Therapeutic window of opportunity assessment in antithrombotic therapy, using a glycoprotein IIb/IIIa inhibitor (tirofiban), in an experimental model of acute ischemic embolic stroke in rabbits

Background

Preliminary preclinical and clinical studies have established efficacy in the use of GP IIb/IIIa inhibitors in the treatment of acute ischemic stroke. This study was designed to assess the therapeutic window of opportunity of tirofiban in stroke and the risk of intracerebral hemorrhage (ICH).

Methods

We conducted a randomized, double-blind, placebo-controlled, experimental preclinical trial. Seventy-one male New Zealand white rabbits were included in the study. Rabbits were embolized by injecting an autologous fibrin-rich blood clot incubated for 22 hours into the common right carotid artery. Rabbits were divided into three groups (3, 6, and 9 hours of ischemia). Each one was randomly divided into two subgroups, placebo and tirofiban (0.4 μg/kg/hour) parenterally infused for 30 min. A neuroscore was performed 24 and 48 hours postembolization. Postmortem pathologic analysis measured infarct volume and ICH.

Results

Analysis of variance analysis showed a significant difference between the volumes of the 3 and 9 hours groups compared with the 6 hours group (P = 0.005, power = 85.9%); there was no significant difference between the placebo and tirofiban subgroups (P = 0.552, power = 9.1%). No significant difference was found among the three groups between placebo and tirofiban (P = 0.109, power = 45.1). Incidence of ICH was 1.4%. Median analysis showed a rise of the infarcted volume in the subgroups between 3 and 6 hours and a decline between 6 and 9 hours was more evident in the tirofiban subgroup. There was no significant difference in neuroscores among subgroups.

Conclusions

There is no statistical significant difference between tirofiban and placebo in reducing the infarct volume, but the results obtained give the impression that tirofiban used in longer periods of ischemia (> 6 hours) starts to show an effect in reducing the size of the infarct. This result points out that tirofiban administered after 6 hours might reduce the infarct by blocking microthrombosis, and protecting the penumbra area to convert in necrosis. No significative difference was found in the clinical outcome. Tirofiban does not increase the incidence of ICH. Further studies need to be made to establish significant differences in order to obtain conclusive results.

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