Kenneth W. Mahaffey, MD and Keith AA Fox, MB ChB on behalf of the ROCKET AF Investigators

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Kenneth W. Mahaffey, MD and Keith AA Fox, MB
ChBon behalf of the ROCKET AF Investigators
Rivaroxaban Once-daily oral direct factor Xa
inhibition Compared with vitamin K antagonism for
prevention of stroke and Embolism Trial in Atrial
Fibrillation
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Relevant Financial Relationships

• Kenneth W. Mahaffey, MD
• Research Grants AstraZeneca, Bayer, BI, BMS,
  Eli Lilly, JJ, Merck, Novartis, Portola, Regado,
  Sanofi-Aventis, The Medicines Company
• Consulting Fees AstraZeneca, Bayer, BI, BMS,
  Eli Lilly, JJ, Merck, Novartis, Sanofi-Aventis
• No stock ownership
• http//www.dcri.duke.edu/research/coi.jsp
• Keith AA Fox, MB ChB
• Research Grants Bayer, Eli Lilly, JJ,
  Sanofi-Aventis
• Consulting Fees Bayer, Eli Lilly, JJ,
  Sanofi-Aventis
• No stock ownership

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BackgroundRivaroxaban
TF/VIIa

• Direct, specific, competitive factor Xa inhibitor
• Half-life 5-13 hours
• Clearance
• 1/3 direct renal excretion
• 2/3 metabolism via CYP 450 enzymes
• Oral, once daily dosing without need for
  coagulation monitoring
• Studied in gt25,000 patients in post-op, DVT, PE
  and ACS patients

X
IX
IXa
VIIIa
Rivaroxaban
Va
Xa
II
IIa
Fibrin
Fibrinogen
Adapted from Weitz et al, 2005 2008
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Study Design

• Risk Factors
• CHF
• Hypertension
• Age ? 75
• Diabetes
• OR
• Stroke, TIA or Systemic embolus

At least 2 or 3 required
Atrial Fibrillation
Rivaroxaban
Warfarin
Randomize Double Blind / Double Dummy (n
14,000)
INR target - 2.5 (2.0-3.0 inclusive)
20 mg daily 15 mg for Cr Cl 30-49 ml/min
Monthly Monitoring Adherence to standard of care
guidelines
Primary Endpoint Stroke or non-CNS Systemic
Embolism
Enrollment of patients without prior Stroke,
TIA or systemic embolism and only 2 factors
capped at 10
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Statistical Methodologies

• Sample Size
• Warfarin event rate 2.3
• Type 1 error 0.05 (2-sided)
• 405 events gt95 power
• 14,000 patients
• Primary Efficacy Evaluation Stroke or non-CNS
  Embolism
• Non-Inferiority Protocol Compliant on
  treatment
• Superiority On Treatment and then by
  Intention-to-Treat
• Primary Safety Evaluation Major or non-Major
  Clinically Relevant Bleeding

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Enrollment45 countries, 1178 sites, 14,264
patients
Poland 528
Finland 16
Lithuania 245
Sweden 28
Hungary 237
Norway 49
Romania 783
Czech Rep 598
Bulgaria 678
Russia 1,292
Denmark 123
Ukraine 1,011
U.K. 159
Canada 750
Netherlands 161
Belgium 96
Korea 204
United States 1,932
China 496
France 71
Taiwan 159
Spain 250
Mexico 168
Germany 530
Hong Kong 73
India 269
Switzerland 7
Thailand 87
Philippines 368
Austria 32
Malaysia 51
Panama 0
Italy 139
Singapore 44
Venezuela 20
Greece 29
Colombia 268
Turkey 101
Israel 189
Peru 84
Australia 242
Brazil 483
South Africa 247
Chile 287
Argentina 569
New Zealand 116
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Study Conduct
Rivaroxaban Warfarin
Randomized, n Lost to Follow-up, n Premature Discontinuation, n () Withdrew Consent, n Median (25th, 75th) Exposure (days) Median (25th, 75th) Follow-up (days) 7131 18 1693 (23.9) 626 589 (396, 805) 706 (522, 884) 7133 18 1589 (22.4) 620 593 (404, 810) 708 (518, 886)
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Baseline Demographics
Rivaroxaban (N7081) Warfarin (N7090)
Age (years) 73 (65, 78) 73 (65, 78)
Female () 40 40
Race () White Black Asian 83 1 13 83 1 13
Region () North America Latin America Asia-Pacific Central Europe Western Europe 19 13 15 38 15 19 13 15 38 15
Creatinine Clearance (ml/min) () 30 - lt50 50 - 80 gt 80 21 47 32 21 48 31
Values are median (IQR) Based on
Intention-to-Treat Population
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Baseline Demographics
Rivaroxaban (N7081) Warfarin (N7090)
CHADS2 Score (mean) 2 () 3 () 4 () 5 () 6 () 3.48 13 43 29 13 2 3.46 13 44 28 12 2
Prior VKA Use () 62 63
Congestive Heart Failure () 63 62
Hypertension () 90 91
Diabetes Mellitus () 40 39
Prior Stroke/TIA/Embolism () 55 55
Prior Myocardial Infarction () 17 18
Based on Intention-to-Treat Population
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Trial ResultsKenneth W. Mahaffey, MD on
Behalf of the ROCKET AF Investigators
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Primary Efficacy OutcomeStroke and non-CNS
Embolism
Rivaroxaban Warfarin
Event Rate 1.71 2.16
Warfarin
Rivaroxaban
Cumulative event rate ()
HR (95 CI) 0.79 (0.66, 0.96) P-value
Non-Inferiority lt0.001
Days from Randomization
No. at risk Rivaroxaban 6958 6211 5786
5468 4406 3407 2472 1496
634 Warfarin 7004 6327 5911
5542 4461 3478 2539 1538 655
Event Rates are per 100 patient-years Based on
Protocol Compliant on Treatment Population
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Primary Efficacy OutcomeStroke and non-CNS
Embolism
  Rivaroxaban Warfarin    
Event Rate Event Rate HR(95 CI) P-value
On Treatment N 14,143 1.70 2.15 0.79 (0.65,0.95) 0.015
ITT N 14,171 2.12 2.42 0.88 (0.74,1.03) 0.117
Rivaroxaban better
Warfarinbetter
Event Rates are per 100 patient-years Based on
Safety on Treatment or Intention-to-Treat thru
Site Notification populations
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Key Secondary Efficacy Outcomes
Rivaroxaban Warfarin
Event Rate Event Rate HR (95 CI) P-value
Vascular Death, Stroke, Embolism 3.11 3.63 0.86 (0.74, 0.99) 0.034
Stroke Type Hemorrhagic Ischemic Unknown Type 0.261.340.06 0.441.420.10 0.59 (0.37, 0.93)0.94 (0.75, 1.17)0.65 (0.25, 1.67) 0.0240.5810.366
Non-CNS Embolism 0.04 0.19 0.23 (0.09, 0.61) 0.003
Myocardial Infarction 0.91 1.12 0.81 (0.63, 1.06) 0.121
All Cause Mortality Vascular Non-vascular Unknown Cause 1.871.530.190.15 2.211.710.300.20 0.85 (0.70, 1.02)0.89 (0.73, 1.10)0.63 (0.36, 1.08)0.75 (0.40, 1.41) 0.0730.2890.0940.370
Event Rates are per 100 patient-years Based on
Safety on Treatment Population
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Key Secondary Efficacy Outcomes
Rivaroxaban Warfarin
Event Rate Event Rate HR (95 CI) P-value
Vascular Death, Stroke, Embolism 4.51 4.81 0.94 (0.84, 1.05) 0.265
Stroke Type Hemorrhagic Ischemic Unknown Type 0.26 1.62 0.15 0.44 1.64 0.14 0.58 (0.38, 0.89) 0.99 (0.82, 1.20 1.05 (0.55, 2.01) 0.012 0.916 0.871
Non-CNS Embolism 0.16 0.21 0.74 (0.42, 1.32 0.308
Myocardial Infarction 1.02 1.11 0.91 (0.72, 1.16) 0.464
All Cause Mortality Vascular Non-vascular Unknown Cause 4.52 2.91 1.15 0.46 4.91 3.11 1.22 0.57 0.92 (0.82, 1.03) 0.94 (0.81, 1.08) 0.94 (0.75, 1.18) 0.80 (0.57, 1.12) 0.152 0.350 0.611 0.195
Event Rates are per 100 patient-years Based on
Intention-to-Treat Population
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Time in Therapeutic Range (TTR)INR Data
INR range Warfarin Median (25th, 75th)
lt1.5 2.7 (0.0 9.0)
1.5 to lt1.8 7.9 (3.5 14.0)
1.8 to lt2.0 9.1 (5.3 13.6)
2.0 to 3.0 57.8 (43.0 70.5)
gt3.0 to 3.2 4.0 (1.9 6.5)
gt3.2 to 5.0 7.9 (3.3 13.8)
gt5.0 0.0 (0.0 0.5)
Based on Rosendaal method with all INR values
included Based on Safety Population
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Primary Efficacy Outcome by Quartiles of
cTTRStroke and non-CNS Embolism
Rivaroxaban Rivaroxaban Warfarin Warfarin
Center TTR Events Event Rate Events Event Rate HR(95 CI)
0.0 - 50.6 2.6 1.8 3.7 2.5 0.71 (0.48, 1.03)
50.7 - 58.5 3.0 1.9 3.5 2.2 0.83 (0.62, 1.29)
58.6 - 65.7 3.1 1.9 3.5 2.1 0.92 (0.62, 1.28)
65.7 - 100.0 2.2 1.3 3.0 1.8 0.77 (0.49, 1.12)
Based on Rosendaal method with all INR values
included Based on Safety Population Event Rates
are per 100 patient-years
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Primary Safety Outcomes
Rivaroxaban Warfarin
Event Rate Event Rate HR (95 CI) P-value
Major and non-major Clinically Relevant 14.91 14.52 1.03 (0.96, 1.11) 0.442
Major 3.60 3.45 1.04 (0.90, 1.20) 0.576
Non-major Clinically Relevant 11.80 11.37 1.04 (0.96, 1.13) 0.345
Event Rates are per 100 patient-years Based on
Safety on Treatment Population
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Primary Safety Outcomes
Rivaroxaban Warfarin
Event Rate or N (Rate) Event Rate or N (Rate) HR (95 CI) P-value
Major gt2 g/dL Hgb drop Transfusion (gt 2 units) Critical organ bleeding Bleeding causing death 3.60 2.77 1.65 0.82 0.24 3.45 2.26 1.32 1.18 0.48 1.04 (0.90, 1.20) 1.22 (1.03, 1.44) 1.25 (1.01, 1.55) 0.69 (0.53, 0.91) 0.50 (0.31, 0.79) 0.576 0.019 0.044 0.007 0.003
Intracranial Hemorrhage 55 (0.49) 84 (0.74) 0.67 (0.47, 0.94) 0.019
Intraparenchymal 37 (0.33) 56 (0.49) 0.67 (0.44, 1.02) 0.060
Intraventricular 2 (0.02) 4 (0.04)
Subdural 14 (0.13) 27 (0.27) 0.53 (0.28, 1.00) 0.051
Subarachnoid 4 (0.04) 1 (0.01)
Event Rates are per 100 patient-years Based on
Safety on Treatment Population
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Adverse Events and Liver Enzyme Data
Rivaroxaban (N7111) Warfarin (N7125)
Any Adverse Event Any Serious Adverse Event AE leading to study drug discontinuation 82.4 37.3 15.7 82.2 38.2 15.2
Epistaxis Peripheral edema Dizziness Nasopharyngitis Cardiac failure Bronchitis Dyspnea Diarrhea 10.1 6.1 6.1 5.9 5.6 5.6 5.3 5.3 8.6 6.2 6.3 6.4 5.9 5.9 5.5 5.6
ALT Elevation gt3 x ULN gt5 x ULN gt3 x ULN and T Bili gt 2 x ULN 2.9 1.0 0.4 2.9 1.0 0.5
Values are N () Based on Safety Population
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Summary

• Efficacy
• Rivaroxaban was non-inferior to warfarin for
  prevention of stroke and non-CNS embolism.
• Rivaroxaban was superior to warfarin while
  patients were taking study drug.
• By intention-to-treat, rivaroxaban was
  non-inferior to warfarin but did not achieve
  superiority.
• Safety
• Similar rates of bleeding and adverse events.
• Less ICH and fatal bleeding with rivaroxaban.
• Conclusion
• Rivaroxaban is a proven alternative to warfarin
  for moderate or high risk patients with AF.

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Study Organization
IDMC Joe Alpert, ChairAllen Skene,
Co-chairGudrun Boysen John Eikelboom Peter
Rothwell
SponsorsJ J and Bayer Christopher Nessel,
Kimberly Schwabe, Scott Berkowitz, John Paolini
Executive Steering Committee
Steering Committee Diego Ardissino, Alvaro
Avezum, Phil Aylward, Barbara Biedermann,
Christoph Bode, Antonio Carolei, Ramon Corbalan,
Laszlo Csiba, Anthony Dalby, Rafael Diaz, Hans
Diener, Geoffrey Donnan, Shaun Goodman, Bas
Hamer, Hein Heidbuchel, Dai-Yi Hu, Kurt Huber,
Gorm Jensen, Matyas Keltai, Basil Lewis, Jose
Lopez-Sandon, Jean Louis Mas, Ayrton Massaro,
Gordon MacInnes, Bo Norrving, Martin Penicka,
Dorairaj Prabhakaran, Risto Roine, Tan Ru San,
Per Anton Sirnes, Veronika Skvortsova, Gabriel
Steg, Harvey White, Lawrence Wong
CEC Manesh Patel Joni O'Briant Lauren Price
Duke Clinical Research Institute Jonathan
Piccini, Karen Hannan, Jyotsna Garg, Lisa
Eskenazi, Angela Kaiser, Patricia Stone
Canadian Heart Research Center Shaun
Goodman Maggie Godin-Edgecomb