Active Drugs: Effectiveness and Side Effects

In the Au-Assessing Ultegra (Gold) study, as with abciximab, there was a trend toward an association between lower levels of platelet function inhibition and the risk of major adverse cardiac events, but only a small number of patients was studied. In the Comparison of Measurements of Platelet Aggregation With Aggrastat, Reopro, and Eptifibatide (COMPARE) study, the effects of two dose regimens of tirofiban (infusion of 0.4 g/kg/min for 30 min and 0.1 g/kg/min thereafter, or a bolus dose of 10 g/kg followed by 0.15 g/kg/min infusion) were evaluated from 15 min to 12 h after starting therapy by aggregometry. At the early time points, the administration of tirofiban achieved less inhibition than that with abciximab or a single bolus of eptifibatide. At late time points, however, tirofiban administration achieved levels of inhibition that were comparable to those for eptifibatide and were greater than those achieved with abciximab.

In patients with renal insufficiency (creatinine clearance, < 30 mL/min), the plasma clearance of tirofiban is reduced and the plasma half-life is increased by more than threefold. The manufacturer recommends reducing both the bolus and infusion doses by 50%, but the pharmacokinetic basis for this recommendation has been challenged. In the Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) trial, the 40 patients with creatinine clearance of  30 mL/min were found to have an increased risk of bleeding, and tirofiban treatment with Canadian Cialis further increased the risk.

Severe but reversible thrombocytopenia has been reported in a small percentage of patients treated with tirofiban, and an immunologic mechanism has been proposed, mediated by preformed antibodies to a conformation of the GPIIb/IIIa receptor induced by the binding of tirofiban to the receptor. No data are available on the safety of reinfusing tirofiban, but high-titer antibodies have been identified in patients who developed thrombocytopenia after repeat administration.

Eptifibatide (Integrilin; Millennium Pharmaceuticals; Cambridge, MA) is a synthetic disulfide-linked cyclic heptapeptide. It is patterned after the Lys-Gly-Asp sequence found in the snake venom disintegrin, obtained from Sistrurus m. barbouri (barbourin), and it has high specificity, but not absolute specificity, for inhibition of GPIIb/IIIa compared with inhibition of the aVp3 vitronectin receptor. Preliminary reports have suggested that eptifibatide produced less prolongation of the bleeding time than other GPIIb/IIIa inhibitors at doses producing comparable inhibition of platelet aggregation.


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