1. ROCKET-AF
Rivaroxaban versus Warfarin in
Nonvalvular Atrial Fibrillation
by Theodore Graphos

2. Objective
The primary objective of this study is to demonstrate
that the efficacy of rivaroxaban, a direct FXa inhibitor,
is non-inferior to that of dose-adjusted warfarin for the
prevention of thromboembolic events in subjects with
non-valvular atrial fibrillation as measured by the
composite of stroke and non-central nervous system
(non-CNS) systemic embolism.

3. Article
JOURNAL
New England Journal of Medicine
▪ Peer-reviewed
AUTHORS
▪ Physicians (mostly cardiologists)
▪ No statistician listed
FUNDING
▪ Johnson & Johnson Pharmaceutical Research and Development
▪ Bayer HealthCare

4. Background A-fib
MEDSCAPE 
Atrial fibrillation (AF) is a relatively common cardiac
arrhythmia that can have adverse consequences related to:
1) A reduction in cardiac output (symptoms)
2) Atrial and atrial appendage thrombus formation
(stroke and peripheral embolization).
In addition, affected patients may be at increased risk for
mortality.

5. Background Stroke Risk
Non-valvular a-fib
• 2- to 7-fold increased risk of stroke
Valvular a-fib
• 17-fold increased risk of stroke

7. Competitors
Dabigatran Rivaroxaban Apixaban Edoxaban
Stroke prevention
RELY ARISTOTLE
A-Fib
RELY-ABLE
ROCKET-AF
AVERROES
<>
Rivaroxaban is currently
Treatment RECOVER EINSTEIN-DVT
FDA approved for VTE
AMPLIFY HOKUSAI
RECOVER-2 & EINSTEIN-PE
prophylaxis after major
Long-term secondary
prophylaxis
REMEDY
EINSTEIN-
AMPLIFY-EXT HOKUSAI
orthopedic surgery
Extension
RESONATE
Prophylaxis in acute
medical illness
VTE
<> MAGELLAN ADOPT <>
The only other new
anticoagulant approved
Prophylaxis after REMODEL (Knee)
major orthopedic
REMOBILIZE (Knee)
for a-fib is dabigatran
surgery RECORD (1-4) NCT00097357 <>
RENOVATE (Hip)
RENOVATE 2 (Hip)
Secondary prevention ATLAS ACS TIMI 46 ENGAGE AF-
ACS
REDEEM APPRAISE-2
NCT00809965 TIMI 48

8. Design & Oversight
ROCKET-AF Executive Committee
• Study design
• Oversight
Duke Clinical Research Institute
• Coordinated the trial
• Primary data analysis
• Independent of the sponsor
Protocol was approved by IRBs at participating sites

9. Structure
Multi-center
 1178 sites, 45 countries
Randomized
Double-blind
Double-dummy
Event-driven
 405 adjudicated endpoint events reached followed
by study closure activities

10. Subjects Inclusion criteria
Subjects meet all of the following:
Non-valvular atrial fibrillation
– “Subjects with atrial fibrillation and valvular disease (either mitral stenosis or
prosthetic valve) are excluded even though they have a clear indication for
anticoagulant therapy since the previous placebo controlled trials of warfarin
therapy did not include these subjects.”
– A-fib with a concomitant valve disorder is associated with a much higher risk of
thromboembolism
Moderate-to-high risk of stroke
– Hx of stroke, TIA, or non-CNS systemic embolism
- OR - CHADS2 score of 2 or more
– >90% were required to have a previous thromboembolism or CHADS2 score of 3 or
more

11. SubjectsExclusion criteria
Cardiac-Related Conditions Hemorrhage Risk-Related Criteria
Excluded mostly due to significantly Excluded mostly due to increased risk
higher risk of thromboembolism of clinically significant bleeding
 Hemodynamically significant mitral valve stenosis  Active internal bleeding
 Prosthetic heart valve (annuloplasty with or without  History of or condition associated with increased
prosthetic ring, commissurotomy and/or valvuloplasty bleeding risk including, but not limited to:
are permitted) – Major surgical procedure or trauma within 30 days
 Planned cardioversion (electrical or pharmacological) before the randomization visit
 Transient atrial fibrillation caused by a reversible – Clinically significant gastrointestinal bleeding
disorder (e.g., thyrotoxicosis, PE, recent surgery, MI) within 6 months before the randomization visit
 Known presence of atrial myxoma or left ventricular – History of intracranial, intraocular, spinal, or
thrombus atraumatic intra-articular bleeding
 Active endocarditis – Chronic hemorrhagic disorder
– Known intracranial neoplasm, arteriovenous
malformation, or aneurysm
 Planned invasive procedure with potential for
uncontrolled bleeding, including major surgery
 Platelet count <90,000/μL at the screening visit
 Sustained uncontrolled hypertension: systolic blood
pressure ≥180 mmHg or diastolic blood pressure ≥100
mmHg

12. SubjectsExclusion criteria
Concomitant Conditions and Therapies
Excluded due to addition of confounding variables
 Severe, disabling stroke (modified Rankin score of 4 to  Anticipated need for chronic treatment with a non-
5, inclusive) within 3 months or any stroke within 14 steroidal anti-inflammatory drug
days before the randomization visit  Systemic treatment with a strong inhibitor of cytochrome
 Transient ischemic attack within 3 days before the P450 3A4, such as ketoconazole or protease inhibitors,
within 4 days before randomization, or planned treatment
randomization visit during the time period of the study
 Indication for anticoagulant therapy for a condition  Treatment with a strong inducer of cytochrome P450 3A4,
other than atrial fibrillation (e.g., VTE) such as rifampin/rifampicin, within 4 days before
 Treatment with: randomization, or planned treatment during the time
period of the study
▫ Aspirin >100 mg daily
 Anemia (hemoglobin <10 g/dL) at the screening visit
▫ Aspirin in combination with thienopyridines  Pregnancy or breast-feeding
within 5 days before randomization
 Any other contraindication to warfarin
▫ Intravenous antiplatelets within 5 days before
randomization  Known HIV infection at time of screening
 Calculated CLCR <30 mL/min at the screening visit (refer
▫ Fibrinolytics within 10 days before randomization to Attachment 4 for calculating CLCR)
▫ Note: Aspirin ≤100 mg monotherapy is allowed  Known significant liver disease (e.g., acute clinical
and thienopyridine monotherapy is allowed. hepatitis, chronic active hepatitis, cirrhosis), or ALT >3x
the ULN
Additional exclusion criteria common to most trials (past drug abuse, hypersensitivity,
conflicts of interest, etc.)

13. SubjectsExclusion criteria
Concomitant Conditions and Therapies
Excluded due to addition of confounding variables
 Severe, disabling strokeTreatment with:4 to
 (modified Rankin score of  Anticipated need for chronic treatment with a non-
5, inclusive) within 3 months or any stroke within 14 steroidal anti-inflammatory drug
• Aspirin >100 mg daily
days before the randomization visit  Systemic treatment with a strong inhibitor of cytochrome
Transient ischemic attack within 3 days before the P450 3A4, such as ketoconazole or protease inhibitors,

randomization visit
• Aspirin in combination with thienopyridines
within 4 days before randomization, or planned treatment
during the time period of the study
 Indication for anticoagulant therapy for5 days before
within a condition randomization
 Treatment with a strong inducer of cytochrome P450 3A4,
other than atrial fibrillation (e.g., VTE) such as rifampin/rifampicin, within 4 days before
• Intravenous antiplatelets within 5 daysplanned treatment during the time
randomization, or before
 Treatment with:
▫ Aspirin >100 mg daily
randomization period of the study
 Anemia (hemoglobin <10 g/dL) at the screening visit
▫ Aspirin in combination with thienopyridines within
• Fibrinolytics 10 days before breast-feeding
 Pregnancy or
within 5 days before randomization
randomization  Any other contraindication to warfarin
▫ Intravenous antiplatelets within 5 days before
 Known HIV infection at time of screening
randomization Note: Aspirin ≤100 mg monotherapy is<30 mL/min at the screening visit (refer
 Calculated CLCR
allowed
▫ Fibrinolytics within 10 days before randomization
and thienopyridine monotherapy is 4 for calculating CLCR)
to Attachment allowed.
▫ Note: Aspirin ≤100 mg monotherapy is allowed  Known significant liver disease (e.g., acute clinical
and thienopyridine monotherapy is allowed. hepatitis, chronic active hepatitis, cirrhosis), or ALT >3x
the ULN
Additional exclusion criteria common to most trials (past drug abuse, hypersensitivity,
conflicts of interest, etc.)

14. SubjectsRandomization
 Central computerized randomization
 1:1 ratio
 Stratified, based on
– Country
– Prior VKA use (> 6 week)
– Prior stroke, TIA, or non-CNS systemic
embolism
Written informed consent was obtained for all subjects

15. SubjectsDemographics
No statistically significant differences in patient characteristics between
treatment arms (though this was not explicitly stated)
P<0.05 for all characteristics

16. SubjectsDemographics
No statistically significant differences in patient characteristics between
treatment arms (though this was not explicitly stated)
P<0.05 for all medications

17. InterventionTreatment Arms
Rivaroxaban Warfarin
20 mg daily Dose-adjusted to
(or 15 mg daily in CrCl of 30 to 49 target INR between 2.0 and 3.0
ml/min)
Why 20 mg? Why warfarin?
• 20 mg dose is based on dose- • Chosen as comparator because
ranging Phase II study warfarin is indicated for the
• Lowest studied dose study population based on the
CHEST guidelines
 Compliance was assessed by periodic pill counts

18. InterventionBlinding
Patients were given "Rivaroxaban" and "Warfarin"
together, but one was a placebo
• Specially-designed point-of-care INR device
• Sham INR values for rivaroxaban patients
• Validated algorithm produced values based on the distribution if
values in warfarin-treated patients similar to those in the study
population

19. Outcomes
Primary
SAFETY
1) Stroke + Systemic embolism
Secondary
2) Stroke + Systemic embolism + Vascular death
EFFICACY
3) Stroke + Systemic embolism + Vascular death + Myocardial infarction
4) Individual components of the composite endpoints
Primary
1) Major and nonmajor clinically relevant bleeding

20. StatisticsPower analysis
• 363 events for 95% power
• Increased by 10% to 405 (more robust)
• Assumed warfarin treatment group event rate
of 2.3% per year
• Assumed annual dropout rate of 15%
• Estimated to need 14,000 subjects to reach
405 events

26. ResultsPrimary Efficacy
A
RESULT: Non-inferior to warfarin

27. ResultsPrimary Efficacy
B
RESULT: Superior to warfarin

28. ResultsPrimary Efficacy
C
RESULT: Not superior to warfarin

29. Analysis
Criticism from FDA reviewers
regarding events occurring
after discontinuation of
rivaroxaban
More events occurred when
patients on rivaroxaban
switched to warfarin than in
patients already on warfarin
Probably due to difficulty
achieving therapeutic INR
(patients already on warfarin
were already therapeutic)

30. ResultsSafety
RESULT: No statistical difference

31. Rivaroxaban better Warfarin better
ResultsSafety

32. ResultsSafety
P<0.001
Rivaroxaban worse
All others - no statistically
significant difference

33. ResultsSecondary Efficacy
B Safety, as treated population
1) Composite of stroke, systemic
embolism, and vascular death
▫ Superior to warfarin
2) Composite of stroke, systemic
embolism, vascular death,
and myocardial infarction
▫ Superior to warfarin
3) Hemorrhagic stroke and non-
CNS embolism events were
statistically different in favor
of rivaroxaban, but the event
counts were very small and
the clinical significance is
minor

34. ResultsSubgroups
Authors report “both safety and efficacy [were] consistent across all
prespecified subgroups.”
However…
Statistically significant differences were recorded for a few patient
characteristics.
Results tended towards superior efficicay of rivaroxaban but with
increased risk of bleeding
Clinical significance is minimal

35. Analysis
• Large population
• Randomization was nearly perfect
• Primary efficacy endpoints were
analyzed using multiple population sets
Strengths
• Warfarin within therapeutic goal only
55% of the time
Weaknesses
• Could not determine if investigators tested
whether or not blinding was maintained
• Thienopyridine usage not reported

36. Analysis
The top 25% of centers that appropriately maintained warfarin within
goal still resulted in a hazard ratio that favored rivaroxaban

37. Conclusions
Author’s conclusions
Rivaroxaban was noninferior to warfarin in the prevention of
subsequent stroke or systemic embolism. There were no significant
differences in rates of major and clinically relevant nonmajor bleeding
between the two study groups, although intracranial and fatal bleeding
occurred less frequently in the rivaroxaban group.
My conclusions
I agree with the author’s conclusion.
Note that rivaroxaban had a higher incidence of GI bleeding.
If approved, rivaroxaban would be a good alternative to warfarin for
busy patients that can reliably take medication and in patients in which
warfarin’s multitude of drug interactions makes it difficult to manage.