Drugs that inhibit platelet function are widely used to decrease the risk of occlusive arterial events in patients with atherosclerosis. There are 3 families of antiplatelet agents with proven clinical efficacy that are currently used in the clinical practice: (1) cyclooxygenase-1 (COX-1) inhibitors, such as aspirin; (2) adenosine diphosphate (ADP) receptor antagonists, such as the thienopyridine compounds ticlopidine and clopidogrel; and (3) glycoprotein IIb/IIIa (GPIIb/IIIa) antagonists. All these drugs are used during coronary interventions and in the medical management of acute coronary syndromes, while only aspirin and the thienopyridine compounds are used in long- term prevention of cardiovascular and cerebrovascular events in patients at risk. Another family of antiplatelet drugs, the phosphopdiesterase inhibitors, include dipyridamole and cilostazol, both of which have been tested in the prevention of cerebrovascular events.
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, purinergic receptor P2Y, G-protein coupled, 12 (P2Y12) . The 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 .
Despite the good risk-to-benefit ratio of antiplatelet agents, the risk of severe bleeding complications, including cerebral hemorrhage, 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 pharmacological effects of aspirin are mediated primarily through its inhibition of prostaglandins and thromboxane synthesis. COX-1 converts arachidonic acid, which is liberated from membrane phospholipids upon platelet activation by some agonists, to prostaglandin (PG) G2 and PGH2. This is then transformed to other metabolites, including thromboxane A2, a potent vasoconstrictor and platelet agonist. Aspirin irreversibly acetylates the serine 529 residue of COX-1, inducing a conformational change of the active site of the enzyme, thus preventing it from binding arachidonic acid . Other drugs inhibiting COX-1, such as sulphinpyrazone and indobufen, have been tested in some clinical trials and found to be potentially effective, but their use in clinical practice is very limited.
Thienopyridines (P2Y12 inhibitors)
Ticlopidine and clopidogrel are prodrugs that are inactive in vitro and need to be metabolized in vivo by the hepatic cytochrome P-450 1A enzymatic pathway to active metabolites to exert their inhibitory effect on platelet function . One study reported that clopidogrel inhibits platelet aggregation in vitro, but this effect was later shown to be artifactual. Both drugs irreversibly and selectively inhibit ADP-induced platelet aggregation (30 to 60% inhibition)—ADP-induced adenylate cyclase downregulation—and cause a dose-dependent reduction of the platelet binding sites for ADP or its poorly hydrolyzable analogue 2-methylthio-ADP (2MeS-ADP) [3-6]. The pharmacological effects of clopidogrel reproduce the platelet function abnormalities that are observed in patients who are congenitally deficient in P2Y12 and in P2Y12 knock-out mice , demonstrating that the drug selectively antagonizes the platelet P2Y12 receptor for ADP, without affecting the other platelet ADP receptor, P2Y1. The ability of thienopyridines to inhibit platelet aggregation induced by several platelet agonists (such as thromboxane A2 analogues, collagen, and low concentrations of thrombin) is accounted for by suppression of the amplifying effect on platelet aggregation of ADP released from platelet dense granules . Ticlopidine or clopidogrel treatment renders thrombin-induced platelet aggregates more susceptible to deaggregation and inhibits shear-induced platelet aggregation [8,9]. Both drugs cause a 2- to 3-fold prolongation of the bleeding time .
The need for thienopyridines to be actively metabolized accounts for the delay until their antiplatelet effects are observed. The antiplatelet effect of ticlopidine is manifest 2 to 3 days after the oral administration of 500 mg daily, reaches its plateau after 4 days of treatment, has a half-life of about 5 days, and persists for approximately 10 days; this time course corresponds to the life span of a circulating platelet . Doses of 250 mg ticlopidine daily induce comparable inhibition of platelet aggregation, while 100 mg daily does not inhibit platelet function even after 14 days of administration . The pharmacological effect of ticlopidine is similar in both sexes and is not significantly affected by renal function .
A maximum degree of inhibition of platelet aggregation similar to that obtained with ticlopidine is observed about 5 days after treatment of healthy volunteers with clopidogrel 75 mg . The delayed onset of action of the antiplatelet effect can be reduced to about 2 to 5 h by a loading dose of 300 to 600 mg, both in healthy volunteers and in patients with atherothrombotic disease [11,12]. The activity of clopidogrel on the inhibition of platelet aggregation is maintained with long-term treatment and is independent of age and presence of atherosclerosis or cirrhosis .
Recently, the active metabolites of ticlopidine and clopidogrel were identified. They are compounds containing an active thiol group and are generated from their prodrugs through a two-step metabolism in the liver. The irreversible modification of the ADP P2Y12 receptor site, which is responsible for the biological activity of the metabolites of the thienopyridines, could be explained by the formation of a disulfide bridge between the reactive thiol group of the active metabolite and a cysteine residue of the P2Y12 receptor [13-15].
A number of mechanisms of action have been reported for dipyridamole, including inhibition of phosphodiesterase inhibitors (PDE) and increase in the local concentration of adenosine, both contributing to the increase in intraplatelet cyclic adenosine monophosphate (cAMP), a potent inhibitor of platelet activation . The increase in the interstitial concentration of adenosine that is associated with dipyridamole treatment could be of benefit independently of its inhibitory effects of platelets, as it is associated with improved ischemic tolerance. In addition, it has been postulated that dipyridamole may exert its antithrombotic effects not only by inhibiting platelet function, but also via mechanisms that involve the vessel wall (eg, stimulation of prostacyclin production, release of tissue plasminogen activator, inhibition of lipid peroxidation and oxidative modification of low-density l ipoproteins, and inhibition of smooth muscle cell proliferation) .
Cilostazol selectively inhibits the PDE3 isoenzyme; its inhibition of platelet aggregation appears to be due to this function, which results in decreased intracellular Ca2+ levels resulting from increased cAMP levels .
Antagonists of the platelet membrane 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 (Figure 1). The GPIIb/IIIa antagonists that are available for clinical use are (1) a humanized murine monoclonal antibody, abciximab; (2) two non-peptide compounds, tirofiban and lamifiban; or (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.
||Figure 1. Mechanisms of action of the three families of antiplatelet agents with proven clinical efficacy that are currently used in the clinical practice: (1) cyclooxygenase-1 (COX-1) inhibitors, such as aspirin, which inhibit the production of the potent platelet agonist thromboxane A2; (2) ADP receptor antagonists, such as the thienopyridine compounds ticlopidine and clopidogrel, which inhibit one of the two platelet receptors for ADP, P2Y12; and (3) glycoprotein (GP) IIb/IIIa antagonists, which inhibit the binding of adhesive proteins to GPIIb/IIIa.
EFFICACY OF ANTIPLATELET AGENTS IN THE PREVENTION OF CEREBROVASCULAR EVENTS
Cerebrovascular events of arterial origin (atherothrombotic events)
Only aspirin has been studied in clinical trails of sufficient potency in this setting. The available data are conflicting regarding the role of aspirin in the primary p revention of cerebrovascular events in patients without atrial fibrillation (AF) or other cardiac diseases associated with heightened risk of arterial embolism.
In two trials that enrolled physicians, aspirin therapy reduced the risk of transient ischemic attacks (TIAs), but did not significantly change the incidence of stroke [19,20]. In the Women’s Health Study, aspirin significantly decreased the global risk of stroke by 17% and that of ischemic stroke by 24%, but increased the risk of hemorrhagic stroke and major bleeding events by 24 and 40%, respectively . The authors of this trial performed a meta-analysis of primary prevention trials, which showed that aspirin significantly reduced the incidence of ischemic stroke in women by 19%, without a reduction in the risk of acute myocardial infarction (AMI) . In contrast, aspirin significantly reduced AMI in men by 32% and showed little increase in risk for stroke . Whether or not these gender differences are the result of chance alone or as of yet unknown causes remains uncertain. Patients with carotid stenosis >50% and carotid bruits do not seem to benefit from aspirin treatment, in terms of reduction of subsequent cerebrovascular events .
Cerebrovascular events in patients with nonvalvular atrial fibrillation
The role of aspirin in the primary prevention of cerebrovascular accidents in patients with AF has been tested in clinical trials, with conflicting results. The Stroke Prevention in Atrial Fibrillation (SPAF) study found that aspirin, given for a mean of 1.3 years, significantly decreased the risk of stroke by 42% . However, the effect of aspirin is lower than that of vitamin K antagonists. The addition of aspirin to low doses of warfarin was inferior to high-dose warfarin (mean international normalized ratio [INR] of 2.4) in preventing ischemic stroke in patients with AF . Aspirin could be the treatment of choice for patients with AF and low risk of cerebrovascular accidents (<75 years of age and absence of hypertension, diabetes, AMI, heart failure, and/or prior embolic events) .
A recent meta-analysis showed that adjusted-dose warfarin and related vitamin K antagonists reduce stroke, disabling stroke, and other major vascular events for those with nonvalvular AF by about one third when compared with antiplatelet therapy .
Cerebrovascular events of arterial origin (atherothrombotic events)
The meta-analysis of the Antiplatelet Trialists’ Collaboration reviewed 195 studies, of which 21 were trials of antiplatelet therapy in more than 18,000 patients with previous TIA or stroke . The large majority of these 21 trials compared aspirin (50 to 1500 mg/day) to placebo. In addition, other drugs, such as dipyridamole, sulphinpyrazone, and ticlopidine, were used alone or in combination with aspirin. The results of the meta-analysis revealed that treatment with antiplatelet agents was associated with a highly statistically significant 23% decrease in nonfatal stroke, 26% decrease in nonfatal AMI, and 12% reduction in total mortality. The first meta-analysis of the same group previously showed that the benefits associated with aspirin treatment were similar for patients who had been enrolled after a previously completed stroke (23% risk reduction) and for patients who previously experienced TIAs (22% risk reduction) .
Aspirin. Most of the positive effects of antiplatelet therapy in the secondary prevention of stroke that has been demonstrated by the Antiplatelet Trialists’ Collaboration are to be attributed to aspirin, which, as already mentioned, was the most widely used antiplatelet drug in the studies that were analyzed. Indeed, also a previous meta-analysis of 10 studies, which included more than 4000 patients, showed that aspirin treatment was associated with a statistically significant 13% decrease in the incidence of events, compared to placebo .
A recent trial showed that vitamin K antagonists (target INR range of 2.0 to 3.0) are not more effective than aspirin for secondary prevention after TIA or minor stroke. A possible protective effect of vitamin K antagonists against ischemic events is offset by increased bleeding complications .
The optimal dose of aspirin in the prevention of cerebrovascular events has long been debated. Based on the results of the meta-analyses of the Antiplatelet Trialists’ Collaboration (no differences in aspirin dose ranging between 50 and 1500 mg/day) , the United Kingdom TIA trial (no differences between 300 and 1200 mg/day) , the Dutch TIA trial (no difference between 30 and 238 mg/day) , and the Swedish Aspirin Low-Dose trial ( SALT; efficacy of aspirin at 75 mg/day) , and considering that the incidence of adverse effects decreases with the daily dose of aspirin, low doses of aspirin (eg, 75-100 mg/day) should be chosen for secondary prevention of stroke.
Thienopyridines. The Canadian American Ticlopidine Study (CATS), a randomized, double-blind, placebo-controlled trial with a mean clinical follow-up of 24 months, showed that ticlopidine (250 mg bid), compared to placebo, significantly reduced the incidence of stroke, MI, or vascular death in men and women who had suffered a recent thromboembolic stroke (relative risk reduction [RRR] 23.3%) . In the Ticlopidine Aspirin Stroke Study (TASS), ticlopidine proved more effective than aspirin (650 mg bid) in reducing the risk of stroke and death in patients with recent transient or mild persistent focal cerebral or retinal ischemia, although the risk of side effects was greater for ticlopidine than it was for aspirin ; the benefit was manifest after the first year of treatment and persisted for the 6 years of follow-up. A subanalysis of the same study showed that ticlopidine is more effective than aspirin in reducing the risk of stroke in a subgroup of patients with a recent minor completed stroke as the qualifying ischemic event . In contrast to the results of TASS, the African-American Stroke Prevention Study (AASPS) found no statistically significant difference between ticlopidine and aspirin (650 mg daily) in the prevention of recurrent stroke, MI, and vascular death in black patients with previous noncardioembolic stroke . Considering the higher incidence of side effects (and the greater cost) associated with the use of ticlopidine, aspirin should therefore be regarded as a better prophylaxis for stroke than ticlopidine, at least in black patients.
The largest trial involving a thienopyridine, the Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events (CAPRIE) trial, enrolled 19,185 patients at risk of ischemic events due to previous MI, ischemic stroke, or peripheral artery disease . The trial showed an 8.7% RRR of the major end points (MI, ischemic stroke, and vascular death) within a mean follow-up of 1.9 years in patients treated with clopidogrel (75 mg daily) compared to patients treated with aspirin (325 mg daily). The benefit associated with clopidogrel therapy seemed to be confined to patients with previous peripheral artery disease. Secondary analyses of the trial showed that clopidogrel demonstrated an amplified clinical benefit versus aspirin in patients with prior cardiac surgery  and in those at high risk of atherothrombotic events, such as those with a previous history of symptomatic atherothrombotic disease or with major risk factors such as diabetes mellitus or hypercholesterolemia [40,41]. However, the 95% CI of the RRR for high-risk patients with preexistent atherosclerotic disease overlaps substantially with that for the entire CAPRIE population, thus failing to prove convincingly that the effect of clopidogrel is really amplified in high-risk patients .
The Management of Atherothrombosis with Clopidogrel in High-Risk Patients with Recent Transient Ischemic Attacks or Ischemic Stroke (MATCH) trial showed that adding aspirin to clopidogrel (both given at 75 mg daily) in high-risk patients with recent ischemic stroke or TIA and at least one additional risk factor was associated with a nonsignificant difference in reducing major vascular events (RRR 6.4%; 95% CI -4.6–16.3), but doubled the RR of life-threatening hemorrhages from 1.3 (clopidogrel) to 2.6% (aspirin plus clopidogrel) . Predefined subgroup analyses did not identify patient groups in whom the combination therapy was advantageous compared to clopidogrel alone. In contrast, the combination of aspirin and clopidogrel was more effective than aspirin alone in reducing asymptomatic embolization, detected by transcranial Doppler ultrasound, in patients with a recently symptomatic carotid stenosis of ≥50% . In this study, the number of strokes was smaller in the combination therapy group (0 vs 4), although the number of patients (110) was too small to reach a statistically significant reduction in clinical end points.
A recent systematic review of randomized trials showed that the thienopyridines are modestly but significantly more effective than aspirin in preventing serious vascular events in patients at high risk (and specifically in TIA/ischemic stroke patients), but there is uncertainty about the size of the additional benefit .
Dipyridamole. In a recent randomized, controlled, open trial (European/Australasian Stroke Prevention in Reversible Ischaemia Trial; ESPRIT), there were 1363 patients who were assigned aspirin (30 to 325 mg daily) with dipyridamole (200 mg twice daily) and 1376 patients who were given aspirin (30 to 325 mg daily) alone within 6 months of a TIA or minor stroke of presumed arterial origin . After a mean follow-up of 3.5 years, primary events (composite of death from all vascular causes, nonfatal stroke, nonfatal MI, or major bleeding complication) arose in 173 (13%) patients on aspirin and dipyridamole and in 216 (16%) on aspirin alone (hazard ratio 0.80, 95% CI 0.66–0.98; absolute risk reduction 1.0% per year, 95% CI 0.1–1.8). Addition of the ESPRIT data to the meta-analysis of previous trials resulted in an overall risk ratio for the composite of vascular death, stroke, or MI of 0.82 (95% CI 0.74–0.91) . Patients on aspirin and dipyridamole discontinued trial medication more often than those on aspirin alone (470 vs 184), mainly because of headache.
A meta-analysis of 29 trials (which included the ESPRIT trial), with 23,019 participants, among whom 1503 vascular deaths and 3438 fatal and nonfatal vascular events occurred during follow-up, showed that dipyridamole, in the presence or absence of another antiplatelet drug, had no clear effect on vascular death (RR 0.99, 95% CI 0.87–1.12) . Compared with control, dipyridamole appeared to reduce the risk of vascular events (RR 0.88, 95% CI 0.81–0.95) in patients presenting with cerebral ischemia. There was no evidence that dipyridamole alone was more efficacious than aspirin.
Cilostazol. The Cilostazol Stroke Prevention Study (CSPS), a double-blind, placebo-controlled trial of prevention of recurrent ischemic stroke in 1095 patients, showed that treatment with cilostazol (100 mg twice daily) for at least 1 year and up to 5 years significantly reduced cerebral infarction (fatal and nonfatal) by 41.7%, compared to placebo .
INCIDENCE OF HEMORRHAGIC STROKE ASSOCIATED WITH THE USE OF ANTIPLATELET AGENTS
The incidence of cerebral hemorrhage 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 hemorrhage has been documented in patients under aspirin treatment for AMI or acute ischemic stroke [49-52]. Moreover, a heightened incidence of hemorrhagic stroke has also been demonstrated during primary [53-55] and secondary  prophylaxis of cardiovascular events. In a meta-analysis of 16 randomized, placebo-controlled clinical trials, including a total of 55,462 patients, treatment with aspirin was associated with a RR of hemorrhagic stroke of 1.84 (p <.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 hemorrhagic stroke in patients on antiplatelet t reatment, mostly with aspirin . It must be noted, however, that the increased incidence of hemorrhagic stroke was always outweighed by a significant decrease in the incidence of ischemic strokes.
Adding aspirin to vitamin K antagonists (VKA) increases the risk of cerebral hemorrhage. A meta-analysis of 5 randomized clinical trials showed that the addition of aspirin to VKA is associated with a RR of cerebral hemorrhage of 2.6 (95% CI, 1.3-5–4, p <.009) . Similar results were found in a retrospective study of more than 10,000 patients with AF (RR 3.0, 95% CI 1.6–5.5) . However, conflicting results were reported in other trials.
Clopidogrel and ticlopidine
The incidence of cerebral hemorrhage in patients treated with clopidogrel or ticlopidine ranged between 0.2 and 0.4% in the CAPRIE, AASPS, and MATCH randomized clinical trials [38,43,60]. Patients enrolled in the aspirin arm of the CAPRIE and AASPS clinical trials had similar rates of cerebral hemorrhage (0–2 to 0.3%) [38,43].
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 hemorrhage by 61% (p = .06) compared with clopidogrel alone . More recently, the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance (CHARISMA) trial showed that the incidence of cerebral hemorrhage was similar in patients treated with aspirin alone and in patients on combined treatment with aspirin and clopiodgrel (0.3% for both treatments) . In contrast, in the Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events (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%) treatment, compared with patients taking aspirin alone (0.1%) .
In the Evaluation of 7E3 for the Prevention of Ischemic Complications (EPIC) study , there was no difference in the occurrence of hemorrhagic or nonhemorrhagic stroke between patients treated with abciximab and patients treated with placebo . The 95% upper one-sided confidence bounds for hemorrhagic 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 hemorrhagic stroke: one in the placebo group and one in the bolus-plus-infusion group .
No significant difference in stroke rate between patients assigned abciximab (n = 22 [0.40%]) and those assigned placebo (n = 9 [0.29%]; p =.46) was found in the combined analysis of data from 4 double-blind, placebo-controlled, randomized trials [63,65-67] conducted between November 1991 and October 1997. These trials encompassed 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. The rate of nonhemorrhagic stroke was 0.17% in patients treated with abciximab and 0.20% in patients treated with placebo (difference, -0.03%; 95% CI, -0.23%–0.17%), and the rates of hemorrhagic stroke were 0.15 and 0.10%, respectively (difference, 0.05%; 95% CI, -0.11–0.21%) . Similar incidence of hemorrhagic strokes in patients treated with abciximab or other GPIIb/IIIa antagonists and placebo were found also in another overview of 6 randomized clinical trials . Among patients treated with abciximab, the rate of hemorrhagic stroke in patients receiving standard-dose heparin in EPIC, CAPTURE (Carotid ACCULINK/ACCUNET Post-Approval Trial to Uncover Unanticipated or Rare Events), and EPILOG (Evaluation in PTCA to Improve Long-Term Outcome with Abciximab GPIIb/IIIa Blockade) was higher than it was in those receiving low-dose heparin in the EPILOG and EPISTENT (Evaluation of Platelet IIb/IIIa Inhibitor for Stenting Trial) trials (0.27 vs 0.04%; p = .057). Therefore, patients undergoing PCI and treated with abciximab should receive low-dose, weight-adjusted heparin .
In general, antiplatelet agents are effective in reducing the incidence of cerebrovascular events in patients at risk and display a very favorable risk-to-benefit ratio. In particular, the incidence of hemorrhagic stroke is only slightly increased compared to untreated patients and is largely outweighed by a significant decrease in the incidence of ischemic strokes. Despite that the currently available antiplatelet agents have a good risk-to-benefit ratio, they suffer some drawbacks, which justifies the unceasing search for agents that can further improve the clinical outcome of patients with atherosclerosis through greater e fficacy and/or safety. Several new antiplatelet drugs are currently under clinical development .
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