G J Hankey1, C L Sudlow, D W Dunbabin. 1. Stroke Unit, Department of Neurology, Royal Perth Hospital, Wellington Street, Perth, Western Australia, Australia, 6001. gjhankey@cyllene.uwa.edu.au
Abstract
BACKGROUND: The most widely studied and prescribed antiplatelet agent for the prevention of stroke and other serious vascular events among high vascular risk patients is aspirin. Aspirin inhibits platelet activation by inhibiting platelet cyclooxygenase and thromboxane production, and reduces the odds of a serious vascular event by about a quarter. The thienopyridines (ticlopidine and clopidogrel) inhibit platelet activation by a different mechanism to aspirin (blocking the ADP receptor on platelets), and so may be more effective than aspirin. OBJECTIVES: The objective of this review was to determine the effectiveness and safety of thienopyridine derivatives (ticlopidine and clopidogrel) versus aspirin for the prevention of serious vascular events (stroke, myocardial infarction (MI) or vascular death) in patients at high risk of such events, and specifically in patients with a previous TIA or ischaemic stroke. SEARCH STRATEGY: We searched the Cochrane Stroke Group trials register (most recent search: March 1999) and the Antithrombotic Trialists' database, and also contacted Sanofi pharmaceutical company. SELECTION CRITERIA: All unconfounded, double blind, randomised trials directly comparing ticlopidine or clopidogrel with aspirin in high vascular risk patients. DATA COLLECTION AND ANALYSIS: Two reviewers independently extracted data and assessed trial quality. Additional data were sought from the principal investigators of the largest trial. MAIN RESULTS: Four trials involving a total of 22,656 high vascular risk patients were included. The trials were of high quality and comparable. Aspirin was compared with ticlopidine in three trials (3471 patients) and with clopidogrel in one trial (19,185 patients). Allocation to a thienopyridine was associated with a modest, yet statistically significant, reduction in the odds of a serious vascular event (12. 0% vs 13.0%; OR: 0.91, 95% CI: 0.84 to 0.98; 2p = 0.01), corresponding to the avoidance of 11 (95% CI: 2 to 19) serious vascular events per 1000 patients treated for about two years. There was also a reduction in stroke (5.7% vs 6.4%; OR: 0.88, 95% CI: 0.79 to 0.98; 7 [95% CI: 1 to 13] strokes avoided per 1000 patients treated for two years). Compared with aspirin, thienopyridines produced a significant reduction in the odds of gastrointestinal haemorrhage and other upper gastrointestinal upset, but a significant increase in the odds of skin rash and of diarrhoea. However, the increased odds of skin rash and diarrhoea were greater for ticlopidine than for clopidogrel. Allocation to ticlopidine, but not clopidogrel, was associated with a significant increase in the odds of neutropenia (2.3% vs 0.8%; OR: 2.7, 95% CI: 1.5 to 4.8). In the subset of patients with TIA/ischaemic stroke, the results were similar to those for all patients combined. However, since these patients are at particularly high risk of stroke, allocation to a thienopyridine was associated with a larger absolute reduction in stroke (10.4% vs 12.0%; OR: 0.86, 95% CI: 0.75 to 0.97; 16 [95% CI: 3 to 28] strokes avoided per 1000 patients treated for two years). REVIEWER'S CONCLUSIONS: The available randomised evidence shows that the thienopyridine derivatives are modestly but significantly more effective than aspirin in preventing serious vascular events in patients at high risk (and specifically in TIA/ischaemic stroke patients), but there is uncertainty about the size of the additional benefit. The thienopyridines are also associated with less gastrointestinal haemorrhage and other upper gastrointestinal upset than aspirin, but an excess of skin rash and diarrhoea. The risk of skin rash and diarrhoea is greater with ticlopidine than with clopidogrel. Ticlopidine, but not clopidogrel, is associated with an excess of neutropenia and of thrombotic thrombocytopenic purpura.
BACKGROUND: The most widely studied and prescribed antiplatelet agent for the prevention of stroke and other serious vascular events among high vascular risk patients is aspirin. Aspirin inhibits platelet activation by inhibiting platelet cyclooxygenase and thromboxane production, and reduces the odds of a serious vascular event by about a quarter. The thienopyridines (ticlopidine and clopidogrel) inhibit platelet activation by a different mechanism to aspirin (blocking the ADP receptor on platelets), and so may be more effective than aspirin. OBJECTIVES: The objective of this review was to determine the effectiveness and safety of thienopyridine derivatives (ticlopidine and clopidogrel) versus aspirin for the prevention of serious vascular events (stroke, myocardial infarction (MI) or vascular death) in patients at high risk of such events, and specifically in patients with a previous TIA or ischaemic stroke. SEARCH STRATEGY: We searched the Cochrane Stroke Group trials register (most recent search: March 1999) and the Antithrombotic Trialists' database, and also contacted Sanofi pharmaceutical company. SELECTION CRITERIA: All unconfounded, double blind, randomised trials directly comparing ticlopidine or clopidogrel with aspirin in high vascular risk patients. DATA COLLECTION AND ANALYSIS: Two reviewers independently extracted data and assessed trial quality. Additional data were sought from the principal investigators of the largest trial. MAIN RESULTS: Four trials involving a total of 22,656 high vascular risk patients were included. The trials were of high quality and comparable. Aspirin was compared with ticlopidine in three trials (3471 patients) and with clopidogrel in one trial (19,185 patients). Allocation to a thienopyridine was associated with a modest, yet statistically significant, reduction in the odds of a serious vascular event (12. 0% vs 13.0%; OR: 0.91, 95% CI: 0.84 to 0.98; 2p = 0.01), corresponding to the avoidance of 11 (95% CI: 2 to 19) serious vascular events per 1000 patients treated for about two years. There was also a reduction in stroke (5.7% vs 6.4%; OR: 0.88, 95% CI: 0.79 to 0.98; 7 [95% CI: 1 to 13] strokes avoided per 1000 patients treated for two years). Compared with aspirin, thienopyridines produced a significant reduction in the odds of gastrointestinal haemorrhage and other upper gastrointestinal upset, but a significant increase in the odds of skin rash and of diarrhoea. However, the increased odds of skin rash and diarrhoea were greater for ticlopidine than for clopidogrel. Allocation to ticlopidine, but not clopidogrel, was associated with a significant increase in the odds of neutropenia (2.3% vs 0.8%; OR: 2.7, 95% CI: 1.5 to 4.8). In the subset of patients with TIA/ischaemic stroke, the results were similar to those for all patients combined. However, since these patients are at particularly high risk of stroke, allocation to a thienopyridine was associated with a larger absolute reduction in stroke (10.4% vs 12.0%; OR: 0.86, 95% CI: 0.75 to 0.97; 16 [95% CI: 3 to 28] strokes avoided per 1000 patients treated for two years). REVIEWER'S CONCLUSIONS: The available randomised evidence shows that the thienopyridine derivatives are modestly but significantly more effective than aspirin in preventing serious vascular events in patients at high risk (and specifically in TIA/ischaemic strokepatients), but there is uncertainty about the size of the additional benefit. The thienopyridines are also associated with less gastrointestinal haemorrhage and other upper gastrointestinal upset than aspirin, but an excess of skin rash and diarrhoea. The risk of skin rash and diarrhoea is greater with ticlopidine than with clopidogrel. Ticlopidine, but not clopidogrel, is associated with an excess of neutropenia and of thrombotic thrombocytopenic purpura.