Effect of ridogrel, a combined thromboxane a2 synthase inhibitor prostaglandin endoperoxide receptor antagonist, on the lysis of platelet-rich coronary arterial thrombi with recombinant tissue-type plasminogen-activator in a canine model
The effect of ridogrel, a combined thromboxane A2 synthase inhibitor/prostaglandin endoperoxide receptor antagonist, on the lysis of platelet-rich thrombi with recombinant tissue-type plasminogen activator (rt-PA) was studied in everted (inside-out) femoral arterial grafts inserted in the left anterior descending coronary arteries of heparinised dogs. Thrombotic occlusion of the everted segment graft with a platelet-rich thrombus, persisting for at least 30 min, occurred spontaneously within 4.3 +/- 3.9 min (mean +/- SD). These dogs were then heparinised and randomised to 1 of 4 blinded treatment groups: double placebo infusion, bolus injections of 0.5 mg/kg rt-PA, repeated at 15 min intervals until recanalisation occurred or up to 4 doses, ridogrel infusion (5 mg/kg bolus followed by continuous infusion of 5 mg/kg over 150 min), or the combination of rt-PA and ridogrel. In the control group, stable occlusion as measured with an electromagnetic flow probe was maintained throughout the observation period. rt-PA produced reperfusion in 3 of 5 dogs, associated with cyclic reocclusion and reflow in 1 dog. Ridogrel administration did not produce recanalisation in any of the animals. The combined administration of ridogrel and rt-PA produced stable reperfusion without reocclusion in all of 5 dogs (p < 0.003 vs control groups), within 41 +/- 17 min. Coronary blood flow after recanalisation was significantly higher (p < 0.05) in dogs given rt-PA and ridogrel (29 +/- 6 ml/min after 10 min and 30 +/- 9 ml/min after 60 min) than in dogs given rt-PA alone (10 +/- 5 ml/min after 10 min and 14 +/- 6 ml/min after 60 min). Ridogrel, alone or in combination with rt-PA, prolonged the template bleeding time from approximately 3.5 min to more than 20 min, whereas rt-PA alone did not significantly affect the bleeding time. The results indicate that ridogrel enhances and sustains recanalisation of platelet-rich arterial thrombosis with rt-PA.