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A PIXABAN IN P ATIENTS WITH A TRIAL
F IBRILLATION

NEJM

10 TH FEBRUARY 2011

Study at 522 centers in 36 countries.
Enrollment began on September 10, 2007, and was completed on December 23, 2009.
Sponsored by Bristol-Myers Squibb and
Pfizer.
Double blind placebo trial

I NCLUSION C RITERIA

50 yearsof age or older and

Atrial fibrillation documented in the
6 months before enrollment or by 12lead electrocardiography on the day of screening.

P LUS 1 OF THESE RISK FACTORS FOR STROKE :
 prior stroke or transient ischemic attack,
 age of 75 years or older,
 arterial hypertension (receiving treatment),
 diabetes mellitus (receiving treatment),
 heart failure (NYHA 2 or higher at the time of enrollment),

LVEF of 35% or less,
 documented peripheral-artery disease.

E XCLUSION C RITERIA

Vitamin K antagonist therapy



Other conditions other than AF requiring anticoagulation valvular disease requiring surgery, a serious bleeding event in the previous 6 months or
 a high risk of bleeding

(e.g., active peptic ulcer disease, a platelets <100 or hemoglobin level of <10, stroke within the previous
10 days, Documented hemorrhagic tendencies, or blood dyscrasias)

 current alcohol or drug abuse






Psychosocial issues, life expectancy of less than 1 year,
Severe CKD (a serum creatinine level of >221 or creat clearance of <25)
ALT or AST level greater than 2 times the upper limit of the normal range
Total bilirubin more than 1.5 times the upper limit of the normal range, and allergy to aspirin.


Patients were randomly assigned to receive apixaban at a dose of 5 mg twice daily or aspirin at a dose of 81 to 324 mg per day.

Randomization was performed with the use of a 24-hour central, computerized, automated voice-response system.

In keeping with the double-dummy design.


A reduced dose of apixaban (2.5 mg twice daily) was used throughout the study for patients who met two of the following criteria:
 an age of 80 years or older,
 a body weight of 60 kg or less,
 or a serum creatinine level of 133 or higher


Primary efficacy outcome

Stroke or systemic embolization

Primary safety outcome

Major bleeds


Secondary outcomes


MI
Death from vascular cause


Death from any cause
Composites of major vascular events

R ESULTS

5999 patients

37% from Northern America or Western Europe

Variable
Body-mass index†
Male sex — no. (%)
Apixaban Aspirin
(N = 2808) (N = 2791)
Age — yr 70±9
Heart rate — beats/min 74±14
Systolic blood pressure 132±16
70±10
74±14
132±16
28±5 28±5
1660 (59) 1617 (58)
Baseline ECG findings — no. (%)
Atrial fibrillation 1923 (68) 1894 (68)
Atrial flutter
Sinus rhythm
19 (1)
707 (25)
20 (1)
730 (26)
Paced or other rhythm 147 (5)
LVH 490 (17)
139 (5)
498 (18)

Risk factors for stroke — no. (%)
Prior stroke or TIA 390 (14) 374 (13)
HTN, on treatment
Heart failure
2408 (86)
1118 (40)
2429 (87)
1053 (38)
NYHA class 1 or 2
NYHA class 3 or 4
932 (33)
186 (7)
LV EF ≤35% 144 (5)
Peripheral-artery disease 66 (2)
878 (31)
175 (6)
144 (5)
87 (3)
Diabetes, on treatment 537 (19) 559 (20)
Mitral stenosis 64 (2) 50 (2)

Classification of atrial fibrillation — no. (%)
Paroxysmal 760 (27) 752 (27)
Persistent
Permanent
CHADS2‡
587 (21) 590 (21)
1460 (52) 1448 (52)
2.0±1.1 2.1±1.1
Mean score
Score — no. (%)
0 or 1
2
1004 (36)
1045 (37)
1022 (37)
954 (34)
≥3 758 (27)
High-school education or more — no. (%)
812 (29)
1635 (58) 1635 (59)
Use of vitamin K antagonist within 30 days before screening 401 (14) 426 (15)
Use of aspirin within 30 days before screening
2137 (76) 2081 (75)

Medication use at baseline — no. (%)
ACE inhibitor or ARB 1790 (64) 1786 (64)
Verapamil or diltiazem 251 (9) 248 (9)
Beta-blocker
Digoxin
Amiodarone
1563 (56)
821 (29)
298 (11)
1534 (55)
754 (27)
328 (12)
Statin 883 (31) 879 (31)

Region — no. (%)
North America
Latin America
Western Europe
Eastern Europe
408 (15)
589 (21)
625 (22)
639 (23)
396 (14)
596 (21)
633 (23)
611 (22)
Asia and South Africa 547 (19) 555 (20)
Study dose of aspirin or aspirin-placebo — no. (%)
81 mg 1816 (65) 1786 (64)
162 mg 718 (26) 750 (27)
243 mg
324 mg
73 (3)
193 (7)
60 (2)
184 (7)
Data not available 7 (<1) 11 (<1)
Study dose of 2.5 mg twice daily of apixaban or apixaban-placebo 179 (6) 182 (7)

OUTCOMES
Outcome Apixaban Aspirin
(N = 2808) (N = 2791)
P Value
%/yr
Stroke or systemic embolism
%/yr
1.6 3.7
Stroke, systemic embolism, or death
4.6 7.2
<0.001
<0.001
Stroke, systemic embolism, myocardial infarction or death from vascular cause
4.2 6.4 <0.001
Stroke, systemic embolism, myocardial infarction, death from vascular cause, or major bleeding
Event
5.3 7.2
0.003

Systemic embolism
0.1
Myocardial infarction
0.8
0.4 0.01
0.9 0.59
Death
From any cause
3.5
From vascular cause
2.7
4.4
3.1
0.07
0.37
Hospitalization for cardiovascular cause
12.6 15.9 <0.001

Bleeding event
Major
%/yr %/yr p-value
1.4 1.2 0.57
Intracranial
Subdural‡
0.4 0.4 0.69
0.1 0.1 —
Other intracranial, excluding hemorrhagic stroke and subdural‡
<0.1 0.1
—
Extracranial or unclassified
Gastrointestinal
1.1 0.9 0.42
0.4 0.4
0.71
Non-gastrointestinal 0.6 0.4 0.22
Fatal§ 0.1 0.2 0.53

L IMITATIONS

Study terminated early due to 1 st interim analysis showed treatment benefit in favour of apixaban greater than 4 sd

Theoretically could inflate the estimated benefit, however boundary had to be exceeded on 2 formal reviews.

F UTHER S TUDIES …

To look at comparison of Apixaban to
Warfarin therapy in reducing stroke and adverse effects .

(ARISTOTLE)

S UMMARY
In summary, among patients with atrial fibrillation who are at high risk for stroke and for whom vitamin K antagonist therapy is unsuitable: apixaban, as compared with aspirin, substantially reduced the risk of stroke, with no significant increase in the risk of major bleeding or intracranial bleeding.
The net clinical benefit of apixaban in these patients was therefore substantial.