Mechanism of action

Tirofiban hydrochloride (tirofiban) is a non-peptidal antagonist of the GP IIb/IIIa receptor, an important platelet surface receptor involved in platelet aggregation. Tirofiban prevents fibrinogen from binding to the GP IIb/IIIa receptor, thus blocking platelet aggregation.

Tirofiban leads to inhibition of platelet function, evidenced by its ability to inhibit ex vivo ADP-induced platelet aggregation and to prolong bleeding time (BT). Platelet function returns to baseline within eight hours after discontinuation.

The extent of this inhibition runs parallel to the tirofiban plasma concentration.

Pharmacodynamic effects

In the 0.4 microgram/kg/min infusion regimen of tirofiban, in the presence of unfractionated heparin and ASA, tirofiban produced a more than 70% (median 89%) inhibition of ex vivo ADP-induced platelet aggregation in 93% of the patients, and a prolongation of the bleeding time by a factor of 2.9 during infusion. Inhibition was achieved rapidly with the 30-minute loading infusion and was maintained over the duration of the infusion.

The tirofiban 25 microgram/kg dose bolus regimen (followed by 18-24 hour maintenance infusion of 0.15 microgram/kg/min), in the presence of unfractionated heparin and oral antiplatelet therapy, produced an average ADP-induced inhibition of maximal aggregation 15 to 60 minutes after onset of treatment of 92% to 95% as measured with light transmission aggregometry (LTA).

Clinical efficacy and safety

PRISM-PLUS study

The double-blind, multicentre, controlled PRISM-PLUS study compared the efficacy of Aggrastat and unfractionated heparin (n=773) versus unfractionated heparin (n=797) in patients with unstable angina (UA) or acute non-Q-wave myocardial infarction (NQWMI) with prolonged repetitive anginal pain or post-infarction angina, accompanied by new transient or persistent ST-T wave changes or elevated cardiac enzymes.

Patients were randomised to either Aggrastat (30 minute loading infusion of 0.4 microgram/kg/min followed by a maintenance infusion of 0.10 microgram/kg/min) and heparin (bolus of 5,000 units (U) followed by an infusion of 1,000 U/hr titrated to maintain an activated partial thromboplastin time (APTT) of approximately two times control), or heparin alone.

All patients received ASA unless contraindicated. Study drug was initiated within 12 hours after the last anginal episode. Patients were treated for 48 hours, after which they underwent angiography and possibly angioplasty/atherectomy, if indicated, while Aggrastat was continued. Aggrastat was infused for a mean period of 71.3 hours.

The combined primary study end-point was the occurrence of refractory ischaemia, myocardial infarction or death at seven days after the start of Aggrastat.

At 7 days, the primary end-point, there was a 32% risk reduction (RR) (12.9% vs. 17.9%) in the Aggrastat group for the combined end-point (p=0.004): this represents approximately 50 events avoided for 1,000 patients treated. After 30 days the RR for the composite end-point of death, MI, refractory ischaemic conditions, or readmissions for UA was 22% (18.5% vs. 22.3%; p=0.029). After six months the relative risk of composite of death, MI, refractory ischaemic conditions, or readmissions for UA was reduced by 19% (27.7% vs. 32.1% ; p=0.024).

Regarding the,composite of death or MI, at seven days for the Aggrastat group