Presentation is loading. Please wait.

Presentation is loading. Please wait.

Stroke Prevention in Atrial Fibrillation Evidence- and Guideline-Based Strategies for Optimizing Clinical Outcomes and Anticoagulation-Based Management.

Similar presentations


Presentation on theme: "Stroke Prevention in Atrial Fibrillation Evidence- and Guideline-Based Strategies for Optimizing Clinical Outcomes and Anticoagulation-Based Management."— Presentation transcript:

1

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

3 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. Welcome and Program Overview

4 Program Faculty PROGRAM CHAIRMAN SAMUEL Z. GOLDHABER, MD Cardiovascular Division Brigham and Womens Hospital Professor of Medicine Harvard Medical School CHRISTIAN T. RUFF, MD, MPH TIMI Study Group Brigham and Womens Hospital Harvard Medical School Boston, MA ELAINE M. HYLEK, MD, MPH Professor of Medicine Department of Medicine Boston University Medical Center Boston, Massachusetts

5 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

6 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 Womens Hospital Professor of Medicine Harvard Medical School New Paradigms in the Science and Medicine of Stroke Prevention for Atrial Fibrillation

7 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

8 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

9 Normal sinus rhythm Atrial fibrillation The ECG of Atrial Fibrillation

10 ParoxysmalSelf-TerminatingPersistent Lasts > 7 Days Permanent Cardioversion Failed or Not Attempted Normal Sinus Rhythm Atrial Fibrillation The 3 Ps and Natural History of Atrial Fibrillation Paroxysmal AF is as likely to cause stroke as persistent or permanent AF

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

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

13 Year Projected Number of People with AF (millions) Miyakasa Y, et al. Circulation. 2006; 114: Atrial Fibrillation: An Epidemic 16 million US Prevalence 1 in 4 lifetime risk in men and women 40 years old

14 Age, years Prevalence, percent Relationship Between Atrial Fibrillation and Age Go AS, et al. JAMA. 2001; 285:

15 Chimowitz. Stroke 1993; 24: 1015 Zabalgoitia. J Am Coll Cardiol 1998; 31: 1622 Atrial Fibrillation Causes Stroke Left Atrial Appendage Thrombus

16 Stroke and Atrial Fibrillation Burden Wolf PA, et al. Stroke 1991; 22: % AF prevalence Strokes attributable to AF Age Range (years) –5960–69 70–79 80–89 Framingham Approximately 5-fold increased risk of stroke Approximately 5-fold increased risk of stroke Quantify stroke risk: CHADS 2 / CHA 2 DS 2 -VASc Quantify stroke risk: CHADS 2 / CHA 2 DS 2 -VASc AF strokes have worse outcomes AF strokes have worse outcomes Costly health care ~ $16 billion/year Costly health care ~ $16 billion/year

17 Ischemic Strokes in Atrial Fibrillation More Likely to be Severely Disabling Framingham Heart Study Lin HJ, et al. Stroke. 1996;27:

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

19 ESC 2012 AF Update Guidelines

20 Anticoagulation in Atrial Fibrillation Effects on Stroke Risk Reduction Anticoagulation in Atrial Fibrillation Effects on Stroke Risk Reduction Warfarin betterControl better AFASAK SPAF BAATAF CAFA SPINAF EAFT 100% 50% 0 -50% -100% Aggregate RRR of stroke: 62% RRR of stroke: 62% RRR All-cause mortality: 26% RRR All-cause mortality: 26% RRR, relative risk reduction. Hart RG, et al. Ann Intern Med. 1999;131:

21 ESC 2012 Update Guidelines HAS-BLED for Evaluation of Bleeding Risk Clinical Characteristic Points H ypertension (systolic BP > 160 mm Hg) 1 A bnormal renal or liver function S troke 1 B leeding 1 L abile INRs 1 E lderly (age > 65 years) 1 D rugs or alcohol Maximum score 9 Pisters R, et al. Chest. 2010;138:

22 Swedish AF Cohort; Circulation 2011; 125:

23 Known Problems With Warfarin 1)Delayed onset/offset 2)Unpredictable dose response 3)Narrow therapeutic index 4)Drug-drug, drug-food interactions 5)Problematic monitoring 6)High bleeding rate 7)Slow reversibility

24 1)Established efficacy 2)Low cost ($4/month; $10/3 mos) 3)Long track record (1954) 4)Centralized anticoagulation clinics that maintain TTRs > 60% 5)Rapid, turnaround genetic testing 6)Point-of-care self-testing 7)INR testing q 12 weeks if stable Warfarin Will Likely Survive: Why? CoumaGen-II. Circ 2012; March 19 ACCP Chest Guidelines 2012

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

26 Comparison Overview of New Anticoagulants with Warfarin FeaturesWarfarin New Agents OnsetSlowRapid DosingVariableFixed Food effectYesNo Drug interactionsManyFew MonitoringYesNo Half-lifeLongShort AntidoteYesNo

27 Sites of Action in Coagulation System Novel Factor Xa and DT Inhibitors Hankey GJ and Eikelboom JW. Circulation 2011;123: RivaroxabanApixabanEdoxabanBetrixaban Xa IIa TF/VIIa XIX IXa VIIIa Va II FibrinFibrinogen Dabigatran Initiation Propagation Fibrin formation Steps in Coagulation Pathway Drugs

28 Novel Oral Anticoagulants Important Comparative Features Circulation 2010;121:1523

29 Comparison of Phase 3 SPAF Trials for NOACs: A Robust Trial Base RivaroxabanApixaban Edoxaban 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 Dabigatran Novel Anticoagulants FIIa Inhibitor Fxa Inhibitor

30 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 ESC 2012 AF Update Guidelines ACCP 2012 Guidelines ACCP 2012 Guidelines Canadian AF Guidelines Canadian AF Guidelines Best Options for AnticoagulationBest Options for Anticoagulation The Consensus is Shifting

31 ESC 2012 UPDATE GUIDELINES For ATRIAL FIBRILLATION

32 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. 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. Information from registries complements clinical trial data. Registries can highlight the disconnect between evidence/guidelines and clinical practice. Registries can highlight the disconnect between evidence/guidelines and clinical practice. The Rationale for AF Registries

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

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

35 OAC, oral anticoagulant Nieuwlaat et al. Eur Heart J 2006; Gage et al. JAMA 2001 CHADS 2 score OAC therapy (%) AF patients in 35 countries: 2003–2004 Modest Use of Vitamin K Antagonists Even in High-Risk Patients European Heart Survey

36 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. 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. 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. Heightened awareness of the disconnect between guidelines/evidence and suboptimal intervention for SPAF. Anticoagulation is necessary as a first step.

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

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

39 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 5 of 5 studies 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 Not significant * Significant in a subgroup of participants undergoing echocardiography in trials included AFI pooled analysis Hart RG et al. Neurology 2007; 69: 546.

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

41 Risk Stratification in Atrial Fibrillation Established Stroke Risk Factors High-Risk Factors Mitral stenosis Mitral stenosis Prosthetic heart valve Prosthetic heart valve History of stroke or TIA History of stroke or TIA Singer DE, et al. Chest 2004;126:429S. Fang MC, et al. Circulation 2005; 112: Moderate-Risk Factors Age > 75 years Age > 75 years Hypertension Hypertension Diabetes mellitus Diabetes mellitus Heart failure or LV function Heart failure or LV function Less Validated Risk Factors Age 65–75 years Coronary artery disease Coronary artery disease Female gender Female gender Thyrotoxicosis Thyrotoxicosis

42 The CHADS 2 Score Stroke Risk Threshold Favoring Anticoagulation Van Walraven C, et al. Arch Intern Med 2003; 163:936. Go A, et al. JAMA 2003; 290: Gage BF, et al. Circulation 2004; 110: Risk of Stroke (%/year) Score(points) 3%/year Approximate Risk Threshold for Anticoagulation

43 The CHADS 2 Score Stroke Risk Score for Atrial Fibrillation C ongestive Heart failure 1 32 H ypertension 1 65 A ge > 75 years 1 28 D iabetes mellitus 1 18 S troke or TIA 2 10 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). Prevalence (%)* Score (points)

44 Goto S, et al. Am Heart J 2008; 156: 855. CV Event Rates in Patients with Atrial Fibrillation Related to CHADS 2 Score REACH Registry

45 The CHA 2 DS 2 -VASc Score Stroke Risk Score for Atrial Fibrillation C ongestive heart failure or LVEF < 35% 1 H ypertension 1 A ge > 75 years 2 D iabetes mellitus 1 S troke/TIA/systemic embolism 2 V ascular Disease (MI/PAD/Aortic plaque) 1 A ge years 1 S ex c ategory (female) 1 Moderate-High risk > 2 Low risk 0-1 Lip GYH, Halperin JL. Am J Med 2010; 123: 484. Weight (points)

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

47 Published Bleeding Risk Scores Patients on Oral Vitamin K Antagonist Anticoagulant Therapy Tay, Lane & Lip. Thromb Haemost 2008; 100: 955. LowModerateHigh Kuijer et al. Arch Intern Med 1999;159: > 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: years old; GI bleed within 2 weeks; prior stroke; comorbidities (recent MI, Hct 1.5 mg/dL) ;1 point for each condition; 0 if absent 65 years old; GI bleed within 2 weeks; prior stroke; comorbidities (recent MI, Hct 1.5 mg/dL) ;1 point for each condition; 0 if absent Gage et al. Am Heart J 2006;151:713. < 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: > 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

48 Advances in the Science and Medicine of SPAF

49 Importance of the HAS-BLED Score H ypertension (> 160 mm Hg systolic) 1 A bnormal renal or hepatic function 1-2 S troke 1 B leeding history or anemia 1 L abile INR (TTR < 60%) 1 E lderly (age > 75 years) 1 D rugs (antiplatelet, NSAID) or alcohol 1-2 High risk (> 4%/year) > 4 Moderate risk(2-4%/year) 2-3 Low risk(< 2%.year) 0-1 Pisters R, et al. Chest 2010; 138: Lip GYH, et al. J Am Coll Cardiol 2010; 57: 173. Weight (points) Risk Score for Predicting Bleeding in Anticoagulated Patients with Atrial Fibrillation

50 Canadian Cardiovascular Society AF Guidelines 2012 Update Assess Thromboembolic Risk (CHADS 2 ) CHADS 2 = 0 CHADS 2 = 1 CHADS 2 > 2 No anti- thrombotic ASAOAC*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 Increasing stroke risk

51 All patients with atrial fibrillation or atrial flutter (paroxysmal, persistent, or permanent), should be stratified using a predictive index for stroke (eg, CHADS 2 ) 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) All patients with atrial fibrillation or atrial flutter (paroxysmal, persistent, or permanent), should be stratified using a predictive index for stroke (eg, CHADS 2 ) 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. When oral anticoagulation therapy is indicated, most patients should receive dabigatran, rivaroxaban, or apixaban* in preference to warfarin. (Conditional recommendation. high-quality evidence). (Conditional recommendation. high-quality evidence). * Once approved by Health Canada. * Once approved by Health Canada. Canadian Cardiovascular Society AF Guidelines 2012 Update

52 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: Europace Aug 24 ESC 2012 AF Update Guidelines

53 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: Europace Aug 24 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 ESC 2012 Guidelines: Identifying Truly Low-Risk Patients with AF

54 CHA 2 DS 2 -VASc vs. CHADS 2 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 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 CHA 2 DS 2 -VASc score are less well validated than those of the CHADS 2 score. The components of the CHA 2 DS 2 -VASc score are less well validated than those of the CHADS 2 score. The C-statistic used to validate the CHA 2 DS 2 -VASc score is only marginally superior to those of other schema. The C-statistic used to validate the CHA 2 DS 2 -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. There is no consensus about how to combine stroke risk and bleeding risk scores into a composite instrument.

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

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

57 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 Womens Hospital Harvard Medical School Boston, MA New Paradigms in the Science and Medicine of Heart Disease

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

59 PropertiesBenefit 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 Properties of an Ideal Anticoagulant

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

61 Ruff CR and Giugliano RP. Hot Topics in Cardiology 2010;4:7-14 Ericksson BI, et al. Clin Pharmacokinet 2009;48:1-22 DabigatranApixabanRivaroxabanEdoxaban Target IIa (thrombin) XaXaXa Hrs to Cmax CYP metabolismNone15%32%NR Bioavailability7%66%80% > 45% TransportersP-gpP-gpP-gp/BCRPP-gp Protein binding35%87%>90%55% Half-life12-14h8-15h9-13h8-10h Renal elimination80%25%33%35% Linear PKYesYesNoYes BCRP = breast cancer resistance protein; CYP = cytochrome P450; NR = not reported; P-gp = P-glycoprotein Comparative Pharmacokinetics/ Pharmacodynamics of Novel Agents

62 The RE-LY Trial: Dabigatran

63 RE-LY Atrial fibrillation 1 Risk Factor Absence of contra-indications 951 centers in 44 countries R Warfarin (INR ) N = 6022 Dabigatran Etexilate 110 mg bid N = 6015 Dabigatran Etexilate 150 mg bid N = 6076 PROBE=Prospective Randomized Open Trial with Blinded Adjudication of Events 1 0 efficacy outcome = stroke or systemic embolism 1 0 safety outcome = major bleeding Non-inferiority margin 1.46 open Blinded

64 Dabigatran 110 vs Warfarin Dabigatran 150 vs Warfarin Non-inferiority P-value < Superiority P-value 0.34 < Margin = 1.46 HR (95% CI) RE-LY Efficacy (Dabigatran) Stroke/Systemic Embolic Event Connolly, et al. N Engl J Med 2009;361:

65 Dabigatran 110 mg Dabigatran 150 mg Stroke/SEE Ischemic Stroke Hemorrhagic Stroke 0.91 ( ) 0.66 ( ) 1.11 ( ) 0.76 ( ) 0.31 ( ) 0.26 ( ) Dabigatran BetterWarfarin Better RE-LY Efficacy (Dabigatran) Connolly, et al. N Engl J Med 2009;361:

66 Major Bleed ICH GI Bleed 0.80 ( ) 0.93 ( ) 0.31 ( ) 0.40 ( ) 1.10 ( ) 1.50 ( ) MI 1.29 ( ) 1.27 ( ) Dabigatran BetterWarfarin Better RE-LY Safety Results (Dabigatran) Connolly, et al. N Engl J Med 2009;361: Dabigatran 110 mg Dabigatran 150 mg

67 D D WARF CHADS 2 P = DabigatranbetterWarfarinbetter Annualized Rate Stroke/SEE (%) P = Dabigatran better Warfarin better RE-LY Efficacy Stratified by CHADS 2 Oldgren J, et al. ACC 2010 D110 mg D150 mg

68 RE-LY Efficacy Stratified by Prior Vitamin K Anatagonist Ezekowitz MD, et al. Circulation 2010;122:

69 (N = 647) RE-LY Cardioversion (Dabigatran) (N = 672)(N = 664) Nagarakanti R, et al. Circulation 2011;123:

70 Prevention of stroke in AF Prevention of stroke in AF Available in 75 mg and 150 mg (twice daily) Available in 75 mg and 150 mg (twice daily) Dose of 75 mg if CrCl mL/min Dose of 75 mg if CrCl mL/min Data in favor of 110 mg weresuggestive, but not entirely convincing Data in favor of 110 mg weresuggestive, but not entirely convincing Dabigatran Approval

71 ROCKET AF: Rivaroxaban

72 Rivaroxaban Warfarin Primary End point: Stroke or non-CNS Systemic Embolism Statistics : non-inferiority, > 95% power, 2.3% warfarin event rate INR target ( inclusive) 20 mg daily 15 mg for Cr Cl Atrial Fibrillation Randomize Double blind / Double Dummy (n = 14,266) Risk Factors CHF CHF Hypertension Hypertension Age 75 Age 75 Diabetes DiabetesOR Stroke, TIA or Systemic embolus Stroke, TIA or Systemic embolus At least 2 required Monthly Monitoring and adherence to standard of care guidelines

73 RivaroxabanWarfarin Event Rate HR (95% CI) P-value On Treatment N = 14, (0.65, 0.95) ITT N = 14, (0.74, 1.03) Rivaroxabanbetter 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 Efficacy Stroke/Systemic Embolic Event

74 ROCKET AF Key Secondary Efficacy EventRivaroxaban(%/yr)Warfarin(%/yr) Hazard Ratio (95% CI) P- value Ischemic Stroke ( ) Hemorrhagic Stroke ( ) MI ( ) Total Mortality ( ) Vascular Mortality ( ) Patel, et al. N Engl J Med 2011; 365(10);

75 ROCKET AF Safety (Rivaroxaban) EventRivaroxaban(%/yr)Warfarin(%/yr) Hazard Ratio (95% CI) P- value Major and Clinically Relevant Bleed ( )0.44 Major Bleed ( )0.58 Fatal Bleed ( )0.003 ICH ( )0.02 Patel, et al. N Engl J Med 2011; 365(10);

76 ROCKET AF Efficacy (Rivaroxaban) Moderate Renal Impairment Fox KA, et al. Eur Heart J 2011;32(19):

77 ROCKET AF Safety Moderate Renal Impairment Fox KA, et al. Eur Heart J 2011;32(19):

78 Prevention of stroke in AF Prevention of stroke in AF Dose 20 mg if CrCl > 50 mL/min Dose 20 mg if CrCl > 50 mL/min Dose of 15 mg if CrCl mL/min Dose of 15 mg if CrCl mL/min Rivaroxaban Approval

79 AVERROES

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

81 AVERROES: Apixaban Stroke or Systemic Embolic Event Major Bleeding HR 0.45 ( ) HR 1.13 ( ) Connolly SJ, et al. N Engl J Med 2011 (epub) Aspirin Apixaban P < Aspirin Apixaban P <

82 ARISTOTLE: Apixaban

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

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

85 ARISTOTLE Efficacy Outcomes Granger CB, et al. NEJM 2011; 365: Outcome Apixaban (N = 9120) Warfarin (N = 9081) HR (95% CI) P Value Event Rate (%/yr) (%/yr) Stroke or systemic embolism* (0.66, 0.95) Stroke (0.65, 0.95) Ischemic or uncertain (0.74, 1.13) 0.42 Hemorrhagic (0.35, 0.75) < Systemic embolism (SE) (0.44, 1.75) 0.70 All-cause death* (0.80, 0.998) Stroke, SE, or all-cause death (0.81, 0.98) Myocardial infarction (0.66, 1.17) 0.37

86 ARISTOTLE Safety End Points EventApixaban(%/yr)Warfarin(%/yr) Hazard Ratio (95% CI) P- value ISTH Major Bleeding ( ) < ICH ( ) < GUSTO Severe ( ) < Gastrointestinal ( ) 0.37 Granger CB, et al. NEJM 2011; 365:

87 ARISTOTLE: Apixaban Renal Function Hohnloser SH, et al. EHJ 2012 (epub August 29) Baseline Cockcroft-Gault eGFR mL/min Annualized Event Rate Stroke or SEEMajor Bleeding

88 Low dose regimen Edoxaban 30 mg qd (n 7000) Active Control Warfarin (n 7000) High dose regimen Edoxaban 60 mg qd (n 7000) AF on Electrical Recording < 12 mo Intended oral A/C CHADS 2 >2 N = 21,105 R Randomization Stratified By 1. CHADS vs Drug Clearance Median Duration of Follow-up 24 Months Primary Objective Edoxaban: Therapeutically as Good as Warfarin DOUBLE BLIND DOUBLE DUMMY SEE = systemic embolic event 1º EP = Stroke or SEE (Noninferiority Boundary HR 1.38) 2º EP = Stroke or SEE or CV mortality Safety EPs = Major Bleeding, Hepatic Function EVENT DRIVEN Ruff CR et al. Am Heart J 2010; 160: Phase III: Protocol Schema

89 89 RE-LY (Dabigatran) ARISTOTLE (Apixaban) ENGAGE AF-TIMI 48* (Edoxaban) ROCKET-AF (Rivaroxaban) # Enrolled18,11318,20121,10514,264 Age (yrs) 72 ± 9 70 [63-76] 72 [64-77] 73 [65-78] Female36%35%38%40% CHADS 2 score 332%30%52%87% VKA naive50%43%41%38% Paroxysmal AF33%15%25%18% Prior stroke/TIA20%19% 18% / 12% 55%** Diabetes23%25%36%40% Prior CHF32%35%56%62% Hypertension79%87%90%91% *Preliminary data **includes prior systemic embolism Connolly SJ et al. N Engl J Med 2009; 361: Patel MR et al. N Engl J Med 2011; 365: Granger CB et al. N Engl J Med 2011; 365: Ruff CR et al. Am Heart J 2010; 160: Pivotal Atrial Fibrillation Trials Baseline Characteristics

90 90 Pivotal Atrial Fibrillation Trials Dose Comparison RE-LYROCKET-AFARISTOTLE ENGAGE AF-TIMI 48 DrugDabigatranRivaroxabanApixabanEdoxaban N18,11314,26618,20121,105 Dose (mg) Frequency 150, 110 bid 20 qd 5 bid 60, 30 qd Initial Dose adj*No mg mg mg mg Dose adj (%) > 25 Dose adj* after randomizationNoNoNoYes DesignPROBE 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: Granger CB et al. N Engl J Med 2011; 365: Ruff CR et al. Am Heart J 2010; 160:635-41

91 Drug Dose (mg) RE-LYROCKET-AFARISTOTLE Dabigatran 110 bid 150 BID Rivaroxaban 20 mg qd Apixaban 5 mg bid Stroke + SEEnon-inferSuperior ITT cohort: non-infer. On Rx cohort: Superior ITT cohort: non-infer. On Rx cohort: SuperiorSuperior ICHSuperiorSuperiorSuperiorSuperior BleedingLowersimilarsimilarLower Mortalitysimilar P = similar Superior: P = Ischemic strokesimilarLowersimilarsimilar Mean TTR64%55%62% Stopped drug21%23%23% WD consent2.3%8.7%1.1% TTR = time in therapeutic range WD consent = withdrawal of consent, no further data available Pivotal Atrial Fibrillation Trials Results to Date

92 92 Efficacy of New Oral Anticoagulants Stroke & SEE Ischemic & Unsp. Stroke Hemorraghic Stroke Miller CS, et al. Am J Cardiol 2012;110(3): Favors NOACs Favors Warfarin 13% 55%

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

94 TTR (%) Apixaban(%/yr)Warfarin(%/yr) HR (95% CI) < ( ) 58.0– ( ) 65.7– ( ) > ( ) P- interaction0.29 Does INR (TTR) Matter? Granger CB, et al. NEJM 2011; 365: ARISTOTLE - Apixaban

95 Does INR Matter? RE-LY (Dabigatran 150 mg) 0.20 < 57.1% –65.5% –72.6% > 72.6% Treatment Group Event Rate / Year Warfarin P-value (interaction) ROCKET AF % % % % ARISTOTLE0.29 < 58.0% –65.7% –72.2 % > 72.2 % Hazard Ratio (95% CI) Study DrugWarfarinFavors Wallentin L, et al. Lancet 2010;376: Patel, et al. NEJM 2011;365(10); Granger CB, et al. NEJM 2011; 365:

96 Warfarin Treatment Interruption Raunsø J, et al. Eur Heart J 2012; 33: All-Cause Death & Thromboembolism

97 Novel Oral Anticoagulant s More Events Off-Drug %/yr P = 0.015P = % 13%

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

99 Granger CB, et al. European Heart Journal 2012; 23 (Supplement): Days after last dose Apixaban to VKA group Warfarin to VKA group n/N%/yearn/N%/year Stroke or systemic embolism 1–3021/ / –21/ / –74/ / –145/ / –3011/ / 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). ARISTOTLE Apixaban Increased Events at End of Trial

100 After the Deluge of SPAF Trials Translating Trials into Practice and Guidelines: 2012 Update Post-Trial, Real World Concerns, Guidelines, and ActionsWhere Have Landmark SPAF Trials Taken Us? How Have Recent Guidelines Made Sense of These Data?

101 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 CHA 2 DS 2 -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 CHA 2 DS 2 -VASc score 2, all three NOACs were superior to warfarin, with a positive net clinical benefit, irrespective of bleeding risk focused update of the ESC Guidelines for the management of atrial fibrillation: Europace Aug 24

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

103 Bleeding Risk with Dabigatran Fact vs Fiction

104 Bleeding Risk with Dabigatran Fact vs Fiction: What Do Regulators Conclude? 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." Disconnect Between Clinical Trials and Post-Marketing Surveillance Bias: A Case Study

105 EMA Report on Dabigatran May 24, 2012 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. What is the updated advice for prescribers?

106 Circulation, Healey et al., 2012 Dabigatran vs. Warfarin: Surgical Bleeding

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

108 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. 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. 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. 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. Conclusions: From Trials and Evidence to Strategy and Practice

109 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 (CHA 2 DS 2 -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. Conclusions

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

111 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

112 Risk Assessment Megatrend CHA 2 DS 2 -VASc has replaced CHADS 2 as the predominant assessment tool to predict stroke risk (ESC 2012 AF Guidelines Update). CHA 2 DS 2 -VASc has replaced CHADS 2 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). 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).

113 Clinical Dilemma and Challenge Stroke Risk Underestimated Paroxysmal AF is difficult to detect. Paroxysmal AF is difficult to detect. 24h Holter is often insufficient. Long-term noninvasive or invasive monitoring may be necessary. 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. 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. The misclassified strokes are really thromboembolic and warrant anticoagulants.

114 Subclinical AF and Risk of Stroke Healey JS, et al. NEJM 2012; 366: Stroke or Systemic Embolism Years Atrial tachyarrhythmia > 6 min 3 months after pacemaker or defibrillator implantation

115 ESC Guidelines: Eur Heart J. 2010;31: Redefining Risk vs Benefit for OAC HAS-BLED Lip GYH. Am J Med. 2011;124: Letter Clinical Characteristic Points HHypertension1 A Abnormal Liver or Renal Function 1 or 2 SStroke1 BBleeding1 L Labile INR 1 EElderly (age > 65) 1 D Drugs or Alcohol 1 or 2 Maximum Score9 HAS-BLED Score Stroke (% / yr) (% / yr) % % % % % >5>5 ?? %

116 Clinical Dilemma: Bleeding Risk Correlates With Stroke Risk The higher the bleeding risk, as assessed by the HAS-BLED Index, the higher the stroke riskA Catch 22 when considering and/or deploying oral anticoagulation. The higher the bleeding risk, as assessed by the HAS-BLED Index, the higher the stroke riskA 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. 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.

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

118 Stroke and Bleeding in Atrial Fibrillation with Chronic Kidney Disease Olesen JB. NEJM 2012; 367: Danish Registry 13,879 were excluded 228 (6.4%) underwent renal-replacement therapy during follow-up 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 146,251 patients were discharged with nonvalvular atrial fibrillation ( )

119 Stroke Risk and Renal Disease Olesen JB. NEJM 2012; 367: Aspirin does not prevent strokeCharacteristic Total Population (n = 132,372) No Renal Disease (n = 127,884) Hazard Ratio (95% CI) P Value Hazard Ratio (95% CI) P Value All participants1.00 Antithrombotic Therapy None1.00 Warfarin0.59 ( )< ( )< Aspirin1.11 ( )< ( )< Warfarin and aspirin 0.70( )< ( )< 0.001

120 Bleeding Risk and Renal Disease Olesen JB. NEJM 2012; 367: Aspirin and warfarin/aspirin increase bleedingCharacteristic Total Population (n = 132,372) No Renal Disease (n = 127,884) Hazard Ratio (95% CI) P Value Hazard Ratio (95% CI) P Value All participants1.00 Antithrombotic Therapy None1.00 Warfarin1.28( )< ( )< Aspirin1.21( )< ( )< Warfarin and aspirin 2.15( )< ( )< 0.001

121 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. Megatrend: Recognizing Overuse of Aspirin

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

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

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

125 NOACs vs Warfarin A View From 30,000 Feet NOACs generally more effective than warfarin for stroke prevention 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 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, overall, reduce mortality NOACs are more convenient for patient/clinician NOACs are more convenient for patient/clinician

126 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

127 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

128 Deciphering the Pharmaco-economic MazeCost-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.silo budgeting.

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

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

131 Guidelines for Bridgingwith Dabigatran (RE-LY) Healey JS. Circulation 2012; 126: 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 (12-18)2-3d*24 h (2 doses) Moderate: > 30 to < (18-24)4 d At least 2 d (48 h) Severe: < 3027 (> 24)> 5d2-4 d

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

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

134 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. 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? 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)? How will their cost compare to current costs (including INR monitoring, dose adjustment, etc)?

135 Selecting Patients for Non-Monitored Oral Anticoagulation (NOAC) Which patients are the best candidates for non- monitored oral anticoagulation? Treatment-naive and de novo patients? And/or patients on warfarin? 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? 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? 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? Patients on warfarin who are doing well, but only with intensive monitoring? Clinical Dilemma #1

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

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

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

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

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

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

142 Guide to the Management of Bleeding in Patients Taking NOAC Hankey GJ and Eikelboom JW. Circulation. 2011; 123: 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: )

143 Antithrombotic Agents A New Era of Alignment and Flexibility? Dabigatran: Superior SPAF compared with warfarin 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 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: 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. Apixaban: Superior SPAF, less major bleeding, lower all-cause mortality.

144 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? 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? 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? 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?

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

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

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

148 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 Womens Hospital Professor of Medicine Harvard Medical School Advances in the Science and Medicine of Stroke Prevention in AF

149 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. 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. 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. Wide fluctuation in her INR has made her question continued warfarin therapy.

150 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. 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? Which of the following should we consider? Are any of these strategies optimal in this patient type? 1)Keep patient on warfarin 2)Replace warfarin with aspirin 3)Replace warfarin with aspirin + clopidogrel 4)Replace warfarin with a non-monitored oral anticoagulant Audience Response System (ARS) Question

151 Atrial Fibrillation Case Study #2 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. 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 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. 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.

152 Atrial Fibrillation Case Study #2 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. 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: It is your opinion that: 1)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. 2)Because of the patient's risk profile, there should be an attempt to provide thromboprophylaxis against embolic stroke.

153 Atrial Fibrillation Case Study #2 The cardiologist has determined that this patient requires antithrombotic management for stroke prevention. The cardiologist has determined that this patient requires antithrombotic management for stroke prevention. At this point you would most likely: At this point you would most likely: 1)Try the patient on warfarin again 2)Try to re-introduce clopidogrel and aspirin 3)Treat the patient with aspirin alone 4)Introduce a non-monitored oral anticoagulant to the patient's regimen. 4)Introduce a non-monitored oral anticoagulant to the patient's regimen.

154 Atrial Fibrillation Case Study #3 An 82-year-old man with hypertension and diabetes has permanent atrial fibrillation. 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 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. 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?

155 1.Warfarin (INR ) 2.Warfarin (INR ) 3.Aspirin 81 mg daily 4.Aspirin 81 mg + clopidogrel 75 mg daily 5.An oral Factor Xa or direct thrombin inhibitor Atrial Fibrillation Case Study #3

156 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…

157 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: 1)Placement of a drug-eluting stent with plan to continue anticoagulation in addition to 1 year of dual antiplatelet therapy 2)Placement of a drug-eluting stent with 1 year of dual antiplatelet therapy alone 3)Placement of a bare metal stent with plan to continue anticoagulation in addition to 1 month of dual antiplatelet therapy 4)Placement of a bare metal stent with 1 month of dual antiplatelet therapy alone Atrial Fibrillation Case Study #4

158 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? 1)Warfarin 2)Dabigatran 3)Apixaban 4)Rivaroxaban 5)All of the above Atrial Fibrillation Case Study #5

159 The major potential benefits of the new non- monitored oral anticoagulants include: The major potential benefits of the new non- monitored oral anticoagulants include: 1)Rapid therapeutic anticoagulant effect 2)Greater safety with regards to intracranial hemorrhage 3)Proven reversal agent 4)All of the above 5)Both 1 and 2 Atrial Fibrillation Knowledge Assessment Question

160 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. 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: The best anticoagulant regimen for stroke prevention is: 1) Dabigatran 150 mg twice daily 2) Dabigatran 75 mg twice daily 3) Warfarin titrated to goal INR 2-3 4) Rivaroxaban 20 mg once daily 5) Rivaroxaban 15 mg once daily Atrial Fibrillation Case Study #6

161 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. Atrial Fibrillation Case Study #7

162 Which of her symptoms could be due to warfarin? 1)Thinning hair 2)Cold intolerance 3)Fatigue 4)Both 1 and 2 5)All of the above Atrial Fibrillation Case Study #7

163 A 69-year-old woman with AF and CHADS 2 score of 4 has a creatinine clearance that is stable at 40 mL/min. Which of the following anticoagulation regimens are suitable for her? 1)Dabigatran 150 mg twice daily 2)Dabigatran 75 mg twice daily 3)Rivaroxaban 20 mg once daily 4)Rivaroxaban 15 mg once daily 5)Both 1 and 4 Atrial Fibrillation Case Study #8

164 What would her options be if her creatinine clearance was stable at 25 mL/min? 1)Dabigatran 75 mg twice daily 2)Rivaroxaban 15 mg once daily 3)Only warfarin can be used in patients with creatinine clearance < 30 mL/min 4)Both 1 and 2 Atrial Fibrillation Case Study #8

165 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. Atrial Fibrillation Case Study #9

166 Which of the following lab tests, if normal, would reassure the team that the patient is not anticoagulated? 1) INR (international normalized ratio) 2) aPTT (activated partial thromboplastin time) 3) PT (prothrombin time) 4) Bleeding time Atrial Fibrillation Case Study #9

167 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? 1)Start dabigatran when his INR < 3 2)Start dabigatran when his INR < 2 3)Start dabigatran 24 hours after his last dose of warfarin Atrial Fibrillation Case Study #10

168 What if you decided to switch the patient to rivaroxaban? 1)Start rivaroxaban when his INR < 3 2)Start rivaroxaban when his INR < 2 3)Start rivaroxaban 24 hours after his last dose of warfarin Atrial Fibrillation Case Study #10

169 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: 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: 1)No antithrombotic therapy 2)Discontinue warfarin and start aspirin 3)Discontinue warfarin and start dabigatran 4)Discontinue warfarin and start rivaroxaban 5)Discontinue warfarin and start apixaban Atrial Fibrillation Case Study #11

170 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? 1)Aspirin 2)Aspirin and clopidogrel 3)Dabigatran 4)Apixaban 5)Rivaroxaban Atrial Fibrillation Case Study #12

171 A 68-year-old man with a mechanical mitral valve develops AF. A 68-year-old man with a mechanical mitral valve develops AF. The best anticoagulant option for him is : The best anticoagulant option for him is : 1)Warfarin 2)Dabigatran 3)Apixaban 4)Rivaroxaban 5)Aspirin Atrial Fibrillation Case Study #13

172 A 76-year-old man with heart failure and hypertension undergoes successful catheter ablation for symptomatic AF. 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? Which of the following is true regarding his anticoagulation management? 1)He no longer requires anticoagulation now that he is in sinus rhythm 2)Patient should be on both aspirin and an anticoagulant 3)Patient should be on an anticoagulant alone 4)Aspirin and clopidogrel together is as effective as anticoagulation in these patients Atrial Fibrillation Case Study #14

173 The cardiologist has determined that this patient requires antithrombotic management for stroke prevention. At this point you would most likely: The cardiologist has determined that this patient requires antithrombotic management for stroke prevention. At this point you would most likely: 1)Try the patient on warfarin again 2)Treat the patient with aspirin alone 3)Introduce the non-monitored oral anticoagulant, apixaban, into the patient's regimen 4)Introduce dabigatran into the patients regimen 5) Introduce rivaroxaban into the patients regimen Atrial Fibrillation Case Study #14

174 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. 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. 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. His estimated GFR is 30 mL/min. Atrial Fibrillation Case Study #15

175 At this point you would: 1)Continue to try to stabilize his INR on warfarin 2)Change to aspirin alone 3)Introduce the non-monitored oral anticoagulant rivaroxaban into the patient's regimen 4)Introduce the non-monitored oral anticoagulant apixaban into the patient's regimen 5)Introduce the non-monitored oral anticoagulant dabigatran into the patient's regimen Atrial Fibrillation Case Study #15

176 An 82-year-old man with hypertension, diabetes, mild congestive heart failure, and previous ischemic stroke, is diagnosed with atrial fibrillation. 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. He has not been taking any anticoagulants. Atrial Fibrillation Case Study #17

177 Which regimen would you initiate for prophylaxis against stroke? Which regimen would you initiate for prophylaxis against stroke? 1)Warfarin (INR ) 2)Aspirin 81 mg + clopidogrel 75 mg daily 3)Rivaroxaban 4)Apixaban 5)Dabigatran Atrial Fibrillation Case Study #17

178 An 82-year-old man with hypertension, diabetes, mild CHF, and a previous ischemic stroke has permanent atrial fibrillation. 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 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. He has a HAS-BLED score of 3. Atrial Fibrillation Case Study #18

179 Which regimen would you continue or switch to for prophylaxis against stroke? Which regimen would you continue or switch to for prophylaxis against stroke? 1)Continue current therapy with warfarin 2)Aspirin 81 mg + clopidogrel 75 mg daily 3)Rivaroxaban 4)Apixaban 5)Dabigatran Atrial Fibrillation Case Study #18

180 A 75-year-old man with a CHADS 2 of 3 has been taking dabigatran 150 mg for SPAF. His estimated GFR was 55 6 months ago and is now 40. A 75-year-old man with a CHADS 2 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: I would now: 1)Continue to monitor patient 2)Switch patient to 75 mg dabigatran twice per day 3)Switch patient to warfarin 4)Switch patient to rivaroxaban 5)Start ASA and clopidogrel Atrial Fibrillation Case Study #19

181 Interactive Question and Answer Session New Paradigms in the Science and Medicine of Heart Disease


Download ppt "Stroke Prevention in Atrial Fibrillation Evidence- and Guideline-Based Strategies for Optimizing Clinical Outcomes and Anticoagulation-Based Management."

Similar presentations


Ads by Google