| Objective: Acute Myocardial Infarction(MI)includes non-ST segment elevation myocardial infarction and ST segment elevation myocardial infarction. Their common physiopathologic mechanism is, owing to stimulation of inflammation, abnormal activation of platelet and mechanic stress, the ruptured unstable plaque and the formation of acute thrombus result in complete blockage in coronary artery and acute myocardial necrosis. The excessive activation of platelet, the initial tethering of leucocytes at sites of vascular injury and the aggregation between platelets with platelets or white cells exerted critical influence during the formation of thrombus. It has been demonstrated that P-selectin is a specific index inflecting the activation of platelet. The ascending plasma levels of a important inflammatory mediators-soluble CD40 ligand- has been deemed to be a independent predictor of adverse cardiac event. Moreover, more cardiologist focus upon the proliferative roll of platelet derived growth factor (PDGF-BB) in patients undergoing percutaneous coronary intervention and stenting. So we performed a prospective randomized pharmacodynamic investigation of four antiplatelet regimens to compare different effects in arresting the reactivity of platelets by assessed the P-selectin expression on platelet membrane and the plasma levels of sCD40L and PDGF-BB. Meanwhile, we compared end events between groups during six-months follow-up.Methods: We enrolled eighty patients with acute ST segment elevated MI according to the American Heart Association/American College of Cardiology criteria. Patients undergoing primary percutaneous coronary intervention were enrolled in a 2×2 factorial study (group A: clopidogrel 300 mg; group B: clopidogrel 600 mg; group C: clopidogrel 300 mg plus tirofiban; and group D: clopidogrel 600 mg plus tirofiban). All patients were aged >18 years and pretreated with 300-mg aspirin loading dose. The clopidogrel loading dose was given to all patients immediately after diagnosed and was followed by 75 mg daily. Tirofiban was administered as a bolus (10μg/kg) followed by an infusion (0.15μg/kg per minute) for 36 hours after the procedure. We initiated cardiovascular intervention within two hours after clopidogrel pretreatment. In addition, all patients had receivedβ-blockers coadministrated with 300 mg aspirin before catheterization and 100 mg was administered daily thereafter. Enzyme linked immunosorbent assay was used to assess circulating levels of sCD40L and PDGF-BB. Flow cytometry were used to assess platelet reactivity. We obtained the venous blood sample at three point of time: before pretreatment, 24 hours and five days after intervention, respectively.Results: 1. Posttreatment P-selectin expression was significantly reduced in all groups compared with baseline expression, whereas treatment with 300-mg clopidogrel alone had the least effect in P-selectin expression. In the groups not treated with tirofiban, a 600-mg loading dose of clopidogrel provided greater platelet inhibition throughout the first 24 hours after stenting, whereas this effect to some extent was attenuated five days after intervention. Inhibition of P-selectin positive platelet was higher in patients treated with tirofiban plus clopidogrel compared with clopidogrel alone (p<0.05).2. Clopidogrel administration as 600 mg pretreatment significantly attenuated the plasma levels of sCD40L at 18-24 hours after stenting. Besides, coadministration of clopidogrel with tirofiban significantly decreased the sCD40L levels than clopidogrel alone after 24 hours (p<0.02 group A vs group C, P<0.03 group B vs group D) and decreased further five days later ( p<0.01 group A vs group C, P<0.01 group B vs group D).3. Pretreatment by clopidogrel with or without tirofiban substantially downregulated the PDGF-BB levels in plasma 24 hours after stenting. Whereas this role was decreased 5 days after intervention. A marked reduce in PDGF-BB plasma level after 5 days was observed in group D(600mg clopidogrel loading plus tirofiban). However, we did not find significance difference about circulating level of PDGF-BB in remaining groups five days after catheterization compared with baseline levels. 4. There were no in-hospital deaths and no strokes or episodes of congestive heart failure. Hematomas were the cause of all bleeding episodes. Minor bleeding occurred in one patient each in group C and D, and major bleeding occurred in one patient in group D. Administration of clopidogrel plus tirofiban provided lower rate of MACE and cerebrovascular events than clopidogrel alone during six-month follow-up, although this difference were not statistics significance.Conclusion: A strategy of parenteral GPIIb/IIIa inhibitor plus high-dose (600-mg) clopidogrel pretreatment administration is associated with superior platelet inhibition and lower MACE occurring compared with a strategy of high-dose (600-mg) or standard-dose (300-mg) clopidogrel loading alone. In the absence of a GPIIb/IIIa inhibitor, 600-mg clopidogrel pretreatment provides better platelet inhibition than standard 300-mg dose. Adminstration with clopidogrel of more than 75mg daily after loading dose will provide surperior inhibition of the proliferative response of vascular smooth muscle cells after PTCA. These results require confirmation in a large-scale clinical trial.
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