See also:

AVERROES study, 2011	TRC10340
[NCT00496769]	download pdf: apixaban | antithrombotics for atrial fibrillation

Treatments

Studied treatment	apixaban 5 mg (or 2.5 mg) twice daily
Control treatment	aspirin 81-324 md daily

Patients

Patients	patients with atrial fibrillation who have failed or are unsuitable for vitamin K antagonist treatment
Inclusion criteria	atrial fibrillation and at least one high-risk factor (prior stroke or transient ischemic attack, an age of 75 years or older, arterial hypertension (receiving treatment), diabetes mellitus (receiving treatment), heart failure (NYHA class 2 or higher at the time of enrollment), a left ventricular ejection fraction of 35% or less, or documented peripheral- artery disease); unsuitability for warfarin therapy due to inability to control international normalized ratio, increased risk for bleeding, patient refusal, or intermediate risk for stroke
Exclusion criteria	presence of conditions other than atrial fibrillation for which the patient required long-term 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 platelet count of <100,000 per cubic millimeter or hemoglobin level of <10 g per deciliter, stroke within the previous 10 days, documented hemorrhagic tendencies, or blood dyscrasias), current alcohol or drug abuse or psychosocial issues, life expectancy of less than 1 year, severe renal insufficiency (a serum creatinine level of >2.5 mg per deciliter or a calculated creatinine clearance of <25 ml per minute), an alanine aminotransferase or aspartate aminotransferase level greater than 2 times the upper limit of the normal range or a total bilirubin more than 1.5 times the upper limit of the normal range, and allergy to aspirin.
Baseline characteristics	age(mean) 70 years  male(%) 59%  systolic blood pressure(mean) 132 mmHg  hypertension(%) 86.5%  diabete mellitus(%) 19%  prior stroke(%) 13.5%  prior TIA or stroke(%) 14%  left ventricular dysfunction(%) 40%  paroxysmal AF(%) 27%  heart failure(%) 39%  subgroup test a  CHADS2 Score (mean) 2.05  CHADS2 Score = 2 (%) 36% (63.8% CHADS2>=2)  CHADS2 Score = 3 (%) 28%

Method and design

Randomized effectives	2808 / 2791 (studied vs. control)
Design	Parallel groups
Blinding	double blind
Follow-up duration	maximum 21 months
Premature discontinuation	Premature discontinuation for efficacy
Number of centre	522
Geographic area	36 countries
Hypothesis	Superiority
Primary endpoint	stroke or systemic embolism

Results

Endpoints and data reported in the trial's publication(s)

Endpoint	Events (%)		Relative Risk	95% CI
	Studied treat.	Control treat.
Stroke or systemic embolism	51 / 2808 (1,8%)	113 / 2791 (4,0%)	0,45	[0,32;0,62]
Stroke, systemic embolism, or death	143 / 2808 (5,1%)	223 / 2791 (8,0%)	0,64	[0,52;0,78]
Stroke, systemic embolism, myocardial infarction or death from vascular cause	132 / 2808 (4,7%)	197 / 2791 (7,1%)	0,67	[0,54;0,83]
Stroke, systemic embolism, myocardial infarction, death from vascular cause, or major bleeding	163 / 2808 (5,8%)	220 / 2791 (7,9%)	0,74	[0,61;0,90]
Stroke	49 / 2808 (1,7%)	105 / 2791 (3,8%)	0,46	[0,33;0,65]
Ischemic Stroke	35 / 2808 (1,2%)	93 / 2791 (3,3%)	0,37	[0,25;0,55]
Hemorrhagic Stroke	6 / 2808 (0,2%)	9 / 2791 (0,3%)	0,66	[0,24;1,86]
Unspecified Stroke	9 / 2808 (0,3%)	4 / 2791 (0,1%)	2,24	[0,69;7,25]
Disabling or fatal Stroke	31 / 2808 (1,1%)	72 / 2791 (2,6%)	0,43	[0,28;0,65]
Systemic embolism	2 / 2808 (0,1%)	13 / 2791 (0,5%)	0,15	[0,03;0,68]
Myocardial infarction	24 / 2808 (0,9%)	28 / 2791 (1,0%)	0,85	[0,50;1,47]
Death From any cause	111 / 2808 (4,0%)	140 / 2791 (5,0%)	0,79	[0,62;1,01]
Death From vascular cause	84 / 2808 (3,0%)	96 / 2791 (3,4%)	0,87	[0,65;1,16]
Hospitalization for cardiovascular cause	367 / 2808 (13,1%)	455 / 2791 (16,3%)	0,80	[0,71;0,91]
Major Bleeding event	44 / 2808 (1,6%)	39 / 2791 (1,4%)	1,12	[0,73;1,72]
Intracranial Major Bleeding event	11 / 2808 (0,4%)	13 / 2791 (0,5%)	0,84	[0,38;1,87]
Subdural Major Bleeding event	4 / 2808 (0,1%)	2 / 2791 (0,1%)	1,99	[0,36;10,84]
Other intracranial bleeding, excluding hemorrhagic stroke and subdural	1 / 2808 (0,0%)	2 / 2791 (0,1%)	0,50	[0,05;5,48]
Extracranial or unclassified bleeding	33 / 2808 (1,2%)	27 / 2791 (1,0%)	1,21	[0,73;2,01]
Gastrointestinal bleeding	12 / 2808 (0,4%)	14 / 2791 (0,5%)	0,85	[0,39;1,84]
Non-gastrointestinal bleeding	20 / 2808 (0,7%)	13 / 2791 (0,5%)	1,53	[0,76;3,07]
Fatal bleeding	4 / 2808 (0,1%)	6 / 2791 (0,2%)	0,66	[0,19;2,35]
Clinically relevant nonmajor bleeding	96 / 2808 (3,4%)	84 / 2791 (3,0%)	1,14	[0,85;1,52]
Minor bleeding	188 / 2808 (6,7%)	153 / 2791 (5,5%)	1,22	[0,99;1,50]

Endpoints used by the meta-analysis and data retained for this trial

Endpoint Studied treat.
n/N Control treat.
n/N Graph RR [95% CI]

Coronary event

24 / 2808
28 / 2791
0,85 [0,50;1,47]

thrombo-embolic event (cerebral or systemic)

51 / 2808
113 / 2791
0,45 [0,32;0,62]

stroke (fatal and non fatal)

49 / 2808
105 / 2791
0,46 [0,33;0,65]

ischemic stroke

35 / 2808
93 / 2791
0,37 [0,25;0,55]

myocardial infarction (fatal and non fatal)

24 / 2808
28 / 2791
0,85 [0,50;1,47]

All cause death

111 / 2808
140 / 2791
0,79 [0,62;1,01]

Major bleeding

44 / 2808
39 / 2791
1,12 [0,73;1,72]

Minor bleeding

188 / 2808
153 / 2791
1,22 [0,99;1,50]

Haemmorhagic stroke

6 / 2808
9 / 2791
0,66 [0,24;1,86]

Fatal bleeding

4 / 2808
6 / 2791
classic 0,66 [0,19;2,35]

Gastrointestinal major bleeding

12 / 2808
14 / 2791
0,85 [0,39;1,84]

Cardiovascular death

84 / 2808
96 / 2791
0,87 [0,65;1,16]

intracranial hemorrhage

11 / 2808
13 / 2791
0,84 [0,38;1,87] 0 2 1.0

Relative risks
Endpoint	Events (%)		Relative Risk	95% CI	Endpoint definition in the trial	Ref
	Studied treat.	Control treat.
Coronary event	24 / 2808 (0,9%)	28 / 2791 (1,0%)	0,85	[0,50;1,47]		16949
thrombo-embolic event (cerebral or systemic)	51 / 2808 (1,8%)	113 / 2791 (4,0%)	0,45	[0,32;0,62]	Stroke or systemic embolism
stroke (fatal and non fatal)	49 / 2808 (1,7%)	105 / 2791 (3,8%)	0,46	[0,33;0,65]	Stroke
ischemic stroke	35 / 2808 (1,2%)	93 / 2791 (3,3%)	0,37	[0,25;0,55]	Ischemic Stroke
myocardial infarction (fatal and non fatal)	24 / 2808 (0,9%)	28 / 2791 (1,0%)	0,85	[0,50;1,47]	Myocardial infarction
All cause death	111 / 2808 (4,0%)	140 / 2791 (5,0%)	0,79	[0,62;1,01]	Death From any cause
Major bleeding	44 / 2808 (1,6%)	39 / 2791 (1,4%)	1,12	[0,73;1,72]	Major Bleeding event
Minor bleeding	188 / 2808 (6,7%)	153 / 2791 (5,5%)	1,22	[0,99;1,50]	Minor bleeding
Haemmorhagic stroke	6 / 2808 (0,2%)	9 / 2791 (0,3%)	0,66	[0,24;1,86]	Hemorrhagic Stroke
Fatal bleeding	4 / 2808 (0,1%)	6 / 2791 (0,2%)	0,66	[0,19;2,35]	Fatal bleeding
Gastrointestinal major bleeding	12 / 2808 (0,4%)	14 / 2791 (0,5%)	0,85	[0,39;1,84]	Gastrointestinal bleeding
Cardiovascular death	84 / 2808 (3,0%)	96 / 2791 (3,4%)	0,87	[0,65;1,16]	Death From vascular cause
intracranial hemorrhage	11 / 2808 (0,4%)	13 / 2791 (0,5%)	0,84	[0,38;1,87]	Intracranial Major Bleeding event
The primary endpoint (if exists) appears in blod characters
Reference(s) used for data extraction: 16949: Mak KHCoronary and mortality risk of novel oral antithrombotic agents: a meta-analysis of large randomised trials.BMJ Open 2012;2:

Endpoint	studied treat.	control treat.	mean diff

Absolute risk reduction (for a follow-up of maximum 21 months)
Endpoint	Events rate		Absolute risk reduction (ARR)
	Studied treat.	Control treat.
Coronary event	8,55‰	1,00%	-0,15%
thrombo-embolic event (cerebral or systemic)	1,82%	4,05%	-2,23%
stroke (fatal and non fatal)	1,75%	3,76%	-2,02%
ischemic stroke	1,25%	3,33%	-2,09%
myocardial infarction (fatal and non fatal)	8,55‰	1,00%	-0,15%
All cause death	3,95%	5,02%	-1,06%
Major bleeding	1,57%	1,40%	0,17%
Minor bleeding	6,70%	5,48%	1,2%
Haemmorhagic stroke	2,14‰	3,22‰	-0,11%
Fatal bleeding	1,42‰	2,15‰	-0,07%
Gastrointestinal major bleeding	4,27‰	5,02‰	-0,07%
Cardiovascular death	2,99%	3,44%	-0,45%
intracranial hemorrhage	3,92‰	4,66‰	-0,07%

Meta-analysis of all similar trials:

antithrombotics in atrial fibrillation for patients ineligible for warfarin

antithrombotics in atrial fibrillation for primary prevention of thromboembolic events

direct factor Xa inhibitors in atrial fibrillation for all type of patients

Reference(s)

TrialResults-center ID	TRC10340
Trials register #	NCT00496769

• Eikelboom JW, O'Donnell M, Yusuf S, Diaz R, Flaker G, Hart R, Hohnloser S, Joyner C, Lawrence J, Pais P, Pogue J, Synhorst D, Connolly SJ. Rationale and design of AVERROES: apixaban versus acetylsalicylic acid to prevent stroke in atrial fibrillation patients who have failed or are unsuitable for vitamin K antagonist treatment.. Am Heart J 2010;159:348-353.e1 - 10.1016/j.ahj.2009.08.026
  Pubmed | Hubmed | Fulltext
• Connolly SJ, Eikelboom J, Joyner C, Diener HC, Hart R, Golitsyn S, Flaker G, Avezum A, Hohnloser SH, Diaz R, Talajic M, Zhu J, Pais P, Budaj A, Parkhomenko A, Jansky P, Commerford P, Tan RS, Sim KH, Lewis BS, Van Mieghem W, Lip GY, Kim JH, Lanas-Zanetti F. Apixaban in Patients with Atrial Fibrillation.. N Engl J Med 2011 Feb 10;: - 10.1056/NEJMoa1007432
  Pubmed | Hubmed | Fulltext

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