The document summarizes results from the ARISTOTLE trial which compared the anticoagulant apixaban to warfarin for preventing strokes in atrial fibrillation patients. The trial found that apixaban was superior to warfarin in reducing strokes and systemic embolisms while also reducing major bleeding events. Apixaban may replace warfarin as a new standard treatment for preventing clots in atrial fibrillation patients due to its improved efficacy and safety profile.

1. Leah Smith
Duquesne University
Class of 2012 PharmD Candidate

2.  Overview of Atrial Fibrillation and its current
treatments
 Comparison of warfarin and apixaban and
their affect on the clotting cascade.
 Population and methods
 Primary and Secondary outcomes, as well as
safety outcomes
 What does this mean for the future of
anticoagulation therapy.

3. •Published in the New England Journal of Medicine
•Lead author Dr. Christopher Granger is the director of cardiac care at
Duke University.
•This was a worldwide study with a majority of the American physicians
associated with Duke University Medical Center and the Duke Clinical
Research Institute.
•Article summarized results from the ARISTOTLE trial
•Apixaban for Reduction in Stroke and Other Thromboembolic Events
in Atrial Fibrillation.
•A majority of the funding came from Bristol-Myers Squibb and Pfizer.
•Additional grants were mentioned from other pharmaceutical
companies including: AstraZeneca, Novartis, GlaxoSmithKline,
Johnson & Johnson, Merck, Bayer Healthcare, etc
•Trial designed by Bristol and Pfizer representative as well as academic
investigators and was approved by the ethics committees of each of the
1034 investigational sites.

4.  To compare apixaban with warfarin for the
prevention of stroke or systemic embolism in
patient with atrial fibrillation and at least one
additional risk factor for stroke.
 Primary purpose to establish non-inferiority to
warfarin.

5.  Epidemiology: AF is the most common
sustained rhythm disturbance and is responsible
for 1/3 of hospitalizations for arrhythmias
 accounts for more than 1.7 million
hospitalizations per year among Medicare
patients.
 Affects approximately 2.2 million adults
 The rate of incidence is expected to double each
year due to the aging population with over 50% of
affected adults being 80 years or older.
DISEASEDEX™ Emergency Medicine Clinical Review
CXMD Atrial Fibrillation

6.  Definition: A supraventricular tachyarrhythmia resulting from uncoordinated
electrical activity causing a mechanical malfunction of the atrial heart muscle.
 Etiology: Any process that irritates, inflames, scars, or stretches the atrial
muscles increase the possibility of fibrillation.
 A single point of repetitive rapid fire, most commonly from the pulmonary vein,
is the main cause of AF.
 90% of AF rapid fire focus points are located in the left atrial muscle which can
extend up to 3 cm into the pulmonary veins.
 Most common causes of AF:
 Increase atrial pressure due to high systemic or pulmonary hypertension.
 Atrial ischemia (CAD)
 Inflammatory atrial diseases: pericarditis, amyloidosis, etc
 Drugs: Alcohol and caffeine
 Endocrine disorders: Hyperthyroidism, Pheochromocytoma
 Postoperative procedures of the cardiothoracic or esophageal regions.
 Hemorrhagic or ischemic stroke.
DISEASEDEX™ Emergency Medicine Clinical Review
CXMD Atrial Fibrillation

7.  There are four identified patterns:
◦ First detected AF: symptomatic or self-limited, paroxysmal or persistent. Two or more
episodes classify as recurrent.
◦ Paroxysmal AF: generally lasting 7 days or less with spontaneously termination.
◦ Persistent AF: longstanding (lasts longer than 7 days) with no spontaneous termination. AF
present more than a year is included.
◦ Permanent AF: persistent AF where an attempt at cardioversion cannot be attempted or has
failed.
 Symptom Class: after a pattern is identified they can be characterized by
symptom class.
 Class 0: completely asymptomatic
 Class 1: symptoms are minimal and do not affect quality of life. No syncope or heart failure
present.
 Class 2: In persistant/permanent mild awareness of symptoms. In paroxysmal, rare episodes
with mild symptoms experienced.
 Class 3: Consistent awareness of symptoms in persistant/permanent. In paroxysmal, more
frequent episodes with moderate to severe symptoms.
 Class 4: Highly symptomatic, severely affecting quality of life in all patterns. Syncope and
Heart Failure most likely present.
 Complications for patients with AF include:
◦ Congestive heart failure
◦ Thromboembolic stroke
◦ Arterial embolism
◦ Tachycardia-induced cardiomyopathy
DISEASEDEX™ Emergency Medicine Clinical Review
CXMD Atrial Fibrillation

8.  Three goals of AF treatment/management:
◦ Ventricular rate control
◦ Correcting any rhythm disturbance
◦ Preventing Thromboembolism
 Target therapeutic goals:
◦ Resting HR: 60-80 bpm
◦ Exercise HR: <100bpm on 6 minute walk
◦ 24 hour average HR with Holter Monitor: <100bpm
◦ INR goal between 2 & 3.
CXMD Atrial Fibrillation

9.  Rate Control
◦ Beta-Blockers and Calcium-Channel Blockers are
considered equal in efficacy.
 BB: Metoprolol, Propranolol, Atenolol, Bisoprolol,
Carvedilol
 Do not use in patients with asthma, advanced heart block,
or acute heart failure.
 CCB: Diltiazem & Verapamil
 Do not use in patient with left ventricular dysfunction and
have drug interactions with CYP450 metabolized drugs.
◦ Digoxin and Amiodarone are considered second
line agent unless CHF is present.
CXMD Atrial Fibrillation

10.  Rhythm control
◦ Normal Heart structure & Hypertension w/o LVH :
 1st line: dronedarone, felcainide, propafenone, sotalol
 2nd line: amiodarone, dofetilide
◦ Hypertension with LVH:
 1st line: dronedarone, amiodarone.
◦ CAD
 1st line: dofetilide, dronedarone, sotalol
 2nd line: amiodarone
◦ Class I-II NYHA HF:
 1st line: amiodarone, dofetilide, dronedarone
◦ Class III NYHA HF:
 1st line: amiodarone, dofetilide
CXMD Atrial Fibrillation

11.  Antithrombotic therapy is indicated in all
patients (except first incidence Class 0) with
AF in addition to anti-platelet or
anticoagulant therapy.
 The use of anti-platelet therapy over
anticoagulation therapy is usually due to
compliance issues or contraindications for
anticoagulation treatment.
CXMD Atrial Fibrillation

12.  Warfarin inhibits the production of vitamin K
which intern inhibits the synthesis of vitamin
K-dependent clotting factors (2, 7, 9 and 10)
 Dosing: initial 2 to 5 mg QD
◦ adjust dose based on INR
◦ usual maintenance 2-10mg QD
 Requires frequent INR testing (no less than
every 4 weeks) and careful diet
considerations with foods containing vitamin
K.
Warfarin DRUGDEX

13.  Has not yet been FDA approved.
 Oral direct factor Xa inhibitor.
◦ 12 hour half life.
◦ 25% renal excretion.
 AVERROES trial has already shown that apixaban in
patients contraindicated for warfarin therapy apixaban,
as compared to aspirin, reduces rate of stroke by 55%
without increasing incidence of major bleeding.
 Dosing is 5mg BID with a decrease to 2.5mg BID if the
patient was 80 years of age or older, a body weight less
than 60kg, and a SCr 1.5mg/dL or more.
 No drug food interactions or consistent monitoring.

14. APIXIBAN
W
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15. Inclusion Criteria: Exclusion Criteria:
 Atrial fibrillation or flutter at time of  AF due to a reversible causes
enrollment or 2 or more episodes of  Moderate to severe mitral stenosis
AF documented by ECG at least 2  Other conditions present that required
weeks apart in the last year.
anticoagulation therapy.
 Prescence of atleast one of the
 Stroke within the past 7 days
following risk factors:
 A requirement of aspirin >165mg a day
◦ At least 75 years old
or a requirement of both aspirin and
◦ Previous stroke clopidogrel.
◦ Transient ischemic attack  Severe renal insufficiency (SCr >2.5mg/
◦ Systemic embolism dL or CrCl <25ml/min)
◦ Symptomatic HF with the past 3
months
◦ Left ventricular ejection fraction of
no more than 40%
◦ Diabetes
◦ Hypertension requiring
pharmacologic agents.

16.  Total patient enrollment: 18,201
◦ 9120 assigned apixaban, 9081warfarin
 A total of 1034 testing sites were used in 39
different countries.
 Investigors tried to enroll >40% of patient
population at each testing site who have were
warfarin naïve.
◦ 57% of total population fell into this category
 Patients were classified as not having received
warfarin is they had not received any vitamin K
antagonist for no more than 30 consecutive days.

18. •Primary Objective: to show non-infereriority of apixaban in comparison to
warfarin for the prevention of stroke systemic embolism in patients with
AF.
•Secondary objectives: determine superiority of apixaban to warfarin with
respect to the incidence of primary outcomes and primary safety
outcomes.
•Primary outcome: Stroke or systemic embolism
•Primary outcome was evaluated as total events and individual events
in systemic embolism, ischemic stroke, and hemorrhagic stroke.
•Secondary outcomes: death from any cause, specifically:
•Stroke or systemic embolism
•Myocardial Infarction
•Pulmonary embolism or DVT
•Primary safety outcomes: major bleeding classified by ISTH
•Secondary safety outcomes: incidence of bleeding not classified as a
major bleed.

19.  Trial design: double-blind, double dummy with patients randomly
assigned to apixaban or dose-adjusted warfarin.
◦ Patients were stratified into whether they have received warfarin
previously & clinical testing site.
 Patients previously on vit K antagonists were instructed
through a washout period and initiated with trial treatment
when their INR fell below 2.0
◦ Apixaban or matching placebo administered in 5mg tab BID or
decreased dose of 2.5mg BID if the patient was 80 years of age
or older, a body weight less than 60kg, and a SCr 1.5mg/dL or
more.
◦ Warfarin or matching placebo administered in 2mg tabs and
titrated until goal INR of 2.0-3.0 was achieved. (each site used
the same protocol for adjustment of warfarin)

20.  In order to prove non-inferiority apixaban group
needed at least 50% RR in primary outcomes (compared
to 62% RR for warfarin)
 Estimated that 448 patients with primary outcome
would provide 90% power to ensure 99% confidence
interval.
◦ Planned on recruiting 18,000
 P-value for non-inferiority calculated one sided while
superiority calculated using two sided calculations.
 Primary and secondary efficacy analysis included the
entire intended to treat population.

24.  Non-inferiority (p<0.001) and superiority (p<0.01)
established.
 Hemorrhagic stroke had a 49% less incidence rate
in apixaban group than warfarin.
 There was a 7.7 absolute reduction in the incidence
of bleeding the apixaban group versus the warfarin
group.
 A 27% relative reduction in incidence of major
bleeding.
 Overall, apixaban reduced the risk of stroke or
systemic embolism by 21%, major bleeding by 31%,
and death by 11%.

25.  Apixaban is more effective than warfarin for stroke
prevention and is associated with a lower risk of
bleeding.
 Mentions Dabigatran
◦ Shown to reduce rate of stroke with similar rates
of bleeding in comparison to warfarin. (RE-LY)
◦ However, increase risk of GI bleed.
 Mentions Rivaroxaban
◦ Was only shown to be non-inferior to warfarin for
stork prevention (ROCKET AF)
◦ Rate of intracranial hemorrhage and fatal
bleeding were lower, however, no difference in
rate for all other types of bleeding.

26.  Strengths
◦ Large international population
◦ Non-inferiority and superiority
◦ Similar sample background in each arm
◦ Assessment on several bleeding scales.
 Limitations
◦ Long term risk reduction (what does the curve looks
like after 2 to 3 years?)
◦ Lists reasons for difference in other novel
anticoagulation trials: PK and PD properties of drug,
patient populations, trial design

27.  Pradaxa: direct thrombin inhibitor
 Rivaroxaban: selective inhibitor of Xa
◦ FDA approved drug but does not yet have the indication
for AF.
 Apixaban: selective inhibitor of Xa
 Possible replacement of apixaban with warfarin especially
in patients with high concerns for stroke or bleeding and
patients non-compliant with restricted vitamin K diet.
 Since Rivaroxaban and Apixaban have the same mechanism
of action, studies may need to be done to determine non-
inferiority/ superiority between the two.
◦ Both have studies versus warfarin.