Low dose tenecteplase restores vessel patency in a clinically relevant porcine animal model

Abstract

Thrombolysis remains the treatment of choice in patients who are far from the catheterization laboratories. Although full dose is advisable low dose has not been preclinically tested. Here we tested the hypothesis that low dose tenecteplase, a recombinant fibrin-specific plasminogen activator can induce efficient thrombolysis even in lower doses than the hitherto indicated, compared to full-dose thrombolytic therapy for ST-segment myocardial infarction. Farm pigs (30-35 kg, n=23) were imposed in a clinically relevant model of thrombosis. We used both the common carotid arteries (CA) and the left anterior descending artery (LAD) below the first diagonal. The vessels were initially externally injured (application of pressure by forceps) followed by an appropriate for the vessel dose of thrombin (100 IU for the LAD and 190 IU for CA). Occluding thrombi was achieved in 80% for the LAD and 57% for the CA. Ten minutes post occlusion the animals were allocated under continuous electrocardiogram and ultrasonic flow meter monitoring to one of the following groups: Group A) half-dose tenecteplase (2000 IU); Group B) Full dose tenecteplase (5000 IU); Group C) saline only. All animals received 60IU heparin and antiplatelet agents. The follow-up was 120 minutes post therapy administration. Sixty minutes after lytic drug administration recanalization occurred in 58% of the occluded arteries in Group A, in 85% in Group B and in 20% in Group C (P=0.028). Both tenecteplase regimens were effective for treating carotid artery thrombosis (71% Group A vs. 75% in Group B vs. 33% in Group C, P=0.286), but low dose was significantly less effective in reestablishing flow in proximally occluded LADs (25 % in Group A vs. 100% in Group B vs. 0% in Group C, P=0.015). All vessels with restored flow at 60 minutes remained patent at least for 1 hr. In Group A, at 60 minutes after tenecteplase administration, flow velocity in LAD reached 30% of the baseline value and 45% in carotids, while in Group B flow was 160% and 55% respectively, suggesting restoration of larger lumen diameter in the treated vessels. Post reperfusion ventricular arrhythmias that required treatment occurred equally in all groups. No differences in hemodynamic tested parameters were observed between the groups. In conclusion, we developed a clinically relevant model useful for testing the efficacy of different thrombolytic regimens. Our data demonstrate that low dose tenecteplase can be successfully used for treating thrombosis of larger diameter vessels, such as the carotids, but appears inadequate for treating LAD thrombotic occlusions.