SPORTIF III trial

SPORTIF III study, 2003	TRC2637
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Treatments

Studied treatment

ximelagatran 36 mg twice daily

Control treatment

warfarin standard dose (target INR 2-3)

Concomittant treatment

Aspirin <100mg/day allowed Other antithrombotic drugs were prohibited.

Remarks

Aspirin was used concurrently for at least half the period on study drug by 13% patients assigned to ximelagatran and 10% on warfarin(p=0.01).

Treatments description

INR obtained(mean)

2.5

Patients

One or more stroke risk factor in addition to AF.High risk patients with non valvular atrial fibrillation.

Inclusion criteria

Age >18,Persistent or paroxysmal AF verified by at least 2 ECG,One or more stroke risk factors in addition to AF(hypertension,age>75,previous stroke TIA or systemic embolism,left ventricular dysfunction,age>65+coronary artery disease,age >65+diabete mellitus)

Exclusion criteria

Mitral stenosis,Transient AF caused by reversible disorder,Stroke within the previous 30 days or TIA within 3 days,Condition associated with increased risk of bleeding,Active infective endocarditis,Current atrial myxoma or left ventricular thrombus,Admission for acute coronary syndrome or percutaeous coronary intervention within 30 days,Requirement for chronic anticoagulation treatment for disorders other than AF,planned cardioversion,Planned major surgery,treatment with platelet inhibitor drugs other than aspirin 100mg/day or less within 10 days or fibrinolytic agents within 30 days before randomisation,Regular use of NSAI drugs,Renal insuffiency,Active liver disease or persistent elevationof liver enzymes,Childbearing potential,pregnancy or lactation,Drug addiction alcohol abuse or both,Anaemia or thrombopenia

Baseline characteristics

age(mean)	70.2
male(%)	69
systolic blood pressure(mean)	139
hypertension(%)	72
diabete mellitus(%)	22
prior TIA or stroke(%)	24
left ventricular dysfunction(%)	34
paroxysmal AF(%)	8
current smoker(%)	8
subgroup test	a

Method and design

Randomized effectives	1704 / 1703 (studied vs. control)
Design	Parallel groups
Blinding	Open
Follow-up duration	17.4 months
Lost to follow-up	4.1%
Number of centre	259
Geographic area	europe,asia,australasia
Primary endpoint	All stroke or systemic embolism
Remarks	Premature termination of study treatment was the result of study endpoint (4% warfarin group,3% ximelegatran) and adverse effects(4% warfarin group,8% ximelegatran group:this difference is related to elevation of liver enzymes in some patients treated with ximelegatran). The trial was a non inferiority trial but the primary analysis was only by intention to treat.
Withdrawals (T1/T0)	18% / 14%

Results

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

Coronary event

24 / 1704
13 / 1703
classic 1,85 [0,94;3,61]

thrombo-embolic event (cerebral or systemic)

40 / 1704
56 / 1703
0,71 [0,48;1,07]

systemic thrombo-embolic complication

4 / 1704
2 / 1703
classic 2,00 [0,37;10,90]

stroke (fatal and non fatal)

36 / 1704
54 / 1703
0,67 [0,44;1,01]

ischemic stroke

32 / 1704
46 / 1703
0,70 [0,45;1,09]

myocardial infarction (fatal and non fatal)

24 / 1704
13 / 1703
classic 1,85 [0,94;3,61]

All cause death

78 / 1704
79 / 1703
0,99 [0,73;1,34]

Bleeding

478 / 1704
547 / 1703
0,87 [0,79;0,97]

Major bleeding

29 / 1704
41 / 1703
0,71 [0,44;1,13]

Minor bleeding

449 / 1704
506 / 1703
0,89 [0,80;0,99]

Haemmorhagic stroke

4 / 1704
9 / 1703
0,44 [0,14;1,44]

Cardiovascular death

40 / 1704
33 / 1703
1,21 [0,77;1,91]

Fatal stroke

10 / 1704
9 / 1703
classic 1,11 [0,45;2,73]

TE event or ischemic stroke or systemic embolism

32 / 1704
46 / 1703
0,70 [0,45;1,09] 0 2 1.0

Endpoint	Events (%)		Relative Risk	95% CI	Endpoint definition in the trial	Ref
Relative risks
Endpoint	Studied treat.	Control treat.	Relative Risk	95% CI	Endpoint definition in the trial	Ref
Coronary event	24 / 1704 (1,4%)	13 / 1703 (0,8%)	1,85	[0,94;3,61]		16949
thrombo-embolic event (cerebral or systemic)	40 / 1704 (2,3%)	56 / 1703 (3,3%)	0,71	[0,48;1,07]		1830
systemic thrombo-embolic complication	4 / 1704 (0,2%)	2 / 1703 (0,1%)	2,00	[0,37;10,90]	abrupt vascular insufficiency asociated with clinical and radiological evidence of arterial occlusion in the absence of another likely mechanism
stroke (fatal and non fatal)	36 / 1704 (2,1%)	54 / 1703 (3,2%)	0,67	[0,44;1,01]	abrupt onset of a focal neurological deficit in the distribution of a brain artery persisting more than 24 hours or due to intracerebral hemorrhage
ischemic stroke	32 / 1704 (1,9%)	46 / 1703 (2,7%)	0,70	[0,45;1,09]
myocardial infarction (fatal and non fatal)	24 / 1704 (1,4%)	13 / 1703 (0,8%)	1,85	[0,94;3,61]	at least 2 of the following :typical chest pain for at least 20 minutes;ECG showing changes of acute myocardial infarction; and cardiac enzyme elevation more than twice the upper limit of normal
All cause death	78 / 1704 (4,6%)	79 / 1703 (4,6%)	0,99	[0,73;1,34]
Bleeding	478 / 1704 (28,1%)	547 / 1703 (32,1%)	0,87	[0,79;0,97]	major and minor bleeding	1830
Major bleeding	29 / 1704 (1,7%)	41 / 1703 (2,4%)	0,71	[0,44;1,13]	bleeding that was fatal or clinically overt and associated with either transfusion of 2 units of blood or a 20g/l decrease in Hb or bleeding that was intracranial,retroperitoneal,spinal,ocular,pericardial or atraumatic articular but not intracerebral
Minor bleeding	449 / 1704 (26,3%)	506 / 1703 (29,7%)	0,89	[0,80;0,99]
Haemmorhagic stroke	4 / 1704 (0,2%)	9 / 1703 (0,5%)	0,44	[0,14;1,44]
Cardiovascular death	40 / 1704 (2,3%)	33 / 1703 (1,9%)	1,21	[0,77;1,91]
Fatal stroke	10 / 1704 (0,6%)	9 / 1703 (0,5%)	1,11	[0,45;2,73]	death from any cause within 30 days of stroke
TE event or ischemic stroke or systemic embolism	32 / 1704 (1,9%)	46 / 1703 (2,7%)	0,70	[0,45;1,09]	thrombo-embolic event, ischemic stroke or systemic embolism
The primary endpoint (if exists) appears in blod characters
Reference(s) used for data extraction: 1830: Olsson SBStroke prevention with the oral direct thrombin inhibitor ximelagatran compared with warfarin in patients with non-valvular atrial fibrillation (SPORTIF III): randomised controlled trial.Lancet 2003 Nov 22;362:1691-8 16949: Mak KHCoronary and mortality risk of novel oral antithrombotic agents: a meta-analysis of large randomised trials.BMJ Open 2012;2:

Endpoint	Events rate		Absolute risk reduction (ARR)
Absolute risk reduction (for a follow-up of 17.4 months)
Endpoint	Studied treat.	Control treat.	Absolute risk reduction (ARR)
Coronary event	1,41%	7,63‰	0,65%
thrombo-embolic event (cerebral or systemic)	2,35%	3,29%	-0,94%
systemic thrombo-embolic complication	2,35‰	1,17‰	0,12%
stroke (fatal and non fatal)	2,11%	3,17%	-1,06%
ischemic stroke	1,88%	2,70%	-0,82%
myocardial infarction (fatal and non fatal)	1,41%	7,63‰	0,65%
All cause death	4,58%	4,64%	-0,06%
Bleeding	28,05%	32,12%	-4,07%
Major bleeding	1,70%	2,41%	-0,71%
Minor bleeding	26,35%	29,71%	-3,36%
Haemmorhagic stroke	2,35‰	5,28‰	-0,29%
Cardiovascular death	2,35%	1,94%	0,41%
Fatal stroke	5,87‰	5,28‰	0,06%
TE event or ischemic stroke or systemic embolism	1,88%	2,70%	-0,82%

Meta-analysis of all similar trials:

antithrombotics in atrial fibrillation for primary prevention of thromboembolic events

direct antithrombins in atrial fibrillation for all type of patients

new oral anticoagulants in atrial fibrillation for all type of patients

Reference(s)

TrialResults-center ID	TRC2637
Trials register #	NA