Antiplatelet Agents

Platelets are at the core of coronary artery thrombosis.14 Platelet activation and adhesion to subendothelial matrix elements occur as a result of plaque rupture. Platelet aggregation may be initiated by shearing forces, fibrinolytics, thrombin, thromboxane A 2, ADP, epinephrine, serotonin, or plasmin. These trigger the arachidonic acid pathway, the protein kinase C pathway, or other pathways that result in platelet aggregation. The final common pathway of platelet activation is exposure of glycoprotein IIb/IIIa receptors on the surface of the platelet. Bivalent fibrinogen molecules cross-link activated platelets together by using these receptors. The glycoprotein IIb/IIIa antagonists are considerably stronger antiplatelet agents than aspirin, because they interrupt platelet activation regardless of agonist. In contrast, aspirin only inhibits platelet aggregation stimulated through thromboxane A 2 and mediated through the arachidonic acid pathway.

GLYCOPROTEIN IIb/IIIa INHIBITORS Several different forms of glycoprotein IIb/IIIa antagonists are available. Abciximab (ReoPro) is a chimeric antibody that binds irreversibly to the glycoprotein IIb/IIIa antagonists. The duration of action is longer than that of the smaller peptide molecules. As a result, benefits may be realized with a shorter duration of infusion. Eptifibatide (Integrelin) is a synthetic heptapeptide that binds reversibly to the glycoprotein IIb/IIIa receptor. Lamifiban and tirofiban (Aggrastat) are synthetic small molecules with reversible binding to the glycoprotein IIb/IIIa receptor. All require a 48- to 72-h infusion to demonstrate sustained benefits. Reversal of platelet inhibition following cessation of infusion is more rapid with the polypeptide or small molecules, offering an advantage when bleeding complications occur.

The glycoprotein IIb/IIIa inhibitors have been evaluated for use in three clinical areas: percutaneous interventional procedures (PCI), in combination with low-dose fibrinolysis, and for medical stabilization of patients with ACS. In EPIC, 2099 high-risk patients receiving PTCA or atherectomy were randomized to abciximab bolus alone, abciximab bolus plus 12-h infusion, or placebo, in conjunction with aspirin and heparin. 15 Patients who received abciximab bolus plus infusion had a 35 percent reduction in the composite end point of death, AMI, or urgent reintervention. Some of this benefit was sustained for up to 3 years (13 percent reduction). Of note, the rate of bleeding was increased twofold in the patients treated with abciximab. The EPILOG trial randomized 2792 patients undergoing PCI to abciximab plus low-dose weight-adjusted heparin, abciximab plus standard-dose heparin, or placebo plus standard-dose heparin. This trial, using lower doses of heparin, retained the reduction in the risk of death, AMI, or urgent revascularization (56 percent at 30 days and 43 percent at 6 months), without an increased risk of bleeding complications.16 As a result of these trials, glycoprotein IIb/IIIa inhibitors are often used in high-risk patients undergoing percutaneous interventions in the cardiac catheterization laboratory.

A variety of glycoprotein IIb/IIIa antagonists have been shown to be efficacious for patients with ACS. In the CAPTURE trial, 17 1265 patients who had failed medical stabilization with heparin and nitroglycerin were randomized to abciximab or placebo bolus and infusion in addition to aspirin, standard-dose heparin, and intravenous nitroglycerin while waiting 24 h for percutaneous intervention. Medical therapy with abciximab resulted in a 71 percent decrease in AMI and 29 percent decrease in composite end point of death, AMI, or urgent reintervention. This reduction in adverse cardiovascular events occurred prior to the percutaneous intervention, suggesting a role for glycoprotein IIb/IIIa antagonists in medical stabilization of refractory unstable angina patients.

Four large trials (PURSUIT, PRISM, PRISM-PLUS, and PARAGON) evaluated glycoprotein IIb/IIIa antagonists for the medical stabilization of patients with unstable angina or non-Q-wave AMI.181 2 and 21 In the PRISM study,18 3232 patients who were already receiving aspirin were randomized to additional treatment with intravenous tirofiban or heparin for 48 h. The composite end point (death, AMI, or refractory ischemia at 48 h) was 32 percent lower in the glycoprotein IIb/IIIa antagonist group. The reduction in mortality rate persisted to 30 days. In PRISM-PLUS,19 1915 patients were randomized to tirofiban, heparin, or both for 3 days. Patients treated with tirofiban and heparin had a reduction in the composite end point of death, AMI, or refractory ischemia at 7 days. Reduction in rates of death and AMI persisted for up to 6 months. Notably, in contrast to the PRISM results, patients who received tirofiban alone had an increased rate of adverse cardiovascular events. PURSUIT randomized 10,948 patients to bolus and infusion treatment with eptifibatide or placebo for up to 72 h. 20 The glycoprotein IIb/IIIa antagonist resulted in 1.5 percent absolute reduction (10 percent relative reduction) in death and nonfatal AMI that was evident by 96 h and persisted to 30 days. The PARAGON trial randomized patients to various doses of lamifiban with or without heparin and did not find that lamifiban reduced clinical events at 30 days; however, there was a 40 percent reduction in death and AMI at 6-month follow-up.21

Taken together, these trials strongly suggest a role for the glycoprotein IIb/IIIa antagonists in the treatment of patients with refractory unstable angina. The various glycoprotein IIb/IIIa antagonists have not been compared with one another in any trial. Long-term benefits have been documented with abciximab and tirofiban. Abciximab differs from the other glycoprotein IIb/IIIa antagonist in terms of duration of infusion (12 h vs 48 to 72 h) and duration of sustained benefit (up to 3 years in the EPIC study). In contrast, the intracranial hemorrhage rate of the glycoprotein IIb/IIIa antagonists is considerably lower (0.1 percent) than with fibrinolysis, although severe catheter site bleeding and transfusion needs are approximately 6 percent.

COMBINATION FIBRINOLYTIC AND GLYCOPROTEIN IIb/IIIa INHIBITORS Although most of the coronary thrombosis is red clot (fibrin and erythrocytes), the central platelet thrombus (white clot) is fully resistant to fibrinolytic therapy. These platelets secrete PAI-1, which is a potent inhibitor of fibrinolysis. In theory, combination therapy with antiplatelet agents and fibrinolytics will attack both components of coronary thrombosis. This is one explanation why even a weak antiplatelet agent reduces mortality rate as much as treatment with streptokinase alone.3

Preclinical studies of low-dose fibrinolytic therapy with glycoprotein IIb/IIIa antagonists that have utilized a reduction in the standard fibrinolytic dose to 50 percent of the standard dose have found that fibrinolysis occurs more rapidly and is more stable. TIMI-14 evaluated abciximab plus either tPA or streptokinase in patients who also received aspirin and low-dose heparin.22 Abciximab was able to increase the rate of TIMI grade 3 flow by 20 to 25 percent (a 10 percent absolute improvement). The SPEED trial is a dose finding trial to determine the optimal doses of abciximab and reteplase to be used together. GUSTO-IV will compare low dose fibrinolysis in combination with abciximab versus standard dose fibrinolysis alone to determine if the theoretical benefits of low dose fibrinolytics in conjunction with glycoprotein IIb/IIIa antagonists can be realized.

ASPIRIN Aspirin should be given as soon as possible to all patients with ACS. In platelets, aspirin prevents formation of thromboxane A 2, an agonist of platelet aggregation. This inhibition persists for the 9 to 10 life of the platelet, since platelets are unable to generate new cyclooxygenase. 23 Aspirin alone has been shown to be efficacious as streptokinase alone.3 Aspirin alone reduces mortality rate by 23 percent. In conjunction with streptokinase, mortality rate is reduced 43 percent. Aspirin used in conjunction with fibrinolytic therapy further reduces ischemic events and coronary artery reocclusion. Doses greater than 160 mg cause immediate near complete inhibition of thromboxane A2. Lower doses may be effective for long-term prophylaxis but may not be effective for acute use. Aspirin reduces vascular events in patients with AMI and patients with unstable angina.424 In patients with prior myocardial infarction or stroke, it reduces vascular events by up to 40 events per 1000 patients.23

The side effects of aspirin are mainly gastrointestinal and dose related. They can be reduced by using diluted or buffered aspirin solutions, lowest possible doses, or concurrent antacid or H2 antagonist administration. In the setting of acute ischemia, the delay in absorption of enteric-coated aspirin may be best avoided. Due to the substantial benefits of aspirin therapy during AMI, it should not be withheld from patients with minor contraindications (vague allergy, history of remote peptic ulcer, or gastrointestinal bleeding).4 Other antiplatelet agents, such as ticlopidine, can be substituted if true aspirin allergy or active peptic ulcer disease exists. 4 The aspirin dose should be at least 160 mg.

TICLOPIDINE This is an antiplatelet agent that inhibits platelet aggregation induced by a wide range of agonists. The inhibitory effect of ticlopidine is delayed 24 to

48 h after its administration.4 It is effective in reducing 6-month vascular death and AMI rate in patients with unstable angina. 25 Side effects include neutropenia, which is more common in patients treated for more than 2 weeks. The dose is 250 mg twice per day.

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