ANTIPLATELET DRUGS

Platelets provide the initial hemostatic plug at sites of vascular injury. They also participate in pathological thromboses that lead to myocardial infarction, stroke, and peripheral vascular thromboses. Potent inhibitors of platelet function have been developed in recent years. These drugs act by discrete mechanisms, and thus in combination their effects are additive or even synergistic. Their availability has led to a revolution in cardiovascular medicine, whereby angioplasty and vascular stenting of lesions now is feasible with low rates of restenosis and thrombosis when effective platelet inhibition is employed.

Aspirin. Processes including thrombosis, inflammation, wound healing, and allergy are modulated by oxygenated metabolites of arachidonate and related polyunsaturated fatty acids that are collectively termed eicosanoids. Interference with the synthesis of eicosanoids is the basis for the effects of many therapeutic agents, including analgesics, antiinflammatory drugs, and antithrombotic agents

In platelets, the major cyclooxygenase product is thromboxane A2, a labile inducer of platelet aggregation and a potent vasoconstrictor. Aspirin blocks production of thromboxane A2 by acetylating a serine residue near the active site of platelet cyclooxygenase (COX-1), the enzyme that produces the cyclic endoperoxide precursor of thromboxane A2. Since platelets do not synthesize new proteins, the action of aspirin on platelet cyclooxygenase is permanent, lasting for the life of the platelet (7 to 10 days). Thus, repeated doses of aspirin produce a cumulative effect on platelet function. Complete inactivation of platelet COX-1 is achieved when 160 mg of aspirin is taken daily. Therefore, aspirin is maximally effective as an antithrombotic agent at doses much lower than those required for other actions of the drug. Numerous trials indicate that aspirin, when used as an antithrombotic drug, is maximally effective at doses of 50 to 320 mg per day (Antithrombotic Trialists' Collaboration, 2002; Patrono et al., 2004). Higher doses do not improve efficacy; moreover, they potentially are less efficacious because of inhibition of prostacyclin production, which can be largely spared by using lower doses of aspirin. Higher doses also increase toxicity, especially bleeding.

Other NSAIDs that are reversible inhibitors of COX-1 have not been shown to have antithrombotic efficacy and in fact may even interfere with low-dose aspirin regimens.

Dipyridamole. Dipyridamole (PERSANTINE) is a vasodilator that, in combination with warfarin, inhibits embolization from prosthetic heart valves. Dipyridamole has little or no benefit as an antithrombotic drug. In trials in which a regimen of dipyridamole plus aspirin was compared with aspirin alone, dipyridamole provided no additional beneficial effect (Antithrombotic Trialists' Collaboration, 2002). A single study suggests that dipyridamole plus aspirin reduces strokes in patients with prior strokes or transient ischemic attack (Diener et al., 1996). A formulation containing 200 mg of dipyridamole, in an extended-release form, and 25 mg of aspirin (AGGRENOX) is available. Dipyridamole interferes with platelet function by increasing the cellular concentration of adenosine 3¢,5¢-monophosphate (cyclic AMP). This effect is mediated by inhibition of cyclic nucleotide phosphodiesterase and/or by blockade of uptake of adenosine, which acts at adenosine A2 receptors to stimulate platelet adenylyl cyclase. The only current recommended use of dipyridamole is in combination with warfarin for postoperative primary prophylaxis of thromboemboli in patients with prosthetic heart valves.

Ticlopidine. Purinergic receptors respond to extracellular nucleotides as agonists. Platelets contain two purinergic receptors, P2Y1 and P2Y12; both are GPCRs for ADP. The ADP-activated platelet P2Y1 receptor couples to the Gq-PLC-IP3-Ca2+ pathway and induces a shape change and aggregation. The P2Y12 receptor couples to Gi and, when activated by ADP, inhibits adenylyl cyclase, resulting in lower levels of cyclic AMP and thereby less cyclic AMP-dependent inhibition of platelet activation. Based on pharmacological studies, it appears that both receptors must be stimulated to result in platelet activation (Jin and Kunapuli, 1998), and inhibition of either receptor is sufficient to block platelet activation. Ticlopidine (TICLID) is a thienopyridine that inhibits the P2Y12 receptor. Ticlopidine is a prodrug that requires conversion to the active thiol metabolite by a hepatic cytochrome P450 enzyme (Savi et al., 2000). It is rapidly absorbed and highly bioavailable. It permanently inhibits the P2Y12 receptor by forming a disulfide bridge between the thiol on the drug and a free cysteine residue in the extracellular region of the receptor and thus has a prolonged effect. Like aspirin it has a short half-life with a long duration of action, which has been termed "hit-and-run pharmacology" (Hollopeter et al., 2001). Maximal inhibition of platelet aggregation is not seen until 8 to 11 days after starting therapy. Thus, "loading doses" of 500 mg sometimes are given to achieve a more rapid onset of action. The usual dose is 250 mg twice per day. Inhibition of platelet aggregation persists for a few days after the drug is stopped.

Adverse Effects. The most common side effects are nausea, vomiting, and diarrhea. The most serious is severe neutropenia (absolute neutrophil count [ANC] <1500/mL), which occurred in 2.4% of stroke patients given the drug during premarketing clinical trials. Fatal agranulocytosis with thrombopenia has occurred within the first 3 months of therapy; therefore, frequent blood counts should be obtained during the first few months of therapy, with immediate discontinuation of therapy should cell counts decline. Platelet counts also should be monitored, as thrombocytopenia has been reported. Rare cases of thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS) have been associated with ticlopidine with a reported incidence of 1 in 1600 to 4800 patients when the drug is used after cardiac stenting; the mortality associated with these cases is reported to be as high as 18% to 57% (Bennett et al., 1998; Bennett et al., 1999). Remission of TTP has been reported when the drug is stopped (Quinn and Fitzgerald, 1999).

Therapeutic Uses. Ticlopidine has been shown to prevent cerebrovascular events in secondary prevention of stroke and is at least as good as aspirin in this regard (Patrono et al., 1998). It also reduces cardiac events in patients with unstable angina; however, its only FDA-approved indication is to reduce the risk of thrombotic stroke in patients who have experienced stroke precursors, and in patients who have had a completed thrombotic stroke. Since ticlopidine has a mechanism of action distinct from that of aspirin, combining the drugs might be expected to provide additive or even synergistic effects. This appears to be the case, and the combination has been used in patients undergoing angioplasty and stenting for coronary artery disease, with a very low frequency of stent thrombosis occurring over a short, 30-day follow-up (<1%) (Leon et al., 1998). As ticlopidine is associated with life-threatening blood dyscrasias and a relatively high rate of TTP, it is generally reserved for patients who are intolerant or allergic to aspirin or who have failed aspirin therapy.

Clopidogrel. The thienopyridine clopidogrel (PLAVIX) is closely related to ticlopidine and appears to have a slightly more favorable toxicity profile with less frequent thrombocytopenia and leukopenia, although thrombotic thrombocytopenic purpura has been reported (Bennett et al., 2000). Clopidogrel is a prodrug with a slow onset of action. The usual dose is 75 mg per day with or without an initial loading dose of 300 mg. The drug is equivalent to aspirin in the secondary prevention of stroke, and in combination with aspirin it appears to be as effective as ticlopidine and aspirin. It is used with aspirin after angioplasty and should be continued for at least 1 year (Steinhubl et al., 2002). In one study, the combination of clopidogrel and aspirin clearly was superior to aspirin alone; this finding suggests that the actions of the two drugs are synergistic, as might be expected from their distinct mechanisms of action (Yusuf et al., 2001). The FDA-approved indications for clopidogrel are to reduce the rate of stroke, MI, and death in patients with recent myocardial infarction or stroke, established peripheral arterial disease, or acute coronary syndrome.

Glycoprotein IIb/IIIa Inhibitors. Glycoprotein IIb/IIIa is a platelet-surface integrin which, by the integrin nomenclature, is designated aIIbb3. This dimeric glycoprotein is a receptor for fibrinogen and von Willebrand factor, which anchor platelets to foreign surfaces and to each other, thereby mediating aggregation. The integrin heterodimer/receptor is activated by platelet agonists such as thrombin, collagen, or thromboxane A2 to develop binding sites for its ligands, which do not bind to resting platelets. Inhibition of binding to this receptor blocks platelet aggregation induced by any agonist. Thus, inhibitors of this receptor are potent antiplatelet agents that act by a mechanism distinct from that of aspirin or the thienopyridine platelet inhibitors. Three agents are approved for use at present, with others under development.

Abciximab. Abciximab (REOPRO) is the Fab fragment of a humanized monoclonal antibody directed against the aIIbb3 receptor. It also binds to the vitronectin receptor on platelets, vascular endothelial cells, and smooth muscle cells. The antibody is used in conjunction with percutaneous angioplasty for coronary thromboses, and when used in conjunction with aspirin and heparin, has been shown to be quite effective in preventing restenosis, recurrent myocardial infarction, and death. The reduction in total events is about 50% in various large trials (Scarborough et al., 1999). The unbound antibody is cleared from the circulation with a half-life of about 30 minutes, but antibody remains bound to the aIIbb3 receptor and inhibits platelet aggregation as measured in vitro for 18 to 24 hours after infusion is stopped. It is given as a 0.25-mg/kg bolus followed by 0.125 mg/kg per minute for 12 hours or longer.

Adverse Effects.. The frequency of major hemorrhage in clinical trials varies from 1% to 10%, depending on the intensity of anticoagulation with heparin. Thrombocytopenia of less than 50,000 m/L is seen in about 2% of patients and may be due to development of neo-epitopes induced by bound antibody. Since the duration of action is long, if major bleeding or emergent surgery occurs, platelet transfusions can reverse the aggregation defect, because free antibody concentrations fall rapidly after cessation of infusion. Readministration of antibody has been performed in a small number of patients without evidence of decreased efficacy or allergic reactions. The expense of the antibody limits its use.

Eptifibatide. Eptifibatide (INTEGRILIN) is a cyclic peptide inhibitor of the fibrinogen binding site on aIIbb3. It blocks platelet aggregation in vitro after intravenous infusion into patients. Eptifibatide is given as a bolus of 180 mg/kg followed by 2 mg/kg per minute for up to 96 hours. It is used to treat acute coronary syndrome and for angioplastic coronary interventions. In the latter case, myocardial infarction and death have been reduced by about 20%. Although the drug has not been compared directly to abciximab, it appears that its benefit is somewhat less than that obtained with the antibody, perhaps because eptifibatide is specific for aIIbb3 and does not react with the vitronectin receptor. The duration of action of the drug is relatively short and platelet aggregation is restored within 6 to 12 hours after cessation of infusion. Eptifibatide generally is administered in conjunction with aspirin and heparin.

Adverse Effects. The major side effect is bleeding, as is the case with abciximab. The frequency of major bleeding in trials was about 10%, compared with about 9% in a placebo group, which included heparin. Thrombocytopenia has been seen in 0.5% to 1% of patients.

Tirofiban. Tirofiban (AGGRASTAT) is a nonpeptide, small-molecule inhibitor of aIIbb3 that appears to have a similar mechanism of action as eptifibatide. Tirofiban has a short duration of action and has efficacy in non-Q-wave myocardial infarction and unstable angina. Reductions in death and myocardial infarction have been about 20% compared to placebo, results similar to those with eptifibatide. Side effects also are similar to those of eptifibatide. The agent is specific to aIIbb3 and does not react with the vitronectin receptor. Meta-analysis of trials using aIIbb3 inhibitors suggests that their value in antiplatelet therapy after acute myocardial infarction is limited (Boersma et al., 2002). Tirofiban is administered intravenously at an initial rate of 0.4 mg/kg per minute for 30 minutes, and then continued at 0.1 mg/kg per minute for 12 to 24 hours after angioplasty or atherectomy. It is used in conjunction with heparin.

Philip W. Majerus and Douglas M. Tollefsen
key words: ANTIPLATELET, DRUGS, Aspirin