Combination therapy with tirofiban and enoxaparin in acute coronary syndromes

Background: Tirofiban, an intravenous glycoprotein IIb/IIIa antagonist, and enoxaparin, a low molecular weight heparin, have each been shown to be eff ective at reducing cardiac ischemic events compared to unfractionated hepar in alone in separate trials of patients with unstable angina and non-Q-wave myocardial infarction. The combination of these agents may offer further t herapeutic benefit. Materials and methods: Fifty-five patients with non-Q-w ave myocardial infarction were randomized to receive double-blind treatment with tirofiban (0.1 mu g/kg/min i.v.) for 48-108 h coadministered with eit her enoxaparin (1 mg/kg sc q 12 h) (n=26) or unfractionated heparin (i.v. a djusted to activated partial-thromboplastin time) (n=27) to evaluate pharma cokinetics, pharmacodynamics, and safety. The primary objective of the stud y was to investigate the effect of unfractionated heparin versus enoxaparin on the plasma clearance of tirofiban. Results: Coadministration of tirofib an and enoxaparin was generally well tolerated. Plasma clearance of tirofib an was 176.7+/-59.8 and 187.5+/-81.8 ml/min, respectively, for enoxaparin a nd unfractionated heparin-treated patients (P=NS). The mean difference was well within the prespecified criterion for comparability, Administration of tirofiban with enoxaparin vs. unfractionated heparin resulted in lesser va riability and a trend towards greater inhibition of platelet aggregation us ing 5 mu M adenosine phosphate agonist. More patients achieved target inhib ition of platelet aggregation >70% in the tirofiban and enoxaparin group (8 4% vs. 65%, P=0.19). Median bleeding time was 21 min for tirofiban and enox aparin vs. greater than or equal to 30 min for tirofiban and unfractionated heparin (P=NS). For a given level of inhibition of platelet aggregation, b leeding time was less prolonged with tirofiban and enoxaparin than tirofiba n and unfractionated heparin (adjusted mean bleeding time 19.6 vs. 24.9 min , P=0.02). Tirofiban plasma concentration and clearance were comparable whe ther coadministered with enoxaparin or unfractionated heparin. There were n o major or minor bleeding events in either group by the TIMI criteria, Inte rpretation: The more consistent inhibition of platelet aggregation and lowe r adjusted bleeding time of tirofiban and enoxaparin vs. tirofiban and unfr actionated heparin support the therapeutic potential of combining these two agents. These data from the first clinical report of coadministration of a glycoprotein IIb/IIIa receptor antagonist and a low molecular weight hepar in are consistent with prior data which show differential pharmacodynamic e ffects of enoxaparin and unfractionated heparin on platelet aggregation. (C ) 1999 Elsevier Science Ireland Ltd. All rights reserved.