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

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.

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

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

Christopher B. Granger, MD 5

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

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

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 <1.05-1.10) 8

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

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) 0.018 0.172 0.230 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) 0.286 0.117 0.263 Superiority met only with per protocol, on treatment +2d analysis Noninferiority met with all analyses  in events post treatment discontinuation

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

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)

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) 0.092 0.024 0.581 0.366 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) 0.442 0.576 0.345 Patel et al, NEJM 2011

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%) 0 161 (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 0.581 0.366 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) 0.442 0.576 0.345 Patel et al, NEJM 2011

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) 0.092 0.024 0.581 0.366 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) 0.100 0.235 0.345 Patel et al, NEJM 2011

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)

Summary of TTR in Historical Warfarin Studies Trial Double blind Target INR (PT ratio) TTR Warfarin Placebo Risk ratio AFASAK (1989) No 2.4-4.2 73% 9/413 (2.18%) 21/398 (5.3%) 0.41 (0.19, 0.89) SPAF I (1991) 2.0-4.5 (1.3-1.8) 71% 8/260 (3.08%) 20/244 (8.20%) 0.38 (0.17, 0.84) BAATAF (1990) 1.5-2.7 (1.2-1.5) 83% 3/487 (0.62%) 13/435 (2.99%) 0.21 (0.06, 0.72) CAFA* (1991) Yes 2.0-3.0 44% 7/237 (2.95%) 11/241 (4.56%) 0.65 (0.26, 1.64) SPINAF (1992) 1.4-2.8 (1.2-1.5) 56% 9/489 (1.84%) 24/483 (4.97%) 0.37 (0.17, 0.79) EAFT (1993) 2.5-4.0 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)

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

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%

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 (0.49-1.13) Yes 4th quartile (TTR >63.9) Safety, OT + 30 d 68/1803 1.93 0.98 (0.69-1.41) No Center TTR >65 Safety, OT + 2 d 41/1545 1.54 0.84 (0.53-1.34) Center TTR >65 Safety, OT + 30 d 49/1545 1.76 1.10 (0.75-1.64) 4th quartile (TTR >67.8) Safety, OT + 2 d 23/1165 1.14 1.02 (0.56-1.84) 4th quartile (TTR >67.8) Safety, OT + 30 d 29/1165 1.38 1.30 (0.79-2.13) 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

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 (0.87-1.44) 1.5 2.0 -0.5 0.73 (0.58-0.92) Major bleeding 2.88 2.90 -0.02 0.95 (0.80-1.13) D150 1.10 -0.30 0.81 (0.62-1.05) 1.1 -0.9 0.53 (0.41-0.67) 3.41 0.51 (0.93-1.31) Noninferiority not met with dabigatran 110 mg vs. optimal INR control Superiority not met with dabigatran 150 mg vs. optimal INR control

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 0.00-50.62% 50.71-58.54% 58.63-65.71% 65.74-100.0% 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% 58.0-65.7% 65.7-72.2% >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

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

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 - 3 excess blood transfusion - 5 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

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

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

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

“The reports of my death are greatly exaggerated” 29

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

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 30-49 ml/min INR target - 2.5 (2.0-3.0 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

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 3.5 (>85% CHADS2 >3) - Prior h/o CVA/SEE = 55% - Mean age 71.5y - Mean CHADS2 score 2.1 (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%

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)

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 (0.94-1.71)]* 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

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

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) 0.018 0.172 0.230 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) 0.015 0.149 0.252 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) 0.286 0.117 0.263

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 (0.66-0.96) 0.95 (0.76-1.18) 0.59 (0.37-0.93) 0.23 (0.09-0.61) 0.88 (0.78-1.03) 0.99 (0.82-1.20) 0.58 (0.38-0.89) 0.74 (0.42-1.32) 0.91 (0.78-1.07) 1.03 (0.85-1.24) 0.65 (0.43-0.98) 0.74 (0.42-1.32) All cause mortality - Hemorrhagic 0.85 (0.70-1.02) 0.56 (0.41-0.92) 0.92 (0.82-1.03) 0.63 (0.44-0.90) 0.93 (0.84-1.04) 0.66 (0.47-0.92) Major hemorrhage - Intracranial 1.04 (0.90-1.20) 0.67 (0.47-0.93) Patel et al, NEJM 2011 FDA briefing document, 2011