Tirofiban: an investigational plateletglycoprotein IIb/IIIa receptor antagonist

The deposition of a platelet rich thrombus on an atherosclerotic plaque is a critical step in the development of unstable coronary syndromes. Currently available therapeutic agents such as aspirin and ticlopidine are relatively weak inhibitors of platelet aggregation. Recently, antagonists to platelet glycoprotein IIb/IIIa (GPIIb/IIIa), a platelet surface integrin whose activation and subsequent binding to fibrinogen is the final common step in the formation of platelet aggregates, have been utilised to treat unstable angina and myocardial infarction. Tirofiban is a novel, specific, low molecular weight GPIIb/IIIa receptor antagonist, which competitively inhibits the platelet fibrinogen receptor. Tirofiban is administered as an intravenous infusion with a mean half-life of 1.6 h. In healthy volunteers, the plasma concentration and half-life of tirofiban are unaffected by pre-treatment with aspirin, although aspirin increases the bleeding time prolongation caused by tirofiban. Tirofiban is excreted by both renal (37%) and non renal mechanisms. Three clinical trials, PRISM, PRISM PLUS, and RESTORE, have evaluated the safety and efficacy of tirofiban in unstable angina and in high-risk percutaneous transluminal coronary angioplasty (PTCA). When compared to heparin in the management of unstable angina, tirofiban decreased the odds of recurrent ischaemia, myocardial infarction, or death by 36% at 48 h, and death by 39% at 30 days. Similarly, the addition of tirofiban to heparin reduced the odds of recurrent ischaemic events for death at 7 days by 34%. RESTORE, a clinical trial evaluating the efficacy and safety of tirofiban in patients undergoing PTCA within 72 h of presentation with unstable angina or myocardial infarction, demonstrated a 38% reduction in a composite end-point at 48 h; the need for urgent PTCA and coronary artery bypass graft (CABG) at 30 days was reduced by 36%. Adverse side-effects, including major bleeding, were not significantly higher with tirofiban treatment. Tirofiban and other GPIIb/IIIa inhibitors represent a major advance in the treatment of unstable coronary syndromes and high-risk PTCA.