Thrombosis and Thromboembolsim October Stroke Prevention in Atrial Fibrillation Risk Stratification and Choice of Antithrombotic Therapy

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1 Thrombosis and Thromboembolsim October 2012 Stroke Prevention in Atrial Fibrillation Risk Stratification and Choice of Antithrombotic Therapy Christian T. Ruff, MD, MPH TIMI Study Group Brigham and Women s Hospital Harvard Medical School Boston, MA 1

2 Disclosures Research Support: Daiichi Sankyo, AstraZeneca, Bristol-Meyers Squibb, Sanofi-Aventis Consultant: Alere and Beckman Coulter 2

3 Atrial Fibrillation: An Epidemic Projected Number of People with AF (millions) US Prevalence 16 million 1 in 4 lifetime risk in men and women 40 years old Based on Projected Incidence Miyakasa Y, et al. Circulation. 2006; 114: Year 3

4 Complications of AF Embolic Stroke Hemodynamic Fatigue Shortness of Breath Systemic Embolism Palpitations CHF 4

5 % Stroke in AF Approximately 5X increased risk of stroke Risk varies significantly depending on clinical factors Embolic strokes from AF have worse outcomes Substantial morbidity and mortality Staggering health care costs ~ $16 billion/year Framingham AF prevalence Strokes attributable to AF Wolf PA, et al. Stroke 1991; 22: Age Range (years) 5

6 Treatment of AF Antithrombotic Therapy Rhythm Control Rate Control 6

7 Antithrombotic Therapy Antithrombotic Therapy Antiplatelet Anticoagulant 7

8 Stroke Prevention in AF Warfarin vs. Aspirin AFASAK I (432) AFASAK II (439) EAFT (403) PATAF (443) SPAF II (440) All Trials (n=5) 33% 100% 50% 0% -50% -100% Warfarin Better Aspirin Better Fuster V, et al. Circulation 2011;123:e

9 CHADS 2 Risk Score Risk Factor Points Congestive Heart Failure 1 Hypertension 1 Age 75 1 Diabetes Mellitus 1 Stroke or TIA 2 Maximum Score 6 CHADS 2 Stroke (% / yr) Gage BF, et al. JAMA. 2001;285: VanWalraven C, et al. Arch Intern Med 2003; 163:936. Nieuwlaat R, et al. (EuroHeart survey) Eur Heart J 2006 (E-published). Go A, et al. JAMA 2003; 290: Gage BF, et al. Circulation 2004; 110:

10 Risk Stratification Threshold for Anticoagulation CHADS 2 Risk of Stroke (%/yr) %/year 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: 2287.

11 Prior ACC/AHA/ESC Guidelines Risk Factor No risk factors CHADS 2 = 0 One moderate risk factor CHADS 2 = 1 Any high risk factor or >1 moderate risk factor CHADS 2 >2 Prosthetic valve Recommended Therapy Aspirin, mg Aspirin, mg or Warfarin (INR , target 2.5) Warfarin (INR , target 2.5) Warfarin (INR , target 3.0) 11

12 CHADS 2 Risk Score Score (points) Prevalence (%) Congestive Heart failure 1 32 Hypertension 1 65 Age >75 years 1 28 Diabetes mellitus 1 18 Stroke 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). Gage BF, et al. JAMA. 2001;285:

13 Redefining Benefit: CHA 2 DS 2 -VASc Risk Factor Points CHF / LV Dysfunction 1 Hypertension 1 Age 75 2 Diabetes Mellitus 1 Stroke / TIA / Embolism 2 Vascular Disease 1 Age Sex Category (female) 1 Maximum Score 9 CHA 2 DS 2 -VASc Score Stroke (% / yr) 1 0 % % % % % % % % % ESC Guidelines: Eur Heart J. 2010;31:

14 Redefining Risk: HAS-BLED Letter Clinical Characteristic Points H Hypertension 1 A Abnormal Liver or Renal Function 1 or 2 S Stroke 1 B Bleeding 1 L Labile INR 1 E Elderly (age > 65) 1 D Drugs or Alcohol 1 or 2 HAS-BLED Score Stroke (% / yr) ? Lip GYH. Am J Med. 2011;124: Maximum Score 9 ESC Guidelines: Eur Heart J. 2010;31:

15 Net Clinical Benefit of Warfarin All-Cause Mortality, Ischemic Stroke, & ICH Friberg L, et al. Circulation 2012; 125:

16 Stroke Prevention Recommendations Fuster V, Chinitz JS. Circulation 2012; 125:

17 The Future Biomarkers RE-LY Stroke, SEE, PE, MI, & Vascular Death Trop NTproBNP Hijazi Z, et al. Circulation 2012; 125: Trop NTproBNP 17

18 The Future Genetics 4q25 Variant Only Predicts Cardioembolic Stroke HR 1.48 ( ) Lemmens R, et al. Stroke 2010; 41:

19 Conclusions Risk Stratification The decision to prescribe anticoagulant therapy to a patient with AF requires balancing their individual risk of stroke and potential for bleeding complications. There will be refinement of risk prediction strategies (CHA 2 DS 2 -VASc, HAS-BLED, addition of biomarkers/genetics) that will result in a greater proportion of patients being eligible for anticoagulation. 19

20 History of Warfarin 20

21 Limitations of Warfarin Delayed onset/offset Multiple food and drug interactions Genetic variability in metabolism (VKORC1 and CYP2C9) Requires frequent monitoring of INR due to limited therapeutic index 21

22 Preventable Strokes AF Patients with Stroke with no Known Contraindication to Anticoagulation No warfarin 61% INR in range 10% Subtherapeutic INR 29% Gladston, DJ, et al. Stroke 2009;40:

23 Properties of an Ideal Anticoagulant Properties Oral, once daily dosing Rapid onset of action Minimal food or drug interactions Predictable anticoagulant effect Extra renal clearance Rapid offset in action Antidote Benefit Ease of administration No need for overlapping parenteral anticoagulant Simplified dosing No coagulation monitoring Safe in patients with renal disease Simplifies management in case of bleeding or intervention For emergencies 23

24 Novel Oral Anticoagulants TTP889 TF/VIIa Dabigatran AZD0837 MCC 977 X Fibrinogen IX IXa VIIIa Va Xa II IIa Fibrin Rivaroxaban Apixaban Edoxaban Betrixaban Eribaxaban Razaxaban YM150 LY TAK 442 Adapted from: Weitz JI, Bates SM. J Thromb Haemost 2005;3:

25 Major Advances In Oral Anticoagulation for SPAF 6 Trial of Warfarin vs. Placebo ROCKET AF (Rivaroxaban) 2010 ENGAGE AF (Edoxaban)? RE-LY (Dabigatran) 2009 ARISTOTLE (Apixaban)

26 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 b.i.d. N=6015 Dabigatran Etexilate 150 mg b.i.d. N= efficacy outcome = stroke or systemic embolism 1 0 safety outcome = major bleeding Non-inferiority margin

27 RE-LY Efficacy: Stroke/SEE Non-inferiority p-value Superiority p-value Dabigatran 110 vs. Warfarin < Dabigatran 150 vs. Warfarin <0.001 <0.001 Margin = 1.46 Connolly, et al. N Engl J Med 2009;361: HR (95% CI) 27

28 RE-LY Efficacy Dabigatran 110 mg Dabigatran 150 mg Stroke/SEE 0.91 ( ) 0.66 ( ) Ischemic Stroke 1.11 ( ) 0.76 ( ) Hemorrhagic Stroke 0.31 ( ) 0.26 ( ) Connolly, et al. N Engl J Med 2009;361: Dabigatran Better Warfarin Better 28

29 RE-LY Safety Dabigatran 110 mg Dabigatran 150 mg Major Bleed 0.80 ( ) 0.93 ( ) ICH 0.31 ( ) 0.40 ( ) GI Bleed 1.10 ( ) 1.50 ( ) MI 1.29 ( ) 1.27 ( ) Connolly, et al. N Engl J Med 2009;361: Dabigatran Better Warfarin Better 29

30 RE-LY Efficacy Stratified by CHADS 2 Annualized Rate Stroke/SEE (%) D110 D150 CHADS 2 D110 D150 WARF P = 0.44 P = Dabigatran Warfarin better better Dabigatran better Warfarin better Oldgren J, et al. ACC

31 RE-LY Efficacy Stratified by Prior VKA Ezekowitz MD, et al. Circulation 2010;122:

32 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 32

33 Atrial Fibrillation Risk Factors CHF At least 2 Hypertension required Age 75 Diabetes OR Stroke, TIA or Systemic embolus Rivaroxaban 20 mg daily 15 mg for Cr Cl Randomize Double blind / Double Dummy (n=14,266) Warfarin INR target ( inclusive) Monthly Monitoring and adherence to standard of care guidelines Primary Endpoint: Stroke or non-cns Systemic Embolism Statistics: non-inferiority, >95% power, 2.3% warfarin event rate 33

34 ROCKET AF Efficacy: Stroke/SEE Rivaroxaban Warfarin Event Rate Event Rate HR (95% CI) P-value On Treatment N=14, (0.65, 0.95) ITT N=14, (0.74, 1.03) Rivaroxaban better Warfarin better Event Rates are per 100 patient-years Based on Safety on Treatment or Intention-to-Treat thru Site Notification populations Patel, et al. N Engl J Med 2011;365(10);

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

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

37 Rivaroxaban Approval Prevention of stroke in AF Dose 20 mg if CrCl >50 ml/min Dose of 15 mg if CrCl ml/min 37

38 Atrial Fibrillation with at Least One Additional Risk Factor for Stroke 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

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

40 ARISTOTLE Key Secondary Efficacy Event Apixaban (%/yr) Warfarin (%/yr) Hazarard Ratio (95% CI) P- value Ischemic Stroke ( ) 0.42 Hemorrhagic Stroke (0.35, 0.75) <0.001 MI (0.66, 1.17) 0.37 Total Mortality ( ) Stroke/SEE/Total Mortality ( ) Granger CB, et al. NEJM 2011; 365:

41 ARISTOTLE Safety Event Rivaroxaban (%/yr) Warfarin (%/yr) Hazarard Ratio (95% CI) P- value ISTH Major Bleeding ( ) <0.001 ICH ( ) <0.001 GUSTO Severe ( ) <0.001 Gastrointestinal ( ) 0.37 Granger CB, et al. NEJM 2011; 365:

42 Phase III: Protocol Schema N = 21,105 DOUBLE BLIND DOUBLE DUMMY AF on Electrical Recording <12 mo Intended oral A/C CHADS 2 >2 R Randomization Stratified By 1. CHADS vs Drug Clearance 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 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

43 Baseline Characteristics in AF Trials 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% CHADS 2 score 3 32% 30% 52% 87% VKA naive 50% 43% 41% 38% Paroxysmal AF 33% 15% 25% 18% Prior stroke/tia 20% 19% 18% / 12% 55%** Diabetes 23% 25% 36% 40% Prior CHF 32% 35% 56% 62% Hypertension 79% 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:

44 AF 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 Initial Dose adj* No mg mg 60, 30 QD mg mg Dose adj (%) >25 Dose adj* after randomization No No No Yes Design PROBE 2x blind 2x blind 2x 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:

45 AF Trials: Results To Date RE-LY ROCKET-AF ARISTOTLE Drug Dose (mg) Dabigatran 110 BID 150 BID Rivaroxaban 20 mg QD Apixaban 5 mg BID Stroke + SEE non-infer Superior ITT cohort: non-infer. On Rx cohort: Superior Superior ICH Superior Superior Superior Superior Bleeding Lower similar similar Lower Mortality similar p=0.051 similar Superior: p=0.047 Ischemic stroke similar Lower similar similar Mean TTR 64% 55% 62% Stopped drug 21% 23% 23% WD consent 2.3% 8.7% 1.1% TTR = time in therapeutic range WD consent = withdrawal of consent, no further data available 45

46 Efficacy of New Oral Anticoagulants Stroke & SEE Ischemic & Unsp. Stroke 13% Hemorraghic Stroke 55% Favors NOACs Miller CS, et al. Am J Cardiol 2012;110(3): Favors Warfarin 46

47 Safety of New Oral Anticoagulants Bleeding Major ICH 51% GI Favors NOACs Miller CS, et al. Am J Cardiol 2012;110(3): Favors Warfarin 47

48 Does INR Matter? Treatment Group Event Rate / Year Warfarin Event Rate / Year p-value (interaction) ROCKET AF % % % % RE-LY (Dabigatran 150 mg) 0.20 <57.1% % % >72.6% ARISTOTLE 0.29 < 58.0% % % > 72.2 % Wallentin L, et al. Lancet 2010;376: Patel, et al. NEJM 2011;365(10); Granger CB, et al. NEJM 2011; 365: Hazard Ratio (95% CI) Study Drug Favors Warfarin

49 Novel Oral Anticoagulants Discontinuation of Drug Problem Rivaroxaban Warfarin Event Rate Event Rate HR (95% CI) P-value On Treatment N=14, (0.65, 0.95) ITT N=14, (0.74, 1.03) Rivaroxaban better Warfarin better Event Rates are per 100 patient-years Based on Safety on Treatment or Intention-to-Treat thru Site Notification populations Patel, et al. N Engl J Med 2011;365(10);

50 NOACs: More Events Off-Drug 3 13% 25% %/yr 1.7 Rivaroxaban Warfarin 1 P=0.015 P= On Treatment ITT 50

51 ESC 2012 AF Guidelines Update Risk Profile Class / Level CHA 2 DS 2 -VASc = 0 No antithrombotic therapy I B CHA 2 DS 2 -VASc = 1 CHA 2 DS 2 -VASc 2 VKA (INR 2-3) Or Dabigatran / Rivaroxaban / Apixaban IIa A VKA (INR 2-3) Or Dabigatran / Rivaroxaban / Apixaban I A 51

52 Issues & Limitations in Clinical Practice Potential Risks of Major Bleeding in Elderly 1,2 and patients with CKD 3 Low body weight and decreased renal function increase drug exposure Increased Risk of Bleeding with AF Ablation 4 Compared with warfarin, periprocedural use increases risk of bleeding Poor Outcomes Following Trauma 5 No method readily available to determine degree of anticoagulation & no antidote High Rates of Early Discontinuation 6 Cost effectiveness? 1 Legrand. M Arch Intern Med 2011; 171: Harper P. N Eng J Med 2012; 366: Olesen J. N Eng J Med 2012; 367: Lakkireddy D. JACC 2012; 59:1-7 5 Cotton B. N Eng J Med 2011; 365: Stanek E. Circulation 2011; 124:A

53 Conclusions New therapies provide the promise of providing safer and more convenient anticoagulation. 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. The development of a clinically tested reversal agent is necessary before widespread adoption. There will be refinement of risk prediction strategies (CHA 2 DS 2 -VASc, HAS-BLED) that will result in a greater proportion of patients being eligible for anticoagulation. 53