Oral anticoagulants versus antiplatelet therapy for preventing further vascular events after transient ischaemic attack or minor stroke of presumed arterial origin.
BACKGROUND
Patients who are entered in clinical trials after a transient ischaemic attack (TIA) or non disabling ischaemic stroke have an annual risk of important vascular events (death from all vascular causes, non-fatal stroke, or non-fatal myocardial infarction) of between 4 and 11 percent. Aspirin, in a daily dose of 30mg or more, offers only modest protection after cerebral ischaemia: it reduces the incidence of major vascular events by 20 percent at most. Secondary prevention trials after myocardial infarction indicate that treatment with oral anticoagulants is associated with a risk reduction approximately twice that of treatment with antiplatelet therapy.


OBJECTIVE
1) To compare the efficacy of oral anticoagulants and antiplatelet therapy in the secondary prevention of vascular events after cerebral ischaemia of presumed arterial origin. 2) To compare the safety of oral anticoagulants and antiplatelet therapy in the secondary prevention of vascular events after cerebral ischaemia of presumed arterial origin.


METHODS
This review draws on the search strategy developed for the Stroke Group as a whole. Relevant trials were identified in the Specialised Register of Controlled Trials (last searched: June 2000). Authors of published trials were contacted for further information and unpublished data.


METHODS
Randomised trials with concealed treatment allocation on long term (> 6 months) secondary prevention after recent (< 6 months) TIA or minor ischaemic stroke of presumed arterial origin were selected. The oral anticoagulant therapy was to be of specified intensity (by means of the International Normalised Ratio (INR)) with warfarin, phenprocoumon or acenocoumarol versus a single antiplatelet drug (or combination of antiplatelet agents).


METHODS
Two reviewers selected trials meeting the inclusion criteria and extracted details of randomisation methods, blinding of treatments and assessments, whether intention-to-treat analysis is possible from the published data, whether treatment groups are comparable with regard to major prognostic risk factors for outcomes, the number of patients who are excluded or lost to follow-up, definition of outcomes, and entry and exclusion criteria. The methodological quality of each trial was assessed by the two reviewers using these extracted data. In addition, target INR for anticoagulant treatment and dose and type of antiplatelet drug, duration of follow-up and the numbers of defined outcome events was recorded. The data were analysed according to the intention-to-treat principle. Subgroup analyses with treatment INR 2.1 - 3.6 versus INR 3.0 - 4.5 was performed. Relative and absolute risk reductions were calculated by means of the statistical software provided by the Cochrane Collaboration.


RESULTS
Four trials, with a total of 1870 patients were selected. In the prevention of ischaemic stroke after cerebral ischaemia of presumed arterial origin, the available data do not allow a robust conclusion on whether anticoagulants (in any intensity) are more efficacious than antiplatelet therapy (low intensity anticoagulation RR 0.96, 95% CI 0.38 to 2.42, high intensity anticoagulation RR 1.02, 95% CI 0.49 to 2.13). Treatment with anticoagulation INR 2.1 - 3.6 does not give an importantly higher bleeding risk than treatment with antiplatelet agents (RR 1.19, 95% CI 0.59 to 2.41). It is clear that oral anticoagulants INR 3.0 - 4.5 are not safe, because they yield a higher risk of major bleeding complications (RR 9.0, 95% CI 3.9 to 21).


CONCLUSIONS
For the secondary prevention of further vascular events after transient ischaemic attack or minor stroke of presumed arterial origin, there is insufficient evidence to justify the routine use of low intensity oral anticoagulants (INR 2.0 - 3.6). More intense anticoagulation (INR 3.0 - 4.5) is not safe and should not be used in this setting.
Algra
A
A
Julius Center for General Practice and Patient Oriented Research / Univ. Department of Neurology, University Medical Center Utrecht, PO Box 85500, Utrecht, Netherlands, 3508 GA. A.Algra@neuro.azu.nl
de Schryver
E L
EL
van Gijn
J
J
Kappelle
L J
LJ
Koudstaal
P J
PJ
D000284:Administration, Oral; D000925:Anticoagulants / Q000008:administration & dosage* / Q000009:adverse effects; D002423:Cause of Death; D006470:Hemorrhage / Q000139:chemically induced; D006801:Humans; D002546:Ischemic Attack, Transient / Q000188:drug therapy*; D010975:Platelet Aggregation Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D016032:Randomized Controlled Trials as Topic; D020521:Stroke / Q000188:drug therapy*
D000925:Anticoagulants; D010975:Platelet Aggregation Inhibitors