeding in this setting Lack standard measurement Do not need one Time since last dose is helpful Dependence on renal function Rivaroxaban, apixaban modest renal effect Cost Highly cost effective in analyses

Deciphering the Pharmaco-economic Maze “Cost-effectiveness”
Cost: Must take into account the costs of caring long-term for debilitated thromboembolic stroke patients and the costs of caring for intracranial hemorrhage when doing a “cost-effectiveness” analysis of NOACs vs warfarin. However, we continue to have mostly “silo budgeting.”

Cost of Dabigatran vs Warfarin
Dabigatran retail: $240/month Warfarin discount retail: $4/month Will the high price of dabigatran cause poor medication adherence? “The cost of medical care looms as the single largest threat to the US economy.” Avorn J. Circulation 2011: 123: 129

Prevent > 50% AF Cases by Modifying Cardiovascular Risk Factors
N = 14,598 middle-aged subjects Over 17 years, 1520 incident cases of AF in the Atherosclerosis Risk in Communities (ARIC) Study 56% of cases explained by elevated CV risk factors, especially hypertension, obesity, diabetes, and smoking Circulation 2011; 123:

Guidelines for “Bridging”with Dabigatran (RE-LY)
Renal Function Impairment (CrCL mL/min) Estimated Half-life, h (Range) Stopping Dabigatran Before Surgery/Procedure High Risk for Bleeding Standard Risk for Bleeding Mild: > 50 to 80 15 (12-18) 2-3d* 24 h (2 doses) Moderate: > 30 to < 50 18 (18-24) 4 d At least 2 d (48 h) Severe: < 30 27 (> 24) > 5d 2-4 d Healey JS. Circulation 2012; 126:

Interrupting Dabigatran and Warfarin RE-LY
1 of 4 patients underwent peri-procedural anticoagulant interruption Stroke rate: 0.5%; major bleeding rate: %, 7 days pre- to 30 days post Dabigatran was withheld an average of 2 days, whereas warfarin was withheld an average of 5 days preop Healey JS. Circulation 2012; 126:

Medication Adherence Failure
Failing to fill or refill a prescription Omitting doses Overdosing Prematurely discontinuing medication Taking someone else’s medication Taking a medication with prohibited foods Taking outdated medications

Questions Regarding the New Non-Monitored, Oral Anticoagulants
Do they represent a significant improvement for patients who have been taking warfarin with consistently therapeutic INR values for months or years? They may. Will the elimination of regular INR measurement reduce or improve compliance? How will their cost compare to current costs (including INR monitoring, dose adjustment, etc)?

Selecting Patients for Non-Monitored Oral Anticoagulation (NOAC)
Clinical Dilemma #1 Which patients are the best candidates for non- monitored oral anticoagulation? Treatment-naive and de novo patients? And/or patients on warfarin? Established patients on warfarin doing "well?" Established on warfarin, doing well, but at high risk for bleeding? High HAS-BLED? Previous stroke? On warfarin, and doing "reasonably" well, but requiring multiple interventions to keep INR/TTR controlled? Patients on warfarin who are doing well, but only with intensive monitoring?

Transitioning Patients from Warfarin to a Non-Monitored Oral Anticoagulant
Clinical Dilemma #2 How do we actually transition patients from warfarin to dabigatran, rivaroxaban, apixaban, or other agents? What INR do we wait for? What are the renal issues that need to be considered for each agent?

How do I Convert a Patient from Warfarin to Dabigatran and Vice Versa?
Warfarin to dabigatran: Discontinue warfarin and start dabigatran when the international normalized ratio (INR) is below 2.0. Dabigatran to warfarin: CrCl > 50 mL/min, start warfarin 3 days before discontinuing dabigatran. CrCl mL/min, start warfarin 2 days before discontinuing dabigatran. CrCl mL/min, start warfarin 1 day before discontinuing dabigatran. CrCl < 15 mL/min, no recommendations can be made. Because dabigatran can contribute to an elevated INR, the INR will better reflect warfarin’s effect after dabigatran has been stopped for at least 2 days. Dabigatran prescribing information 2010

Managing Patients Who Are on Non-Monitored Oral Anticoagulation and Have Had a Stroke
Clinical Dilemma #3 How do we approach a patient who has had an embolic stroke while on a non-monitored oral anticoagulant? Should we switch? Why? Why not? To what agent would we switch? From one non- monitored oral anticoagulant to another? To warfarin? If we switch to warfarin, at what INR? What if the patient is at risk for hemorrhage?

What Should I Do if my Patient Has an Ischemic Stroke on Dabigatran?
Consider: Is the patient compliant with dabigatran? Check aPTT or thrombin time– if dose taken within past 12 hours, these levels should be prolonged. If the stroke is cryptogenic, consider adding antiplatelet therapy. Convert dabigatran to warfarin (target INR 2-3 or higher?). Switch to another NOAC?

Aligning Specific Patient and Risk Profiles with Specific NOACS: Apixaban, Dabigatran, Rivaroxaban
Clinical Dilemma #4 Based on AVERROES, RE-LY, ARISTOTLE, and ROCKET- AF, should we be aligning specific, non-monitored oral anticoagulants with specific risk groups? Should the warfarin-intolerant/ineligible patient be "steered" toward apixaban? The "high-risk" patient be steered toward rivaroxaban? The intermediate-risk patient be "steered" toward apixaban or dabigatran? How do we know whether this kind of alignment is evidence-based, or if it is an artifact of the trial designs?

What Should We Use For Hemorrhage on a Non-Monitored Oral Anticoagulant?
Clinical Dilemma #5 What should be our clinical approach to a patient who has had a hemorrhage on a non-monitored oral anticoagulant? Does it depend on the type of hemorrhage? Other factors? Should we ever consider warfarin in these patients?

Guide to the Management of Bleeding in Patients Taking NOAC
Patients with bleeding on NOAC therapy Mild bleeding Moderate-Severe bleeding Life-threatening bleeding Delay next dose or discontinue treatment as appropriate Mechanical compression Surgical intervention Fluid replacement and hemodynamic support Blood product transfusion Oral charcoal Hemodialysis ? Prothrombin Complex Concentrate? (Circulation 2011; 2011: 124: ) Consideration of rFVIIa or PCC Charcoal filtration ? Prothrombin Complex Concentrate (Circulation 2011; 2011: 124: ) Hankey GJ and Eikelboom JW. Circulation. 2011; 123:

Antithrombotic Agents A New Era of “Alignment and Flexibility?”
Dabigatran: Superior SPAF compared with warfarin Rivaroxaban: Once-daily administration and less dependence on kidneys for metabolism; non-inferior in ITT analysis in very high-risk patient population Apixaban: Safety equivalent to aspirin in AVERROES, and superior stroke prevention in warfarin intolerant or ineligible Apixaban: Superior SPAF, less major bleeding, lower all-cause mortality.

SPAF Clinical Trial Programs Translational Dilemmas and Cautionary Notes
Do clinical trial results apply to “real world” medicine in busy clinical practices with brief office visits and minimal telephone follow-up? Are patients who participate in clinical trials healthier/more motivated than most? Does this make favorable results more likely in both the new drug and the comparison groups? Do the costs of a “copay” affect patient decisions to fill a prescription for a potentially more effective, safer drug vs a less expensive but less effective alternative? 144

Unresolved Issues with NOACs
No established methods of monitoring No known therapeutic ranges Lack of a proven antidote Uncertain management of bleeding Long term safety: to be determined No head-to-head comparisons of new agents

Properties of Ideal Anticoagulant Do NOACS Fit the Bill?
Proven efficacy √ Low bleeding risk √ Fixed dosing √ Good oral bioavailability √ No routine monitoring needed √ Reversibility: ?PCC, FEIBA, rVIIa Rapid onset of action √ Few drug or food interactions √

NOACs: Advancing Opportunities to Connect Guidelines with Practice
Lower stroke rates Fewer major and fatal bleeds, especially ICH Lower dose options for chronic kidney disease, elderly, and the “frail” or “underweight” patient Use in conjunction with RF reduction: treat congestive heart failure, diabetes, hypertension, obesity Facilitate periprocedural treatment Should improve medication adherence—no injections/ no routine lab blood testing

So What Now? Trials in Translation
Advances in the Science and Medicine of Stroke Prevention in AF So What Now? Trials in Translation Applying Evidence-Driven Strategies to AF Patients at the Front Lines of Clinical Practice Audience Response System-Based Interactions Samuel Z. Goldhaber, MD Program Chairman Director, VTE Research Group Cardiovascular Division Brigham and Women’s Hospital Professor of Medicine Harvard Medical School

Atrial Fibrillation Case Study #1
A 71-year-old white female with a history of chronic, non-valvular AF, controlled hypertension, and a history of mild congestive heart failure has been evaluated by a cardiologist and found to be a suitable candidate for warfarin therapy. Due to logistical barriers that make monitoring difficult and dietary variations, the patient has had difficulty controlling her INR. Wide fluctuation in her INR has made her question continued warfarin therapy.

Audience Response System (ARS) Question
Because of her high risk for embolic stroke, her cardiologist is considering alternative forms of thromboprophylaxis for SPAF. She has a HAS-BLED SCORE of 2. Which of the following should we consider? Are any of these strategies optimal in this patient type? Keep patient on warfarin Replace warfarin with aspirin Replace warfarin with aspirin + clopidogrel Replace warfarin with a non-monitored oral anticoagulant

An 81-year-old white female with a history of chronic, non-valvular AF, a history of a previous ischemic stroke, and a history of mild congestive heart failure has been on a combination of clopidogrel and aspirin therapy because she was found to be intolerant of warfarin. She is on a proton pump blocker, an ACE inhibitor, a diuretic, and digoxin. She is admitted to the hospital for a GI bleed, and is found to have a hematocrit of 29 and a hemoglobin of 9.8. The aspirin and clopidogrel are discontinued.

The patient stabilizes, and the cardiologist is consulted to determine the subsequent course of her antithrombotic treatment. She has a HAS-BLED score of 3. It is your opinion that: Because of the documented GI bleed, the patient should not be treated with antithrombotic agents, because the risk of bleeding outweighs the risk of stroke and its complications. Because of the patient's risk profile, there should be an attempt to provide thromboprophylaxis against embolic stroke.

The cardiologist has determined that this patient requires antithrombotic management for stroke prevention. At this point you would most likely: Try the patient on warfarin again Try to re-introduce clopidogrel and aspirin Treat the patient with aspirin alone Introduce a non-monitored oral anticoagulant to the patient's regimen.

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 and has a history of falls. He has a CHADS-VASc score of 3, and a HAS— BLED score of 2. Which regimen would you prescribe for prophylaxis against thromboembolism?

Which regimen would you prescribe for prophylaxis against thromboembolism? Warfarin (INR ) Warfarin (INR ) Aspirin 81 mg daily Aspirin 81 mg + clopidogrel 75 mg daily An oral Factor Xa or direct thrombin inhibitor

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…”

A 71-year-old man with AF, heart failure, and a prior history of stroke presents with unstable angina and proceeds to cardiac catheterization where a culprit lesion is identified. Optimal management includes: Placement of a drug-eluting stent with plan to continue anticoagulation in addition to 1 year of dual antiplatelet therapy Placement of a drug-eluting stent with 1 year of dual antiplatelet therapy alone Placement of a bare metal stent with plan to continue anticoagulation in addition to 1 month of dual antiplatelet therapy Placement of a bare metal stent with 1 month of dual antiplatelet therapy alone

A 67-year-old female with a history of mitral stenosis with subsequent mechanical mitral valve replacement has AF. Which of the following anticoagulants can be used for stroke prevention in this patient? Warfarin Dabigatran Apixaban Rivaroxaban All of the above

Knowledge Assessment Question
Atrial Fibrillation Knowledge Assessment Question The major potential benefits of the new non-monitored oral anticoagulants include: Rapid therapeutic anticoagulant effect Greater safety with regards to intracranial hemorrhage Proven reversal agent All of the above Both 1 and 2

An 82-year-old man with AF has had several admissions over the past 6 months for heart failure complicated by worsening renal function. His creatinine clearance is currently 20 mL/min but frequently fluctuates to mL/min. He has a HAS-BLED score of 3. The best anticoagulant regimen for stroke prevention is: Dabigatran 150 mg twice daily Dabigatran 75 mg twice daily Warfarin titrated to goal INR 2-3 Rivaroxaban 20 mg once daily Rivaroxaban 15 mg once daily

A 79-year-old woman with a CHADS-VASc score of 2 who has been on warfarin for the past 2 years returns to clinic for routine follow-up. Her INR control has been excellent and she has never experienced a stroke or had significant bleeding. Her HAS-BLED score is 2. Her complaints today are thinning hair, cold intolerance, and fatigue. Her laboratory work is normal including a TSH.

Which of her symptoms could be due to warfarin? Thinning hair Cold intolerance Fatigue Both 1 and 2 All of the above

A 69-year-old woman with AF and CHADS2 score of 4 has a creatinine clearance that is stable at 40 mL/min. Which of the following anticoagulation regimens are suitable for her? Dabigatran 150 mg twice daily Dabigatran 75 mg twice daily Rivaroxaban 20 mg once daily Rivaroxaban 15 mg once daily Both 1 and 4

What would her options be if her creatinine clearance was stable at 25 mL/min? Dabigatran 75 mg twice daily Rivaroxaban 15 mg once daily Only warfarin can be used in patients with creatinine clearance < 30 mL/min Both 1 and 2

A 74-year-old man with AF on dabigatran is involved in a motor vehicle accident and needs emergency surgery. It is unclear if he is taking this medication but the surgeon is concerned about operating on him if he is fully anticoagulated.

Which of the following lab tests, if normal, would reassure the team that the patient is not anticoagulated? INR (international normalized ratio) aPTT (activated partial thromboplastin time) PT (prothrombin time) Bleeding time

A 60-year-old man with AF has been on warfarin but it has been very difficult to control his INR. You have decided to switch to dabigatran. Which of the following is true regarding transitioning a patient from warfarin to dagibatran? Start dabigatran when his INR < 3 Start dabigatran when his INR < 2 Start dabigatran 24 hours after his last dose of warfarin

What if you decided to switch the patient to rivaroxaban? Start rivaroxaban when his INR < 3 Start rivaroxaban when his INR < 2 Start rivaroxaban 24 hours after his last dose of warfarin

A 78-year-old female with AF, systolic heart failure, hypertension, diabetes, and a history of significant GI bleeding has been on warfarin for many years but has had a difficult time controlling her INR with frequent supertherapeutic values despite intensive monitoring and titration of her warfarin dose. Her HAS-BLED score is 3. The best treatment option for her is: No antithrombotic therapy Discontinue warfarin and start aspirin Discontinue warfarin and start dabigatran Discontinue warfarin and start rivaroxaban Discontinue warfarin and start apixaban

A 76-year-old woman with heart failure, hypertension, diabetes, and declining renal function (creatinine clearance 35 mL/min) has an embolic stroke due to newly diagnosed AF. She refuses to take warfarin. What is the best validated antithrombotic regimen in this particular patient? Aspirin Aspirin and clopidogrel Dabigatran Apixaban Rivaroxaban

A 68-year-old man with a mechanical mitral valve develops AF. The best anticoagulant option for him is: Warfarin Dabigatran Apixaban Rivaroxaban Aspirin

A 76-year-old man with heart failure and hypertension undergoes successful catheter ablation for symptomatic AF. Which of the following is true regarding his anticoagulation management? He no longer requires anticoagulation now that he is in sinus rhythm Patient should be on both aspirin and an anticoagulant Patient should be on an anticoagulant alone Aspirin and clopidogrel together is as effective as anticoagulation in these patients

The cardiologist has determined that this patient requires antithrombotic management for stroke prevention. At this point you would most likely: Try the patient on warfarin again Treat the patient with aspirin alone Introduce the non-monitored oral anticoagulant, apixaban, into the patient's regimen Introduce dabigatran into the patient’s regimen Introduce rivaroxaban into the patient’s regimen

A 75-year-old male with a history of chronic, non-valvular AF, diabetic renal disease, previous history of ischemic stroke, history of mild HF, and controlled hypertension has been on warfarin therapy. The HAS-BLED score is 4. For the past 6 months, despite repeated visits for monitoring and warfarin dose adjustment, his INR has varied between 1.5 and 4.3. His estimated GFR is 30 mL/min.

At this point you would: Continue to try to stabilize his INR on warfarin Change to aspirin alone Introduce the non-monitored oral anticoagulant rivaroxaban into the patient's regimen Introduce the non-monitored oral anticoagulant apixaban into the patient's regimen Introduce the non-monitored oral anticoagulant dabigatran into the patient's regimen

An 82-year-old man with hypertension, diabetes, mild congestive heart failure, and previous ischemic stroke, is diagnosed with atrial fibrillation. He has not been taking any anticoagulants.

Which regimen would you initiate for prophylaxis against stroke? Warfarin (INR ) Aspirin 81 mg + clopidogrel 75 mg daily Rivaroxaban Apixaban Dabigatran

An 82-year-old man with hypertension, diabetes, mild CHF, and a previous ischemic stroke has permanent atrial fibrillation. He has been on warfarin for about 5 years and his INR has remained constant between 2.3 and 2.7. He has a HAS-BLED score of 3.

Which regimen would you continue or switch to for prophylaxis against stroke? Continue current therapy with warfarin Aspirin 81 mg + clopidogrel 75 mg daily Rivaroxaban Apixaban Dabigatran

A 75-year-old man with a CHADS2 of 3 has been taking dabigatran 150 mg for SPAF. His estimated GFR was 55 mL/min 6 months ago and is now 40 mL/min. I would now: Continue to monitor patient Switch patient to 75 mg dabigatran twice per day Switch patient to warfarin Switch patient to rivaroxaban Start ASA and clopidogrel

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