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 andAtrial fibrillation documented in

the 6 months before enrollment or by 12-lead 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 Aspirin(N = 2808) (N =

2791)Age — yr 70±9 70±10Heart rate — beats/min 74±14 74±14Systolic blood pressure 132±16 132±16Body-mass index† 28±5 28±5Male sex — no. (%) 1660 (59) 1617 (58)

Baseline ECG findings — no. (%)Atrial fibrillation 1923 (68) 1894 (68)Atrial flutter 19 (1) 20 (1)Sinus rhythm 707 (25) 730 (26)Paced or other rhythm 147 (5) 139 (5)LVH 490 (17) 498 (18)

Risk factors for stroke — no. (%)Prior stroke or TIA 390 (14) 374 (13)HTN, on treatment 2408 (86) 2429 (87)Heart failure 1118 (40) 1053 (38)

NYHA class 1 or 2 932 (33) 878 (31)NYHA class 3 or 4 186 (7) 175 (6)

LV EF ≤35% 144 (5) 144 (5)Peripheral-artery disease 66 (2) 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 587 (21) 590 (21)Permanent 1460 (52) 1448 (52)CHADS2‡Mean score 2.0±1.1 2.1±1.1Score — 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 1790 (64) 1786 (64)Verapamil or diltiazem 251 (9) 248 (9)Beta-blocker 1563 (56) 1534 (55)Digoxin 821 (29) 754 (27)Amiodarone 298 (11) 328 (12)Statin 883 (31) 879 (31)

Region — no. (%)North America 408 (15) 396 (14)Latin America 589 (21) 596 (21)Western Europe 625 (22) 633 (23)Eastern Europe 639 (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 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 embolism1.6 3.7 <0.001

Stroke, systemic embolism, or death 4.6 7.2 <0.001

Stroke, systemic embolism, myocardial infarctionor death from vascular cause

4.2 6.4 <0.001Stroke, systemic embolism, myocardial infarction,

deathfrom vascular cause, or major bleedingEvent

5.3 7.2 0.003

Systemic embolism 0.1 0.4 0.01

Myocardial infarction 0.8 0.9 0.59

DeathFrom any cause

3.5 4.4 0.07From vascular cause

2.7 3.1 0.37

Hospitalization for cardiovascular cause 12.6 15.9 <0.001

Bleeding event %/yr %/yr p-valueMajor 1.4 1.2 0.57

Intracranial 0.4 0.4 0.69Subdural‡ 0.1 0.1 —Other intracranial, excluding hemorrhagic stroke and subdural‡

<0.1 0.1 —

Extracranial or unclassified 1.1 0.9 0.42

Gastrointestinal 0.4 0.4 0.71Non-gastrointestinal 0.6 0.4 0.22

Fatal§ 0.1 0.2 0.53

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.