Transcript Advanced Practice of Pharmacy Experience: Journal Club Mai Nguyen

Title
Rivaroxaban Versus Warfarin in Nonvalvular
Atrial Fibrillation
Clinical
Trial
Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition
Compared with Vitamin K Antagonist for Prevention of Stroke
and Embolism Trial in Atrial Fibrillation (ROCKET AF)
Authors
Patel MR, Mahaffey KW, et al.
Citation
Patel MR, Mahaffey KW, et al. Rivaroxaban versus Warfarin in
Nonvalvular Atrial Fibrillation. New England Journal of
Medicine. 2011;365:883-891.
Funding
 Johnson & Johnson Pharmaceutical Research and
Development
 Bayer Healthcare

Atrial fibrillation is associated with an increase in
the risk of ischemic stroke by a factor of 4 to 5 and
accounts for up to 15% of strokes in persons of all
ages and 30% in persons over the age of 80.1

Current guidelines for preventing stroke in patients
with atrial fibrillation recommend using warfarin, a
vitamin K antagonist, with a target INR of 2-3, as
the standard care of therapy.
 However, warfarin has many food and drug interactions,
and requires frequent monitoring and dose adjustments.

Rivaroxaban (Xarelto®):
3
 First oral, selective inhibitor of Factor Xa
approved by the FDA on July 1, 2011.
 FDA indicated for prophylaxis of deep vein
thrombosis (DVT) which may lead to
pulmonary embolism (PE) in patients
undergoing knee or hip replacement surgery.
 Convenient once daily, oral dosing
 No need for routine monitoring of INR or
other coagulation parameters.

To compare once daily oral rivaroxaban
with dose-adjusted warfarin for the
prevention of stroke and systemic embolism
in patients with nonvalvular atrial
fibrillation who were at moderate to high
risk for stroke.

Primary hypothesis: rivaroxaban is
noninferior to warfarin for the prevention of
stroke or systemic embolism.
Trial Design
 Prospective, multicenter, double-blind, randomized event-
driven trial
 14,264 participants underwent randomization from
December 18, 2006, through June 17, 2009.
 The study was terminated on May 28, 2010.
Setting
 Study was conducted at 1,178 sites in 45 countries.

Inclusion Criteria:
 Men or women aged ≥ 18 years with nonvalvular atrial
fibrillation (ECG evidence), who were at moderate-to-high risk
for stroke.
▪ Elevated risk factors: history of stroke, transient ischemic attack, or
systemic embolism OR
▪ At least 2 of the following risk factors: heart failure or left ventricular
ejection fraction of ≤ 35%, hypertension, age ≥ 75 years, or DM
 Female subjects must be postmenopausal, surgically sterile, or
abstinent.
▪ If sexually active, must use effective method of birth control before
entry and throughout the study.
▪ Must have a negative pregnancy test at screening.
Exclusion Criteria
Cardiac-Related
Conditions:
Mitral valve stenosis, prosthetic heart valve, active endocarditis, etc…
Hemorrhage
Risk-Related
Criteria:
Active internal bleeding, planned invasive procedure with potential
for uncontrolled bleeding, including major surgery, platelet count
<90,000/μL, sustained uncontrolled hypertension, etc…
Concomitant
Conditions and
Therapies:
Severe, disabling stroke within 3 months or any stroke within 14 days
before randomization, treatment with ASA >100mg daily, pregnant or
breast-feeding, CrCl <30ml/min at screening, etc…
Study
Participation and
Follow-Up
Related Criteria:
Serious concomitant illness associated with life expectancy of less
than 2 years, drug addiction or alcohol abuse within 3 years, have
received experimental drug within 30 days, inability or unwillingness
to comply with study-related procedures, etc…

Baseline Demographics:
 Median age was 73 years
 39.7% women; 60.3% male
 90.5% of patients had hypertension
 54.8% of patients had previous stroke or
systemic embolism
 62.4% of patients had previous use of warfarin

Baseline characteristics did not differ significantly
between the two treatment groups.

14,264 patients were randomly assigned
to receive:
 Fixed-dose rivaroxaban 20 mg daily or 15 mg
daily in patients with CrCl 30-49 mL/min
AND placebo (n = 7,131)
 Dose-adjusted warfarin (target INR 2.0-3.0)
AND placebo (n = 7,133)

Patients were seen at weeks 1, 2, and 4,
then monthly for duration of study to
measure INR, primary endpoint events,
TIA, MI, medical/surgical procedures,
adverse events and vital stats

Median duration of treatment: 590 days

Median follow-up period: 707 days
Primary
Endpoint
Secondary
Endpoints
Safety
Endpoint
Composite of stroke (ischemic or
hemorrhagic) and systemic embolism
 Composite of stroke, systemic embolism, or death
from cardiovascular causes
 Composite of stroke, systemic embolism, death
from cardiovascular causes, or myocardial
infarction
 Individual components of the composite
endpoints.
Composite of major and non-major
clinically relevant bleeding events

Primary Analysis:
 Performed in the per-protocol population
▪ Included all patients who received at least one dose of a study
drug, did not have major protocol violation, and were followed
for events while receiving drug or within 2 days after
discontinuation.
 Power of 95%
▪ 363 events needed; study used 405 events
 One-sided significance level of 0.025

If noninferiority was achieved in the
primary analysis,
 Primary Superiority Analysis:
▪ Performed in the as-treated safety population
▪ Included patients who received at least one dose of a study
drug and were followed for events, regardless of adherence
to the protocol, while they were receiving the assigned
study drug or within 2 days after discontinuation.
▪ Two-sided significance level of 0.05
▪ Key secondary endpoints were also tested for
superiority in the as-treated safety population.

Testing for noninferiority and superiority was
also performed in the intention-to-treat
population
 Included all patients who underwent randomization and were
followed for events during treatment or after premature
discontinuation
Hazard ratios, confidence intervals, and P values
were calculated using Cox proportional-hazards
models
 Warfarin group:

 Rosendaal method - calculate overall time that INR
values fell within therapeutic range

Hazard Ratio (AKA Relative Risk or Risk
Ratio):
 The ratio of risk of an outcome event occurring in the
experimental group compared to the risk of the same
outcome event occurring in the control group.
 HR < 1.0 indicates the therapy decreased the risk of
developing the adverse outcome
 HR = 1.0 indicates no difference between treatments
 HR > 1.0 indicates the therapy increased the risk of
developing the adverse outcome

NNT (primary endpoint – stroke and systemic embolism):
 ARR = 241/7,004 – 188/6,958 = 0.0074
 NNT = 1/0.0074 = 135

NNH (safety endpoint – major and nonmajor bleeding):
 ARI = 1,475/7,111 – 1,449/7,125 = 0.004
 NNH = 1/0.004 = 250


In patients with atrial fibrillation,
rivaroxaban was noninferior to warfarin
for the prevention of stroke or systemic
embolism.
There was no significant difference in the
risk of major bleeding between groups,
although intracranial and fatal bleeding
occurred less frequently in the
rivaroxaban group.
STRENGTHS
LIMITATIONS
In warfarin group, INR values
were within therapeutic range
only 55% of the time.
 Switching from per-protocol
population to as-treated safety
population to achieve
superiority.
 The primary endpoint of stroke
was a composite of ischemic
and hemorrhagic strokes.
 No inclusion of data for
increased GI bleeding


Randomized, double-blind,
multi-center study with a large
sample size

Treatment groups appeared
similar at baseline
 Included almost 40% females

Duke Clinical Research
Institute coordinated the trial,
managed database, and
performed primary analyses
independently of the sponsors.

Rivaroxaban is a potential alternative to
warfarin, especially for patients with compliance
issues.

Things to consider:
 Cost
 No Antidote
 Monitoring for coagulation parameters needed
 How to bridge patients when switching from
warfarin to rivaroxaban?
 Long-term effects?
1.
Patel MR, et al. Rivaroxaban versus Warfarin in Nonvalvular Atrial
Fibrillation. New England Journal of Medicine. 2011; 365:883-891.
2.
Supplement to: Patel MR, et al. Rivaroxaban versus Warfarin in
Nonvalvular Atrial Fibrillation. New England Journal of Medicine.
2011; 365:883-891. DOI: 10.1056/NEJMoa1009638.
3.
Xarelto® (rivaroxaban) Product Package Insert. 2011; July. Janssen
Pharmaceuticals, Inc. Titusville, NJ.