Drugs that inhibit platelet function are widely used to decrease the risk of occlusive arterial events in patients with atherosclerosis. There are three families of anti-platelet agents with proven clinical efficacy: (1) cyclo-oxygenase inhibitors, such as aspirin; (2) adenosine diphosphate (ADP) receptor antagonists, such as the thienopyridine compounds, ticlopidine and clopidogrel; and (3) glycoprotein IIb/IIIa antagonists. All these drugs are used during coronary interventions and in the medical management of acute coronary syndromes, while only aspirin and thienopyridine compounds are used in the long-term prevention of cardiovascular and cerebrovascular events in patients at risk.
Both aspirin and the thienopyridines selectively inhibit a single pathway of platelet activation: aspirin affects the arachidonate-thromboxane pathway, while the thienopyridines affect the ADP pathway by irreversibly blocking the ADP receptor P2Y12 . The good antithrombotic efficacy of these drugs, despite their selective mechanism of action, is explained by the fact that both the arachidonate-thromboxane pathway and the ADP pathway contribute to the amplification of platelet activation and are essential for the full aggregation response of platelets under several experimental conditions .
Antagonists of the platelet membrane glycoprotein complex IIb/IIIa (GPIIb-IIIa) inhibit the final common step in platelet aggregation, which involves the binding of adhesive proteins to GPIIb-IIIa or integrin αIIbβ3, which is essential for platelet-to-platelet bridging. The GPIIb-IIIa antagonists that are available for clinical use are as follows: (1) a humanized murine monoclonal antibody, abciximab; (2) two non-peptide compounds, tirofiban and lamifiban; and (3) a peptide, eptifibatide, based on a snake venom sequence and presumably a mimetic of the γ-chain peptide of fibrinogen . Oral GPIIb-IIIa antagonists have been tested in several randomized clinical trials and were found to be associated with excess mortality. Based on these data, it was concluded that oral GPIIb-IIIa antagonists are neither efficacious nor safe and were therefore abandoned . Intravenous GPIIb-IIIa antagonists are used, in combination with other antithrombotic therapies, in patients undergoing coronary interventions and in the medical management of acute coronary syndromes.
Despite the good risk-to-benefit ratio of anti-platelet agents, the risk of severe bleeding complications, including cerebral haemorrhage, is slightly increased, albeit to a much lesser extent than that associated with the use of other antithrombotic drugs, such as anticoagulants or thromobolytic agents.
The incidence of cerebral haemorrhage during aspirin treatment in most studies is too low for a statistically significant effect of aspirin to be detected. Nonetheless, an increased incidence of cerebral haemorrhage has been documented in patients under aspirin treatment for acute myocardial infarction or acute ischaemic stroke [3-6]. Moreover, a heightened incidence of haemorrhagic stroke has also been demonstrated during primary [7-9] and secondary  prophylaxis of cardiovascular events. A meta-analysis of 16 randomized, placebo-controlled clinical trials, including a total of 55 462 patients, showed that treatment with aspirin was associated with a relative risk of haemorrhagic stroke of 1.84 (P < 0.001) . In absolute terms, one could predict 12 incident cases of stroke per 10 000 patients chronically treated with aspirin. The Antiplatelet Trialists' Collaboration also reported a statistically significant 22% increased incidence of haemorrhagic stroke in patients on anti-platelet treatment, mostly with aspirin . It must be noted, however, that the increased incidence of haemorrhagic stroke was always outweighed by a significant decrease in the incidence of ischaemic strokes.
Adding aspirin to vitamin K antagonists (VKA) increases the risk of cerebral haemorrhage. A meta-analysis of five randomized clinical trials showed that the addition of aspirin to VKA is associated with a relative risk of cerebral haemorrhage of 2.6 (95% CI 1.3 to 5.4, P < 0.009) . Similar results were found in a retrospective study of more than 10 000 patients with a trial fibrillation (RR 3.0, 95% CI 1.6 to 5.5) . However, conflicting results were reported in other trials [15-19].
Clopidogrel and ticlopidine
The incidence of cerebral haemorrhage in patients treated with clopidogrel or ticlopidine ranged between 0.2% and 0.4% in the CAPRIE, AASPS and MATCH randomized clinical trials [20-22]. Patients enrolled in the aspirin arm in the CAPRIE and AAASPS clinical trials had similar rates of cerebral haemorrhage (0.2-0.3%) [20,21].
Combination of aspirin and clopidogrel
In the MATCH trial of patients with cerebrovascular disease, the combination of clopidogrel with aspirin increased the risk of cerebral haemorrhage by 61% (P = 0.06) compared with clopidogrel alone . More recently, the CHARISMA trial showed that the incidence of cerebral haemorrhage was similar in patients treated with aspirin alone and in patients on a combined treatment with aspirin and clopiodgrel (0.3% for both treatments) . In contrast, in the CURE study of patients with acute coronary syndromes, the incidence of intracranial bleeding tended to be higher in patients on combined clopidogrel and aspirin (0.15%) compared with patients on aspirin alone (0.1%) .
In the EPIC study , there was no difference in the occurrence of haemorrhagic or non-haemorrhagic strokes between patients treated with abciximab and patients treated with placebo . The 95% upper one-sided confidence bounds for haemorrhagic stroke rates were 0.9%, 0.7% and 1.1% for the placebo, abciximab bolus and abciximab bolus-plus-infusion groups, respectively. Two deaths (0.09%) were attributable to major bleeding from haemorrhagic stroke: one in the placebo group and one in the bolus-plus-infusion group .
Combined analysis of data from four double-blind, placebo-controlled, randomized trials [25,27-29] conducted between November 1991 and October 1997 at a total of 257 academic and community hospitals in the United States and Europe, for a total of 8555 patients undergoing percutaneous coronary intervention (PCI) with or without stent deployment, showed no significant difference in stroke rate between patients assigned abciximab (n = 22 (0.40%)) and those assigned placebo (n = 9 (0.29%); P = 0.46). The rate of non-haemorrhagic stroke was 0.17% in patients treated with abciximab and 0.20% in patients treated with placebo (difference, −0.03%; 95% CI −0.23% to 0.17%), and the rates of haemorrhagic stroke were 0.15% and 0.10%, respectively (difference, 0.05%; 95% CI −0.11% to 0.21%) . A similar incidence of haemorrhagic strokes in patients treated with abciximab or another GPIIb-IIIa antagonists and placebo was also found in another overview of six randomized clinical trials . Among patients treated with abciximab, the rate of haemorrhagic stroke in patients receiving standard-dose heparin in EPIC, CAPTURE and EPILOG was higher than in those receiving low-dose heparin in the EPILOG and EPISTENT trials (0.27% vs. 0.04%; P = 0.57). Therefore, patients undergoing PCI and treated with abciximab should receive low-dose, weight-adjusted heparin .
In general, the risk-to-benefit ratio of anti-platelet agents is very good. In particular, the incidence of haemorrhagic stroke is only slightly increased compared to untreated patients. In addition, it must be noted that the increased incidence of haemorrhagic stroke is outweighed by a significant decrease in the incidence of ischaemic strokes. Despite the fact that the currently available anti-platelet agents have a good risk-to-benefit ratio, they have some drawbacks, which justifies the unceasing search for agents that can further improve the clinical outcome of patients with atherosclerosis through greater efficacy and/or safety. Several new anti-platelet drugs are currently under clinical development .
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