Thrombolysis With Recombinant Tissue Plasminogen Activator and Tirofiban in Stroke

Intravenous use of recombinant tissue plasminogen activator (rtPA) is the only thrombolytic treatment that has been approved in acute stroke. It is efficacious, but it needs to be administered within 3 hours after stroke, includes a notable risk of intracerebral bleeding, and probably has lower efficiency with a longer interval of treatment onset. Thus, alternative approaches, including substances that are more effective than rtPA and bear a lower risk of intracranial hemorrhage, are desirable.

The glycoprotein IIb/IIIa (GPIIb/IIIa) receptor antagonists have been advocated recently as potentially promising agents for acute stroke therapy. The platelet GPIIb/IIIa receptor mediates blood clotting by forming stable fibrin bonds between activated thrombocytes. The GPIIb/IIIa receptor antagonists selectively inhibit the platelet integrin αIIbβIII fibrinogen receptor and thereby inhibit ADP-induced platelet aggregation.

In animal models of brain infarction, GPIIb/IIIa thrombocyte receptor antagonists have been shown to reduce the cerebral infarct volume considerably, probably by the prevention of microvascular thrombosis, resulting in improved postischemic cerebral blood flow. In humans the GPIIb/IIIa platelet receptor antagonist abciximab has been shown to dissolve intravascular thrombi and to improve neurological outcome after stroke and carotid artery stenting. Notably, the use of GPIIb/IIIa receptor antagonists in ischemic cerebrovascular disease and manifest brain infarction does not seem to be associated with a high rate of fatal or symptomatic intracranial hemorrhage. In particular, the combination of half the dosage of thrombolytic agents together with the GPIIb/IIIa receptor antagonists has been reported to be effective in terms of reperfusion and safe in terms of bleeding complications in acute myocardial ischemia.

Tirofiban, a nonpeptide GPIIb/IIIa antagonist, appears particularly suited for thrombolytic action because its action can be controlled well: the half-life of tirofiban in plasma is approximately 1.6 hours, ie, the prolonged bleeding time normalizes within 4 hours after discontinuation of drug administration. Since rtPA is known to induce hypercoagulation after thrombolysis, tirofiban may antagonize this hypercoagulation and thereby help to maintain the cerebral blood vessels patent after induction of thrombolysis with a systemic low dose of rtPA. In a pilot trial we have applied tirofiban for this purpose since 1999. In a previous publicationit could be shown that tirofiban does not increase the rate of asymptomatic or symptomatic hemorrhages in stroke.

The preliminary results suggest that rtPA+T is a promising option for acute stroke treatment.