1. Rivaroxaban Should be the Anticoagulant of Choice in High-Risk Non Valvular Atrial Fibrillation
Con: Sanjay Kaul, MD
Division of Cardiology
Cedars-Sinai Heart Institute Professor, Cedars-Sinai Medical Center &
Geffen School of Medicine at UCLA
Los Angeles, California 1

2. I have no real or apparent conflicts of interest to report.
Sanjay Kaul, MD
I have no real or apparent conflicts of interest to report.

3. Le Roi est mort, vive le Roi ! "The King is dead. Long live the King."
King Charles VII
of France 3

4. "The King is dead.
Long live the King."
Manesh Patel, MD 4

5. Christopher B. Granger, MD5

6. Interpreting The Results of ROCKET-AF Issues for Discussion
Statistical plan - Assessment of efficacy in non-inferiority & superiority trials
- Appropriate population: ITT vs On treatment (or Per-protocol)
- Proper “event window” (events post treatment discontinuation) - Double counting of hemorrhagic stroke (for efficacy and safety)
Adequacy of Warfarin management - Time in therapeutic range: surrogate vs marker of quality of care
- Constancy or HESDE: comparison with historical and contemporary trials - Impact on outcomes
Benefit-risk assessment
- Efficacy vs safety: overall and when warfarin “skillfully used”
- Cost
- Lack of monitoring vs. lack of reversibility - Optimal dose (no dose-ranging study in intended population) 6 6

7. Objective of Noninferiority Assessment
The new treatment is not inferior to (“not much worse than”, not “as good as”) the standard treatment
Employed when standard placebo controlled trials are considered unethical or impractical
Therapeutic utility may be based on the ancillary advantages in safety, tolerability, cost, convenience 7

8. Operational Criterion for “As Effective” Federal Register 1995 60(14):39180-1
“…for products intended to treat life threatening
diseases, diseases with irreversible morbidity, and
contagious diseases that pose serious health risks to others, it is essential for public health protection that a new therapy be as effective as existing, approved therapies.”
Point estimate of the test drug favored it over control
Upper bound of 95% CI very close to showing superiority (HR < ) 8

9. FDA Draft Noninferiority Guidance (2010)
Non-inferiority analysis - Both the “as treated” and ITT populations should be analyzed - Agreement of ITT and as treated analyses increases confidence in the trial’s results
Superiority analysis - The primary analysis should be ITT because as treated analysis are prone to bias from informative censoring 9

10. ROCKET-AF: Primary Efficacy Outcome (NIM = 1.38)
Broad Data Scope (OT/PP vs ITT; Rx Discontinuation Time)
Endpoint
Rivaroxaban
Warfarin HR
(95% CI)
P-value
Event Rate (100 Pt-Yr)
Per protocol OT + 2 d OT+ 7 d OT+ 30 d
188/6958 (1.71) 219/6958 (1.98) 247/6958 (2.16)
241/7004 (2.16) 253/7004 (2.25) 279/7004 (2.36)
0.79 (0.66, 0.96) 0.88 (0.74, 1.06) 0.90 (0.76, 1.07)
ITT Follow-up Site notification Regardless of exposure
257/7081 (2.18) 269/7081 (2.12) 293/7081 (2.20)
285/7090 (2.39) 306/7090 (2.42) 320/7090 (2.40)
0.91 (0.77, 1.08) 0.88 (0.74, 1.03) 0.91 (0.78, 1.07)
Superiority met only with per protocol, on treatment +2d analysis
Noninferiority met with all analyses
 in events post treatment discontinuation

11. ROCKET-AF: Post-Treatment Primary Efficacy Events
Safety: Days 3 to 30 after the Last Dose
Endpoint
Rivaroxaban
Warfarin HR
(95% CI)
P-value
Event Rate (100 Pt-Yr)
All participants
64/6843
(12.63)
42/6807
(8.36)
1.51
(1.02, 2.23)
0.037
Completed study medication (65%)
22/4587
(6.42)
6/4652
(1.73)
3.72
(1.51, 9.16)
0.004
Excess events at end of trial with rivaroxaban

12. Excess Events at End of Trial with Rivaroxaban
ROCKET-AF
Excess Events at End of Trial with Rivaroxaban
? Rebound hypercoagulability - Warfarin-naïve patients Rx with warfarin x 30 d = 3.78/100 Pt-Yrs Rivaroxaban patiens transitioning to warfarin = 6.42/100 Pt-Yrs HR = 1.7
? Inadequate anticoagulation (no formal transition/bridging plan) - Both under-anticoagulation as well as over-anticoagulation with R -  bleeding: 113 vs 68 related to INR>3 with Riva (HR = 1.65)

13. ROCKET-AF: Primary Efficacy & Safety Outcomes Best-Case Scenario (Safety/OT with Double Counting)
Endpoint
Rivaroxaban (N=7061)
Warfarin (N=7082)
HR (95% CI)
P-value
Event Rate
Efficacy (includes hemorrhagic stroke)
Stroke/SEE
189 (2.68%)
243 (3.43%)
0.79 (0.66, 0.96)
0.034
Total stroke Hemorrhagic Ischemic Unknown Type
184 (2.61%) 29 (0.41%) 149 (2.11%) 7 (0.10%)
221 (3.12%) 50 (0.71%) 161 (2.27%) 11 (0.16%)
0.69 (0.84, 1.01) 0.59 (0.37, 0.93) 0.95 (0.76, 1.18) 0.65 (0.25, 1.67)
Non-CNS Embolism
5 (0.07%)
22 (0.31%)
0.23 (0.09, 0.61)
0.003
Safety (includes hemorrhagic stroke)
Principal safety endpoint Major hemorrhage Non-major CR bleed
1475 (20.7%) 395 (5.6%) 1185 (16.7%)
1449 (20.3%) 386 (5.4%) 1151 (16.2%)
1.03 (0.96, 1.11) 1.04 (0.90, 1.20) 1.04 (0.96, 1.13)
Patel et al, NEJM 2011

14. ROCKET-AF: Primary Efficacy & Safety Outcomes Scenario (Safety/OT without Double Counting)
Endpoint
Rivaroxaban (N=7061)
Warfarin (N=7082)
HR (95% CI)
P-value
Event Rate
Efficacy (excludes hemorrhagic stroke)
Stroke/SEE
160 (2.27%)
193 (2.73%)
0.83 (0.68, 1.02)
0.080
Total stroke Hemorrhagic Ischemic Unknown Type
155 (2.61%) 0
149 (2.11%) 7 (0.10%)
171 (3.12%) (2.27%) 11 (0.16%)
0.91 (0.73, 1.13) NA 0.95 (0.76, 1.18) 0.65 (0.25, 1.67)
0.385 NA
Non-CNS Embolism
5 (0.07%)
22 (0.31%)
0.23 (0.09, 0.61)
0.003
Safety (includes hemorrhagic stroke)
Principal safety endpoint Major hemorrhage Non-major CR bleed
1475 (20.7%) 395 (5.6%) 1185 (16.7%)
1449 (20.3%) 386 (5.4%) 1151 (16.2%)
1.03 (0.96, 1.11) 1.04 (0.90, 1.20) 1.04 (0.96, 1.13)
Patel et al, NEJM 2011

15. ROCKET-AF: Primary Efficacy & Safety Outcomes Scenario (Safety/OT without Double Counting)
Endpoint
Rivaroxaban (N=7061)
Warfarin (N=7082)
HR (95% CI)
P-value
Event Rate
Efficacy (includes hemorrhagic stroke)
Stroke/SEE
189 (2.68%)
243 (3.43%)
0.79 (0.66, 0.96)
0.034
Total stroke Hemorrhagic Ischemic Unknown Type
184 (2.61%) 29 (0.41%) 149 (2.11%) 7 (0.10%)
221 (3.12%) 50 (0.71%) 161 (2.27%) 11 (0.16%)
0.69 (0.84, 1.01) 0.59 (0.37, 0.93) 0.95 (0.76, 1.18) 0.65 (0.25, 1.67)
Non-CNS Embolism
5 (0.07%)
22 (0.31%)
0.23 (0.09, 0.61)
0.003
Safety (excludes hemorrhagic stroke)
Principal safety endpoint Major hemorrhage Non-major CR bleed
1446 (20.3%) 366 (5.2%) 1185 (16.7%)
1399 (19.6%) 336 (4.7%) 1151 (16.2%)
1.04 (0.97, 1.11) 1.09 (0.94, 1.26) 1.04 (0.96, 1.13)
Patel et al, NEJM 2011

16. ROCKET-AF: Time in Therapeutic Range (TTR) INR Data
INR range
Warfarin
Mean
Median (25th, 75th)
<1.5
8.5%
2.7 (0.0 – 9.0)
1.5 to <1.8
10.4%
7.9 (3.5 – 14.0)
1.8 to <2.0
10.3%
9.1 (5.3 – 13.6)
2.0 to 3.0
55.2%
57.8 (43.0 – 70.5)
>3.0 to 3.2
4.8%
4.0 (1.9 – 6.5)
>3.2 to 5.0
9.9%
7.9 (3.3 – 13.8)
>5.0
1.0%
0.0 (0.0 – 0.5)
Based on Safety population using Rosendaal method with all INR values included
Overestimated in ROCKET-AF (all days of all patients in TR/total days)

17. Summary of TTR in Historical Warfarin Studies
Trial
Double blind
Target INR
(PT ratio)
TTR
Warfarin
Placebo
Risk ratio
AFASAK (1989) No
73%
9/413 (2.18%)
21/398 (5.3%)
0.41 (0.19, 0.89)
SPAF I (1991)
( )
71%
8/260 (3.08%)
20/244 (8.20%)
0.38 (0.17, 0.84)
BAATAF (1990)
( )
83%
3/487 (0.62%)
13/435 (2.99%)
0.21 (0.06, 0.72)
CAFA* (1991)
Yes
44%
7/237 (2.95%)
11/241 (4.56%)
0.65 (0.26, 1.64)
SPINAF (1992)
( )
56%
9/489 (1.84%)
24/483 (4.97%)
0.37 (0.17, 0.79)
EAFT (1993)
59%
21/507 (4.14%)
54/405 (13.3%)
0.31 (0.19, 0.51)
4/6 historical studies had higher TTR than ROCKET-AF
CAFA had lower TTR (trial prematurely terminated)

18. Time in Therapeutic Range (TTR) Real-World Experience
Study
Setting
Mean TTR
Baker et al
AC clinics
Community-based
Overall
63%
51%
55%
Rose et al
VAHC AC clinics
48% (<6m) 64% (>6m)
ROCKET-AF
RCT
Anticoagulation quality in ROCKET-AF
reflective of “real-world” experience

19. Time in Therapeutic Range (TTR) Recent Trials
Study
Double blind
Mean TTR
SPORTIF III No
66%
SPORTIF V
Yes
68%
ACTIVE W
64%
AMADEUS
RE-LY
EMBRACE AC
73%
ARISTOTLE
62%
ROCKET-AF
55%

20. Primary Efficacy Analysis by Site TTR
Center TTR
Warfarin
R vs W HR (95% CI)
Non-inferiority (M2=1.38)
n/N
Events/100 Pt-Yr
4th quartile (TTR >63.9) Safety, OT + 2 d
55/1803
1.75
0.75
( )
Yes
4th quartile (TTR >63.9) Safety, OT + 30 d
68/1803
1.93
0.98
( ) No
Center TTR >65 Safety, OT + 2 d
41/1545
1.54
0.84
( )
Center TTR >65 Safety, OT + 30 d
49/1545
1.76
1.10
( )
4th quartile (TTR >67.8) Safety, OT + 2 d
23/1165
1.14
1.02
( )
4th quartile (TTR >67.8) Safety, OT + 30 d
29/1165
1.38
1.30
( )
As noted in previous, smaller studies, the characteristics of patients with and without high residual reactivity differed substantially.
However, the indication for PCI was similar between the two groups.
Optimal INR control and broader “event window” shift the results in favor of warfarin 21

21. Assessment of Noninferiority in RE-LY
Impact of Target INR
Endpoint
Optimal INR control (64%)
Suboptimal INR control
D110
(%) W
ARD HR
Stroke/SEE
1.60
1.40
0.20
1.12
( )
1.5
2.0
-0.5
0.73
( )
Major bleeding
2.88
2.90
-0.02
0.95
( )
D150
1.10
-0.30
0.81
( )
1.1
-0.9
0.53
( )
3.41
0.51
( )
Noninferiority not met with dabigatran 110 mg vs. optimal INR control
Superiority not met with dabigatran 150 mg vs. optimal INR control

22. TTR is a Marker of Quality of Care
Insights from ROCKET-AF and ARISTOTLE
TTR quartiles
Experimental Rx
Warfarin
P-value
(interaction)
Event Rate (100 Pt-Yr)
ROCKET-AF % % % %
45/1735 (1.77)
53/1746 (1.94) 54/1734 (1.90) 37/1676 (1.33)
62/1689 (2.53)
63/1807 (2.18) 62/1758 (2.14) 55/1826 (1.80)
0.734
ARISTOTLE <58.0% % % >72.2%
70/2266 (1.75)
54/2251 (1.30) 51/2256 (1.21) 36/2266 (0.83)
88/2252 (2.28)
68/2278 (2.18) 65/2266 (1.55) 44/2251 (1.02)
0.29
Reduced event rates in both treatment groups with improved TTR suggests TTR might be a marker of quality of care

23. Risk difference (per 10,000 patients-yrs)
ROCKET-AF: Rivaroxaban vs. Warfarin (Safety/OT)
Key Benefit-Risk Summary Graph
Utility ~0
(most severe)
All-cause death
-34
Disabling stroke
-12
Systemic embolism
-15
Non-disabling stroke 2
Myocardial infarction
-21
Major bleeding 14 44
Non-major clinically- relevant bleeding
Utility ~1
(least severe)
-150
-100
-50 50
100
150
Risk difference (per 10,000 patients-yrs)
Favors Rivaroxaban
Favors Warfarin

24. Benefit Risk Benefit-Risk Balance in ROCKET-AF (Safety/On Treatment)
1000 Patients Treated with Rivaroxaban instead of Warfarin
Riva vs Warfarin
Benefit
3 fewer hemorrhagic strokes
4 fewer ischemic strokes/SEE
No monitoring/fixed dose
Limited potential for drug/food interaction
Risk
7 excess bleeding excess blood transfusion excess Hgb drop >2g/dL
6 excess SAEs leading to Rx discontinuation
Increased cost/no antidote
Benefit exceeds risk, but differences are marginal (NNT>250)!
What about broader event window and ITT scenario? 25 25

25. Does ROCKET-AF Provide Compelling Evidence to Justify Rivaroxaban as First-Choice Rx in NVAF?
Quality of
Warfarin Rx
Non-inferiority
“As effective
As”
Non-efficacy
benefit
Safety Superiority
Cost/
Ancillary
As used in the study - Safety, OT + 2d - Safety, OT + 30d
Yes Yes
No No
No/Yes No/Yes
Skillfully used (TTR >68%) - Safety, OT + 2d - Safety, OT + 30d
As used in ROCKET, non-inferior efficacy established, but not superior safety
When skillfully used, non-inferior efficacy or superior safety not established

26. When Should Rivaroxaban (or Daibigatran) Not be Preferred Over Warfarin?
Severe renal impairment (Cr Cl <15 to 30mL/min)
Non-adherence (dabigatran only); Non-affordability
Dyspepsia, h/o GI hemorrhage (dabigatran only)
Need for rapid reversibility
Prosthetic heart valves
Hemodynamically-significant heart valve disease
Acute coronary syndromes, TIA, ischemic strokes, DVTs, PE
P-gp affecting drugs (rifampim, ? quinidine); ketoconazole
? h/o MI (dabigatran only)
? dual antiplatelet therapy (only 8% took clopidogrel in RE-LY)
DC Cardioversion
Patients with optimal INR who value patient-doctor relationship-building monthly visits and want to know extent of Rx effect 27

27. Who Are the Ideal Candidates for Rivaroxaban?
History of TIA/stroke (optimal benefit-risk)
Poor anticoagulant control on warfarin
Patients unable, unwilling, or desiring not to undergo regular coagulation tests
History of rare side effects from warfarin (skin necrosis)
? Increased risk of ICH (not studied in RCTs) 28

28. “The reports of my death are greatly exaggerated”29

30. Recommendations for Thromboprophylaxis in Atrial Fibrillation
HAS-BLED Score
0-2
(Bleeding risk 2%/y)
>3
(Bleeding risk 3%/y)
(Stroke risk 0%/y)
Aspirin alone
No treatment 1
(Stroke risk 1%/y)
OAC - Dabigatran 150 mg bid
- Warfarin (INR = 2-3)
? Dabigatran 110 mg bid
>2
(Stroke risk >2%/y)
- Rivaroxaban 20mg qd
? Left atrial appendage closure device
CHA2DS2-VASc
Score

31. Double Blind / Double Dummy Adherence to standard of care guidelines
Risk Factors
CHF
Hypertension
Age  75
Diabetes OR
Stroke, TIA or Systemic embolus
ROCKET-AF: Study Design
At least 2 or 3 required*
Atrial Fibrillation
Rivaroxaban
Warfarin
Randomize
Double Blind / Double Dummy
(n ~ 14,000)
20 mg daily
15 mg for Cr Cl ml/min
INR target - 2.5
( inclusive)
Monthly Monitoring
Adherence to standard of care guidelines
Primary Endpoint: Noninferiority on stroke or non-CNS Systemic Embolism
* Enrollment of patients without prior Stroke, TIA or systemic embolism and only 2 factors capped at 10%
Rocket AF Investigators, AHA 2010

32. Anti-Xa or Anti-IIa Rx Strategy for NVAF ROCKET-AF vs. RE-LY Comparison
Treatment groups
Rivaroxaban vs warfarin
Dabigatran vs warfarin
Design
Double-blind, non-inferiority
Open-label, non-inferiority
Patients
14,264 in 45 countries
18,113 in 44 countries
Risk
- Mean age 73 y
- Mean CHADS2 score (>85% CHADS2 >3)
- Prior h/o CVA/SEE = 55%
- Mean age 71.5y
- Mean CHADS2 score (32% CHADS2 >3)
- Prior h/o CVA/SEE = 20%
Median Duration of Follow-Up
589 days of exposure, 707 days including period off drug during follow-up
2 years (about 730 days)
Warfarin-naive
37.5%
50%
Time in Therapeutic Range (TTR)
57.8%
64%

33. Anti-Xa or Anti-IIa Rx Strategy for NVAF ROCKET-AF vs RE-LY Comparison (ITT)
Endpoint
ROCKET-AF
RE-LY
Rivaroxaban
(N=7,081)
Warfarin
(N=7,090)
Dabigatran 150mg
(N=6.076)
(N=6,022)
Stroke
-SEE
2.11%/yr
2.42%/yr
1.11%/yr
1.69%/yr
0.88 (0.74,1.03)
0.65 (0.52, 0.81)
Ischemic stroke
1.62%/yr
1.64%/yr
0.92%/yr
1.2%/yr
0.99 (0.82, 1.20)
0.75 (0.58, 0.97)
Hemorrhagic stroke
0.26%/yr
0.44%/yr
0.10%/yr
0.38%/yr
0.58 (0.38, 0.89)
0.26 (0.14, 0.49)
Major bleeding
3.60%/yr
3.45%/yr
3.11%/yr
3.36%/yr
1.04 (0.90, 1.20)
0.93 (0.81, 1.07)

34. Myocardial infarction
Anti-Xa or Anti-IIa Rx Strategy for NVAF ROCKET-AF vs RE-LY Comparison (ITT)
Endpoint
ROCKET-AF
RE-LY
Rivaroxaban
(N=7,081)
Warfarin
(N=7,090)
Dabigatran 150mg
(N=6.076)
(N=6,022)
Myocardial infarction
1.02%/yr
1.11%/yr
0.74%/yr
0.53%/yr
0.91 (0.72, 1.16)
1.38 (1.00, 1.91)
[1.27 ( )]*
All cause mortality
4.52%/yr
4.91%/yr
3.64%/yr
4.13%/yr
0.92 (0.82, 1.03)
0.88 (0.77, 1.00)
* revised data

35. Ketoconazole, Ritonavir
Anti-Xa or Anti-IIa
How to Choose (when there are no direct comparisons)?
Characteristic
Dabigatran
Rivaroxaban
Renal dysfunction + ++
Dosing & adherence
+ (bid)
++ (qd)
Drug interactions
Rifampin, quinidine
Amiodarone, verapamil
Ketoconazole, Ritonavir
GI side effects/
dyspepsia -
MI signal
Pharmacological properties and safety/tolerability more important
than treatment target 36

36. ROCKET-AF: Primary Efficacy Outcome
Broad Data Scope (OT/PP vs ITT; Rx Discontinuation Time)
Endpoint
Rivaroxaban
Warfarin HR
(95% CI)
P-value
Event Rate (100 Pt-Yr)
Per protocol OT + 2 d OT+ 7 d OT+ 30 d
188/6958 (1.71) 219/6958 (1.98) 247/6958 (2.16)
241/7004 (2.16) 253/7004 (2.25) 279/7004 (2.36)
0.79 (0.66, 0.96) 0.88 (0.74, 1.06) 0.90 (0.76, 1.07)
Safety OT + 2 d OT+ 7 d OT+ 30 d
189/7061 (1.70) 220/7061 (1.96) 251/7061 (2.16)
243/7082 (2.15) 255/7082 (2.24) 281/7082 (2.38)
0.79 (0.65, 0.95) 0.88 (0.73, 1.05) 0.91 (0.76, 1.07)
ITT Follow-up Site notification Regardless of exposure
257/7081 (2.18) 269/7081 (2.12) 293/7081 (2.20)
285/7090 (2.39) 306/7090 (2.42) 320/7090 (2.40)
0.91 (0.77, 1.08) 0.88 (0.74, 1.03) 0.91 (0.78, 1.07)

37. ROCKET-AF: Major Outcomes
Broad Data Scope (OT/PP vs ITT; Rx Discontinuation Time)
HR for Rivaroxaban vs. Warfarin
Safety population
ITT population
Endpoint
On treatment
Site notification
Data cutoff
Stroke/SEE Ischemic Hemorrhagic SEE
0.79 ( ) 0.95 ( )
0.59 ( )
0.23 ( )
0.88 ( )
0.99 ( )
0.58 ( ) ( )
0.91 ( )
1.03 ( )
0.65 ( )
0.74 ( )
All cause mortality Hemorrhagic
0.85 ( ) ( )
0.92 ( ) ( )
0.93 ( )
0.66 ( )
Major hemorrhage Intracranial
1.04 ( ) ( )
Patel et al, NEJM 2011
FDA briefing document, 2011