Comprehensive MetaAnalysis Comparing the Efficacy and Safety of

  • Slides: 35
Download presentation
Comprehensive Meta-Analysis Comparing the Efficacy and Safety of NOACs with Warfarin in AF An

Comprehensive Meta-Analysis Comparing the Efficacy and Safety of NOACs with Warfarin in AF An Analysis Including 71, 683 Patients from Four Large Randomized Clinical Trials Christian T. Ruff, MD, MPH TIMI Study Group Brigham and Women’s Hospital Harvard Medical School Boston, MA 1

Pivotal Warfarin-Controlled Trials Stroke Prevention in AF Warfarin vs. Placebo 2, 900 Patients NOACs

Pivotal Warfarin-Controlled Trials Stroke Prevention in AF Warfarin vs. Placebo 2, 900 Patients NOACs vs. Warfarin 71, 683 Patients ROCKET AF (Rivaroxaban) 2010 6 Trial of Warfarin vs. Placebo 1989 -1993 RE-LY (Dabigatran) 2009 ENGAGE AF-TIMI 48 (Edoxaban) 2013 ARISTOTLE (Apixaban) 2011 2

Comparative PK/PD of NOACs Dabigatran Rivaroxaban Apixaban Edoxaban IIa (thrombin) Xa Xa Xa Hours

Comparative PK/PD of NOACs Dabigatran Rivaroxaban Apixaban Edoxaban IIa (thrombin) Xa Xa Xa Hours to Cmax 1 -3 2 -4 3 -4 1 -2 Half-life, hours 12 -17 5 -13 12 10 -14 80 33* 27 50 Transporters P-gp CYP Metabolism, % None 32 <4 Target Renal Clearance, % CYP = cytochrome P 450; P-gp = P-glycoprotein *33% renally cleared; 33% excreted unchanged in urine Pradaxa [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc. 2013 Xarelto [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc. 2011 Weinz et al. Drug Dispos Metab 2009; 37: 1056– 1064 ELIQUIS Summary of Product Characteristics. Bristol Myers Squibb/Pfizer EEIG, UK Matsushima et al. Am Assoc Pharm Sci 2011; abstract Ogata, et al. J Clin Pharmacol 2010; 50: 743– 753 Mendell, et al. Am J Cardiovasc Drugs 2013; 13: 331– 342 Bathala, et al. Drug Metab Dispos 2012; 40: 2250– 2255 3

NOAC SPAF Trials RE-LY ROCKET-AF ARISTOTLE ENGAGE AF Dabigatran Rivaroxaban Apixaban Edoxaban 18, 113

NOAC SPAF Trials RE-LY ROCKET-AF ARISTOTLE ENGAGE AF Dabigatran Rivaroxaban Apixaban Edoxaban 18, 113 14, 266 18, 201 21, 105 150, 110 20 5 60, 30 Twice Daily Once Daily Dose Adjustment No 20 → 15 5 → 2. 5 60 → 30 30 → 15 At Baseline 0 21 5 25 No No No >9% 2. 0 -3. 0 PROBE* 2 x blind Drug # Randomized Dose (mg) Frequency After Randomization Target INR (Warfarin) Design *PROBE = prospective, randomized, open-label, blinded end point evaluation Connolly SJ, et al. N Engl J Med 2009; 361: 1139 -1151 Patel MR, et al. N Engl J Med 2011; 365: 883 -891 Granger CB, et al. N Engl J Med 2011; 365: 981 -992 Giugliano RP, et al. N Engl J Med 2013; e-pub ahead of print DOI: 10. 1056/NEJMoa 1310907 4

Baseline Characteristics RE-LY (Dabigatran) ROCKET-AF (Rivaroxaban) ARISTOTLE (Apixaban) ENGAGE AF (Edoxaban) # Randomized 18,

Baseline Characteristics RE-LY (Dabigatran) ROCKET-AF (Rivaroxaban) ARISTOTLE (Apixaban) ENGAGE AF (Edoxaban) # Randomized 18, 113 14, 264 18, 201 21, 105 Age, years 72 ± 9 73 [65 -78] 70 [63 -76] 72 [64 -78] Female, % 37 40 35 38 Paroxysmal AF 32 18 15 25 VKA naive 50 38 43 41 Aspirin Use 40 36 31 29 CHADS 2 0 -1 2 3 -6 33 13 32 35 87 30 34 53 47 36 Connolly SJ, et al. N Engl J Med 2009; 361: 1139 -1151 Patel MR, et al. N Engl J Med 2011; 365: 883 -891 Granger CB, et al. N Engl J Med 2011; 365: 981 -992 Giugliano RP, et al. N Engl J Med 2013; e-pub ahead of print DOI: 10. 1056/NEJMoa 1310907 5

Trial Metrics RE-LY (Dabigatran) ROCKET-AF (Rivaroxaban) ARISTOTLE (Apixaban) ENGAGE AF (Edoxaban) Median Follow-Up, years

Trial Metrics RE-LY (Dabigatran) ROCKET-AF (Rivaroxaban) ARISTOTLE (Apixaban) ENGAGE AF (Edoxaban) Median Follow-Up, years 2. 0 1. 9 1. 8 2. 8 Median TTR 66 58 66 68 Lost to Follow-Up, N 20 32 90 1 *TTR, time in therapeutic range Connolly SJ, et al. N Engl J Med 2009; 361: 1139 -1151 Patel MR, et al. N Engl J Med 2011; 365: 883 -891 Granger CB, et al. N Engl J Med 2011; 365: 981 -992 Giugliano RP, et al. N Engl J Med 2013; e-pub ahead of print DOI: 10. 1056/NEJMoa 1310907 6

All NOACS: Stroke or SEE Risk Ratio (95% CI) 0. 66 (0. 53 -

All NOACS: Stroke or SEE Risk Ratio (95% CI) 0. 66 (0. 53 - 0. 82) RE-LY [150 mg] ROCKET AF 0. 88 (0. 75 - 1. 03) ARISTOTLE 0. 80 (0. 67 - 0. 95) ENGAGE AF-TIMI 48 0. 88 (0. 75 - 1. 02) Combined 0. 81 (0. 73 - 0. 91) [60 mg] [Random Effects Model] N=58, 541 0. 5 Heterogeneity p=0. 13 p=<0. 0001 Favors NOAC 1 Favors Warfarin 2 Ruff CT, et al. Lancet 2013 [in-press] 7

Secondary Efficacy Outcomes Risk Ratio (95% CI) Ischemic Stroke 0. 92 (0. 83 -

Secondary Efficacy Outcomes Risk Ratio (95% CI) Ischemic Stroke 0. 92 (0. 83 - 1. 02) Hemorrhagic Stroke 0. 49 (0. 38 - 0. 64) MI 0. 97 (0. 78 - 1. 20) All-Cause Mortality 0. 90 (0. 85 - 0. 95) p=0. 10 p<0. 0001 p=0. 77 0. 2 p=0. 0003 0. 5 Favors NOAC 1 2 Favors Warfarin Heterogeneity p=NS for all outcomes Ruff CT, et al. Lancet 2013 [in-press] 8

All NOACS: Major Bleeding Risk Ratio (95% CI) 0. 94 (0. 82 - 1.

All NOACS: Major Bleeding Risk Ratio (95% CI) 0. 94 (0. 82 - 1. 07) RE-LY [150 mg] ROCKET AF 1. 03 (0. 90 - 1. 18) ARISTOTLE 0. 71 (0. 61 - 0. 81) ENGAGE AF-TIMI 48 0. 80 (0. 71 - 0. 90) Combined 0. 86 (0. 73 - 1. 00) [60 mg] [Random Effects Model] N=58, 498 Heterogeneity p=0. 001 0. 5 p=0. 06 Favors NOAC 1 Favors Warfarin 2 Ruff CT, et al. Lancet 2013 [in-press] 9

Secondary Safety Outcomes Risk Ratio (95% CI) 0. 48 (0. 39 - 0. 59)

Secondary Safety Outcomes Risk Ratio (95% CI) 0. 48 (0. 39 - 0. 59) ICH p<0. 0001 1. 25 (1. 01 - 1. 55) GI Bleeding 0. 2 p=0. 043 0. 5 Favors NOAC 1 2 Favors Warfarin Heterogeneity ICH, p=0. 22 GI Bleeding, p=0. 009 Ruff CT, et al. Lancet 2013 [in-press] 10

Subgroups: Stroke or SEE Age Gender Diabetes Prior Stroke or TIA Cr. Cl CHADS

Subgroups: Stroke or SEE Age Gender Diabetes Prior Stroke or TIA Cr. Cl CHADS 2 Score VKA Status Center-Based TTR Risk Ratio (95% CI) P-Interaction <75 0. 85 (0. 73 - 0. 99) p=0. 38 ≥ 75 0. 78 (0. 68 - 0. 88) Female 0. 78 (0. 65 - 0. 94) Male 0. 84 (0. 75 - 0. 94) No 0. 83 (0. 74 - 0. 93) Yes 0. 80 (0. 69 - 0. 93) No 0. 78 (0. 66 - 0. 91) Yes 0. 86 (0. 76 - 0. 98) <50 0. 79 (0. 65 - 0. 96) 50 -80 0. 75 (0. 66 - 0. 85) >80 0. 98 (0. 79 - 1. 22) 0 -1 0. 75 (0. 54 - 1. 04) 2 0. 86 (0. 70 - 1. 05) 3 -6 0. 80 (0. 72 - 0. 89) Naive 0. 75 (0. 66 - 0. 86) Experienced 0. 85 (0. 70 - 1. 03) <66% 0. 77 (0. 65 - 0. 92) ≥ 66% 0. 82 (0. 71 - 0. 95) 0. 5 Ruff CT, et al. Lancet 2013 [in-press] Favors NOAC 1 Favors Warfarin p=0. 52 p=0. 73 p=0. 30 p=0. 12 p=0. 76 p=0. 31 p=0. 60 2 11

Subgroups: Major Bleeding Age Gender Diabetes Prior Stroke or TIA Cr. Cl CHADS 2

Subgroups: Major Bleeding Age Gender Diabetes Prior Stroke or TIA Cr. Cl CHADS 2 Score VKA Status Center-Based TTR Risk Ratio (95% CI) P-Interaction <75 0. 79 (0. 67 - 0. 94) p=0. 28 ≥ 75 0. 93 (0. 74 - 1. 17) Female 0. 75 (0. 58 - 0. 97) Male 0. 90 (0. 72 - 1. 12) No 0. 71 (0. 54 – 0. 93) Yes 0. 90 (0. 78 - 1. 04) No 0. 85 (0. 72 - 1. 01) Yes 0. 89 (0. 77 - 1. 02) <50 0. 74 (0. 52 - 1. 05) 50 -80 0. 91 (0. 76 - 1. 08) >80 0. 85 (0. 66 - 1. 10) 0 -1 0. 60 (0. 45 - 0. 80) 2 0. 88 (0. 65 - 1. 20) 3 -6 0. 86 (0. 71 - 1. 04) Naive 0. 84 (0. 76 - 0. 93) Experienced 0. 87 (0. 70 - 1. 08) <66% 0. 69 (0. 59 - 0. 81) ≥ 66% 0. 93 (0. 76 - 1. 13) 0. 2 Ruff CT, et al. Lancet 2013 [in-press] 0. 5 Favors NOAC 1 2 Favors Warfarin p=0. 29 p=0. 12 p=0. 70 p=0. 57 p=0. 09 p=0. 78 p=0. 022 12

Low Dose Regimens Efficacy & Safety Outcomes Dabigatran 110 mg & Edoxaban 30 mg

Low Dose Regimens Efficacy & Safety Outcomes Dabigatran 110 mg & Edoxaban 30 mg Risk Ratio (95% CI) Stroke or SEE 1. 03 (0. 84 - 1. 27) Ischemic Stroke 1. 28 (1. 02 - 1. 60) p=0. 74 p=0. 045 0. 33 (0. 23 - 0. 46) Hemorrhagic Stroke p<0. 0001 MI 1. 25 (1. 04 - 1. 50) p=0. 019 0. 89 (0. 83 - 0. 96) All-Cause Mortality p=0. 003 0. 65 (0. 43 - 1. 00) Major Bleeding p=0. 05 0. 31 (0. 24 - 0. 41) ICH p<0. 0001 0. 89 (0. 57 - 1. 37) GI Bleeding N=26, 107 Heterogeneity P=NS for outcomes except: Major Bleeding, p=<0. 001 GI Bleeding, p=0. 01 p=0. 58 0. 2 0. 5 Favors Low Dose NOAC 1 2 Favors Warfarin Ruff CT, et al. Lancet 2013 [in-press] 13

Comprehensive Meta-Analysis Comparing the Efficacy and Safety of NOACs with Warfarin in AF An

Comprehensive Meta-Analysis Comparing the Efficacy and Safety of NOACs with Warfarin in AF An Analysis Including 71, 683 Patients from Four Large Randomized Clinical Trials Christian T. Ruff, MD, MPH TIMI Study Group Brigham and Women’s Hospital Harvard Medical School Boston, MA 14

Disclosures Research Support: Daiichi Sankyo, Astra. Zeneca Consultant and Advisory Boards: Boehringer Ingelheim, Daiichi

Disclosures Research Support: Daiichi Sankyo, Astra. Zeneca Consultant and Advisory Boards: Boehringer Ingelheim, Daiichi Sankyo, Bristol. Meyers Squibb 15

Stroke Prevention in AF Warfarin vs. Placebo AFASAK-1 (671) SPAF (421) BAATAF (420) CAFA

Stroke Prevention in AF Warfarin vs. Placebo AFASAK-1 (671) SPAF (421) BAATAF (420) CAFA (378) SPINAF (571) EAFT (439) All Trials (n=6) 64% 100% 50% Warfarin Better Hart RG, et al. Ann Intern Med 2007; 146: 857 -867. 0% -50% -100% Warfarin Worse 16

Pivotal Warfarin-Controlled Trials Stroke Prevention in AF Warfarin vs. Placebo 2, 900 Patients NOACs

Pivotal Warfarin-Controlled Trials Stroke Prevention in AF Warfarin vs. Placebo 2, 900 Patients NOACs vs. Warfarin 71, 683 Patients ROCKET AF (Rivaroxaban) 2010 6 Trials of Warfarin vs. Placebo 1989 -1993 RE-LY (Dabigatran) 2009 ENGAGE AF-TIMI 48 (Edoxaban) 2013 ARISTOTLE (Apixaban) 2011 17

Meta-Analysis First to contain data from all 4 phase 3 warfarin-controlled trials Robust sample

Meta-Analysis First to contain data from all 4 phase 3 warfarin-controlled trials Robust sample size − − Precision in assessing relative benefit of NOACs in key clinical subgroups Effects of agents on important secondary outcomes Pooled data for FXa and thrombin inhibitors − − − Target key coagulation enzymes Trials share similar design Agents used interchangeably clinically and grouped together by Guidelines Separate meta-analysis of low dose dabigatran and edoxaban Comprehensive picture of the NOACs as a therapeutic option 18

Comparative PK/PD of NOACs Dabigatran Rivaroxaban Apixaban Edoxaban IIa (thrombin) Xa Xa Xa Hours

Comparative PK/PD of NOACs Dabigatran Rivaroxaban Apixaban Edoxaban IIa (thrombin) Xa Xa Xa Hours to Cmax 1 -3 2 -4 3 -4 1 -2 Half-life, hours 12 -17 5 -13 12 10 -14 80 33* 27 50 Transporters P-gp CYP Metabolism, % None 32 <4 Target Renal Clearance, % CYP = cytochrome P 450; P-gp = P-glycoprotein *33% renally cleared; 33% excreted unchanged in urine Pradaxa [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc. 2013 Xarelto [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc. 2011 Weinz et al. Drug Dispos Metab 2009; 37: 1056– 1064 ELIQUIS Summary of Product Characteristics. Bristol Myers Squibb/Pfizer EEIG, UK Matsushima et al. Am Assoc Pharm Sci 2011; abstract Ogata, et al. J Clin Pharmacol 2010; 50: 743– 753 Mendell, et al. Am J Cardiovasc Drugs 2013; 13: 331– 342 Bathala, et al. Drug Metab Dispos 2012; 40: 2250– 2255 19

NOAC SPAF Trials RE-LY ROCKET-AF ARISTOTLE ENGAGE AF Dabigatran Rivaroxaban Apixaban Edoxaban 18, 113

NOAC SPAF Trials RE-LY ROCKET-AF ARISTOTLE ENGAGE AF Dabigatran Rivaroxaban Apixaban Edoxaban 18, 113 14, 266 18, 201 21, 105 150, 110 20 5 60, 30 Twice Daily Once Daily Dose Adjustment No 20 → 15 5 → 2. 5 60 → 30 30 → 15 At Baseline 0 21 5 25 No No No >9% 2. 0 -3. 0 PROBE* 2 x blind Drug # Randomized Dose (mg) Frequency After Randomization Target INR (Warfarin) Design *PROBE = prospective, randomized, open-label, blinded end point evaluation Connolly SJ, et al. N Engl J Med 2009; 361: 1139 -1151 Patel MR, et al. N Engl J Med 2011; 365: 883 -891 Granger CB, et al. N Engl J Med 2011; 365: 981 -992 Giugliano RP, et al. N Engl J Med 2013; e-pub ahead of print DOI: 10. 1056/NEJMoa 1310907 20

Baseline Characteristics RE-LY (Dabigatran) ROCKET-AF (Rivaroxaban) ARISTOTLE (Apixaban) ENGAGE AF (Edoxaban) # Randomized 18,

Baseline Characteristics RE-LY (Dabigatran) ROCKET-AF (Rivaroxaban) ARISTOTLE (Apixaban) ENGAGE AF (Edoxaban) # Randomized 18, 113 14, 264 18, 201 21, 105 Age, years 72 ± 9 73 [65 -78] 70 [63 -76] 72 [64 -78] Female, % 37 40 35 38 Paroxysmal AF 32 18 15 25 VKA naive 50 38 43 41 Aspirin Use 40 36 31 29 CHADS 2 0 -1 2 3 -6 33 13 32 35 87 30 34 53 47 36 Connolly SJ, et al. N Engl J Med 2009; 361: 1139 -1151 Patel MR, et al. N Engl J Med 2011; 365: 883 -891 Granger CB, et al. N Engl J Med 2011; 365: 981 -992 Giugliano RP, et al. N Engl J Med 2013; e-pub ahead of print DOI: 10. 1056/NEJMoa 1310907 21

Trial Metrics RE-LY (Dabigatran) ROCKET-AF (Rivaroxaban) ARISTOTLE (Apixaban) ENGAGE AF (Edoxaban) Median Follow-Up, years

Trial Metrics RE-LY (Dabigatran) ROCKET-AF (Rivaroxaban) ARISTOTLE (Apixaban) ENGAGE AF (Edoxaban) Median Follow-Up, years 2. 0 1. 9 1. 8 2. 8 Median TTR 66 58 66 68 Lost to Follow-Up, N 20 32 90 1 *TTR, time in therapeutic range Connolly SJ, et al. N Engl J Med 2009; 361: 1139 -1151 Patel MR, et al. N Engl J Med 2011; 365: 883 -891 Granger CB, et al. N Engl J Med 2011; 365: 981 -992 Giugliano RP, et al. N Engl J Med 2013; e-pub ahead of print DOI: 10. 1056/NEJMoa 1310907 22

All NOACS: Stroke or SEE Risk Ratio (95% CI) 0. 66 (0. 53 -

All NOACS: Stroke or SEE Risk Ratio (95% CI) 0. 66 (0. 53 - 0. 82) RE-LY [150 mg] ROCKET AF 0. 88 (0. 75 - 1. 03) ARISTOTLE 0. 80 (0. 67 - 0. 95) ENGAGE AF-TIMI 48 0. 88 (0. 75 - 1. 02) Combined 0. 81 (0. 73 - 0. 91) [60 mg] [Random Effects Model] N=58, 541 0. 5 Heterogeneity p=0. 13 p=<0. 0001 Favors NOAC 1 Favors Warfarin 2 Ruff CT, et al. Lancet 2013 [in-press] 23

Secondary Efficacy Outcomes Risk Ratio (95% CI) Ischemic Stroke 0. 92 (0. 83 -

Secondary Efficacy Outcomes Risk Ratio (95% CI) Ischemic Stroke 0. 92 (0. 83 - 1. 02) Hemorrhagic Stroke 0. 49 (0. 38 - 0. 64) MI 0. 97 (0. 78 - 1. 20) All-Cause Mortality 0. 90 (0. 85 - 0. 95) p=0. 10 p<0. 0001 p=0. 77 0. 2 p=0. 0003 0. 5 Favors NOAC 1 2 Favors Warfarin Heterogeneity p=NS for all outcomes Ruff CT, et al. Lancet 2013 [in-press] 24

All NOACS: Major Bleeding Risk Ratio (95% CI) 0. 94 (0. 82 - 1.

All NOACS: Major Bleeding Risk Ratio (95% CI) 0. 94 (0. 82 - 1. 07) RE-LY [150 mg] ROCKET AF 1. 03 (0. 90 - 1. 18) ARISTOTLE 0. 71 (0. 61 - 0. 81) ENGAGE AF-TIMI 48 0. 80 (0. 71 - 0. 90) Combined 0. 86 (0. 73 - 1. 00) [60 mg] [Random Effects Model] N=58, 498 Heterogeneity p=0. 001 0. 5 p=0. 06 Favors NOAC 1 Favors Warfarin 2 Ruff CT, et al. Lancet 2013 [in-press] 25

Secondary Safety Outcomes Risk Ratio (95% CI) 0. 48 (0. 39 - 0. 59)

Secondary Safety Outcomes Risk Ratio (95% CI) 0. 48 (0. 39 - 0. 59) ICH p<0. 0001 1. 25 (1. 01 - 1. 55) GI Bleeding 0. 2 p=0. 043 0. 5 Favors NOAC 1 2 Favors Warfarin Heterogeneity ICH, p=0. 22 GI Bleeding, p=0. 009 Ruff CT, et al. Lancet 2013 [in-press] 26

Subgroups: Stroke or SEE Age Gender Diabetes Prior Stroke or TIA Cr. Cl CHADS

Subgroups: Stroke or SEE Age Gender Diabetes Prior Stroke or TIA Cr. Cl CHADS 2 Score VKA Status Center-Based TTR Risk Ratio (95% CI) P-Interaction <75 0. 85 (0. 73 - 0. 99) p=0. 38 ≥ 75 0. 78 (0. 68 - 0. 88) Female 0. 78 (0. 65 - 0. 94) Male 0. 84 (0. 75 - 0. 94) No 0. 83 (0. 74 - 0. 93) Yes 0. 80 (0. 69 - 0. 93) No 0. 78 (0. 66 - 0. 91) Yes 0. 86 (0. 76 - 0. 98) <50 0. 79 (0. 65 - 0. 96) 50 -80 0. 75 (0. 66 - 0. 85) >80 0. 98 (0. 79 - 1. 22) 0 -1 0. 75 (0. 54 - 1. 04) 2 0. 86 (0. 70 - 1. 05) 3 -6 0. 80 (0. 72 - 0. 89) Naive 0. 75 (0. 66 - 0. 86) Experienced 0. 85 (0. 70 - 1. 03) <66% 0. 77 (0. 65 - 0. 92) ≥ 66% 0. 82 (0. 71 - 0. 95) 0. 5 Ruff CT, et al. Lancet 2013 [in-press] Favors NOAC 1 Favors Warfarin p=0. 52 p=0. 73 p=0. 30 p=0. 12 p=0. 76 p=0. 31 p=0. 60 2 27

Subgroups: Major Bleeding Age Gender Diabetes Prior Stroke or TIA Cr. Cl CHADS 2

Subgroups: Major Bleeding Age Gender Diabetes Prior Stroke or TIA Cr. Cl CHADS 2 Score VKA Status Center-Based TTR Risk Ratio (95% CI) P-Interaction <75 0. 79 (0. 67 - 0. 94) p=0. 28 ≥ 75 0. 93 (0. 74 - 1. 17) Female 0. 75 (0. 58 - 0. 97) Male 0. 90 (0. 72 - 1. 12) No 0. 71 (0. 54 – 0. 93) Yes 0. 90 (0. 78 - 1. 04) No 0. 85 (0. 72 - 1. 01) Yes 0. 89 (0. 77 - 1. 02) <50 0. 74 (0. 52 - 1. 05) 50 -80 0. 91 (0. 76 - 1. 08) >80 0. 85 (0. 66 - 1. 10) 0 -1 0. 60 (0. 45 - 0. 80) 2 0. 88 (0. 65 - 1. 20) 3 -6 0. 86 (0. 71 - 1. 04) Naive 0. 84 (0. 76 - 0. 93) Experienced 0. 87 (0. 70 - 1. 08) <66% 0. 69 (0. 59 - 0. 81) ≥ 66% 0. 93 (0. 76 - 1. 13) 0. 2 Ruff CT, et al. Lancet 2013 [in-press] 0. 5 Favors NOAC 1 2 Favors Warfarin p=0. 29 p=0. 12 p=0. 70 p=0. 57 p=0. 09 p=0. 78 p=0. 022 28

ACTIVE-W: Stroke or SEE TTR ≥ 65% TTR < 65% Event Rate (%) P-interaction

ACTIVE-W: Stroke or SEE TTR ≥ 65% TTR < 65% Event Rate (%) P-interaction = 0. 013 RR = 1. 83 RR = 1. 11 P < 0. 0001 P = 0. 47 Clopi + ASA VKA Years Connolly SJ, et al. Circulation 2008; 118: 2029 -2037 Years 29

ACTIVE-W: Major Bleeding TTR ≥ 65% TTR < 65% P-interaction = 0. 0006 RR

ACTIVE-W: Major Bleeding TTR ≥ 65% TTR < 65% P-interaction = 0. 0006 RR = 0. 68 P = 0. 027 P = 0. 08 Event Rate (%) RR = 1. 55 Years Connolly SJ, et al. Circulation 2008; 118: 2029 -2037 Years 30

Low Dose Regimens Efficacy & Safety Outcomes Dabigatran 110 mg & Edoxaban 30 mg

Low Dose Regimens Efficacy & Safety Outcomes Dabigatran 110 mg & Edoxaban 30 mg Risk Ratio (95% CI) Stroke or SEE 1. 03 (0. 84 - 1. 27) Ischemic Stroke 1. 28 (1. 02 - 1. 60) p=0. 74 p=0. 045 0. 33 (0. 23 - 0. 46) Hemorrhagic Stroke p<0. 0001 MI 1. 25 (1. 04 - 1. 50) p=0. 019 0. 89 (0. 83 - 0. 96) All-Cause Mortality p=0. 003 0. 65 (0. 43 - 1. 00) Major Bleeding p=0. 05 0. 31 (0. 24 - 0. 41) ICH p<0. 0001 0. 89 (0. 57 - 1. 37) GI Bleeding N=26, 107 Heterogeneity P=NS for outcomes except: Major Bleeding, p=<0. 001 GI Bleeding, p=0. 01 p=0. 58 0. 2 0. 5 Favors Low Dose NOAC 1 2 Favors Warfarin Ruff CT, et al. Lancet 2013 [in-press] 31

Conclusions NOACs significantly reduce stroke ( 19%) − Primarily driven by reduction in hemorrhagic

Conclusions NOACs significantly reduce stroke ( 19%) − Primarily driven by reduction in hemorrhagic stroke ( 51%) NOACs significantly reduce mortality ( 10%) Trend toward less bleeding − − Substantial reduction in ICH ( 52%) Increased GI bleeding ( 25%) The relative efficacy and safety of NOACs consistent across a wide spectrum of AF patients − Even less bleeding when INR not as well controlled Low dose NOAC regimens reduce mortality and have a very favorable bleeding profile but more ischemic events Differences in agents, patients, and trials may not be accounted for − Heterogeneity major bleeding and GI bleeding 32

BACK – UP 33

BACK – UP 33

Factor Xa Inhibitors: Stroke or SEE Risk Ratio (95% CI) ROCKET AF 0. 88

Factor Xa Inhibitors: Stroke or SEE Risk Ratio (95% CI) ROCKET AF 0. 88 (0. 75 - 1. 03) ARISTOTLE 0. 80 (0. 67 - 0. 95) ENGAGE AF-TIMI 48 0. 88 (0. 75 - 1. 02) Combined 0. 86 (0. 78 - 0. 94) [Random Effects Model] p=0. 0011 N=46, 443 0. 5 Heterogeneity p=0. 65 Favors NOAC 1 Favors Warfarin 2 34

Factor Xa Inhibitors: Bleeding Risk Ratio (95% CI) 1. 03 (0. 89, 1. 18)

Factor Xa Inhibitors: Bleeding Risk Ratio (95% CI) 1. 03 (0. 89, 1. 18) ROCKET 0. 70 (0. 61, 0. 81) ARISTOTLE 0. 80 (0. 71, 0. 90) ENGAGE AF-TIMI 48 0. 83 (0. 68, 1. 02) Combined [Random Effects Model] N=46, 400 Heterogeneity p=0. 0006 0. 5 Favors NOAC 1 Favors Warfarin 2 35