AVERROSE Apixaban in AF

Report
APIXABAN IN
PATIENTS WITH
ATRIAL
FIBRILLATION
AVERROES
APIXABAN IN PATIENTS WITH ATRIAL
FIBRILLATION
NEJM
 10TH 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
INCLUSION CRITERIA
 50
yearsof age or older and
 Atrial fibrillation documented in the
6 months before enrollment or by 12lead electrocardiography on the day
of screening.
PLUS 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.
EXCLUSION CRITERIA
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

RESULTS
5999 patients
 37% from Northern America or Western Europe

Variable
Apixaban
(N = 2808)
Age — yr
70±9
Heart rate — beats/min 74±14
Systolic blood pressure 132±16
Body-mass index†
28±5
Male sex — no. (%)
1660 (59)
Aspirin
(N = 2791)
70±10
74±14
132±16
28±5
1617 (58)
Baseline ECG findings — no. (%)
Atrial fibrillation
1923 (68)
Atrial flutter
19 (1)
Sinus rhythm
707 (25)
Paced or other rhythm
147 (5)
LVH
490 (17)
1894 (68)
20 (1)
730 (26)
139 (5)
498 (18)
Risk factors for stroke — no. (%)
Prior stroke or TIA
390 (14)
HTN, on treatment
2408 (86)
Heart failure
1118 (40)
NYHA class 1 or 2
932 (33)
NYHA class 3 or 4
186 (7)
LV EF ≤35%
144 (5)
Peripheral-artery disease 66 (2)
Diabetes, on treatment 537 (19)
Mitral stenosis
64 (2)
374 (13)
2429 (87)
1053 (38)
878 (31)
175 (6)
144 (5)
87 (3)
559 (20)
50 (2)
Classification of atrial fibrillation — no. (%)
Paroxysmal
760 (27)
752 (27)
Persistent
587 (21)
590 (21)
Permanent
1460 (52)
1448 (52)
CHADS2‡
Mean score
2.0±1.1
2.1±1.1
Score — no. (%)
0 or 1
1004 (36)
1022 (37)
2
1045 (37)
954 (34)
≥3
758 (27)
812 (29)
High-school education or more — no. (%)
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
Verapamil or diltiazem
Beta-blocker
Digoxin
Amiodarone
Statin
1790 (64)
251 (9)
1563 (56)
821 (29)
298 (11)
883 (31)
1786 (64)
248 (9)
1534 (55)
754 (27)
328 (12)
879 (31)
Region — no. (%)
North America
Latin America
Western Europe
Eastern Europe
Asia and South Africa
408 (15)
589 (21)
625 (22)
639 (23)
547 (19)
396 (14)
596 (21)
633 (23)
611 (22)
555 (20)
Study dose of aspirin or aspirin-placebo — no. (%)
81 mg
1816 (65)
1786 (64)
162 mg
718 (26)
750 (27)
243 mg
73 (3)
60 (2)
324 mg
193 (7)
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
P Value
(N = 2808) (N = 2791)
%/yr
%/yr
Stroke or systemic embolism
1.6
3.7
<0.001
Stroke, systemic embolism, or death
4.6
7.2
<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
0.4
0.01
Myocardial infarction
0.8
0.9
0.59
4.4
0.07
3.1
0.37
Death
From any cause
3.5
From vascular cause
2.7
Hospitalization for cardiovascular cause
12.6
15.9
<0.001
Bleeding event
Major
%/yr %/yr p-value
1.4
1.2
0.57
Intracranial
0.4
0.4
0.69
Subdural‡
0.1
0.1
—
Other intracranial, excluding hemorrhagic stroke
and subdural‡
<0.1 0.1
—
Extracranial or unclassified
1.1
Gastrointestinal
0.4
Non-gastrointestinal 0.6
0.9
0.4
0.4
0.42
0.71
0.22
Fatal§
0.2
0.53
0.1
LIMITATIONS


Study terminated early due to 1st 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.
FUTHER STUDIES…
 To
look at comparison of Apixaban to
Warfarin therapy in reducing stroke and
adverse effects.

(ARISTOTLE)
SUMMARY
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.

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