The intravenous rt-PA in patients with the ischemic stroke can achieve revascularization within the time frame(<4.5h)of the thrombolytic therapy, restore the bloodstream of ischemic cerebral tissue, save the ischemic penumbra, and minimize the area of cerebral infarction24. However, the clinical effect of the rt-PA is limited. This limitation may be related to the brain ischemia caused by the delayed reperfusion25,26. The rt-PA can activate the coagulation cascade in the treatment of ischemic stroke, resulting in the formation of thrombin. As the most effective platelet activator, thrombin can cause platelet aggregation and form thrombus27. The IVT with the rt-PA can also lead to fibrin deposition, and the activated glycoprotein (GP) Ⅱb/Ⅲa receptor can further promote platelet aggregation and accumulation28. Based on the above mechanisms, the recanalization rate following the rt-PA treatment after the intravenous thrombolysis is only about 46%, and a considerable proportion of the patients who achieved revascularization also had re-occlusion (about 14%-34%) 3,4. Therefore, the platelet aggregation and thrombolytic resistance of the rt-PA are the most likely causes of the recanalization failure.
Studies have shown that the use of antiplatelet aggregation drugs in the early stage of thrombolytic therapy can increase the risk of bleeding. Previous studies have also shown that the standard dose of the rt-PA (0.9 mg/kg) increases the risk of a cerebral hemorrhage in patients who were received antiplatelet therapy29–31, the guidelines do not recommend the addition of antiplatelet drugs within 24 hours of intravenous thrombolysis32. A recently analysis demonstrated that low-dose rt-PA was associated with significant reduction of sICH and non-inferior performance in efficacy for moderate stroke patients in China33. As mentioned above, there is still a high incidence of re-occlusion after intravenous thrombolysis, and it is mostly caused by platelet aggregation, so this study prospectively added tirofiban to prevent platelet aggregation after intravenous thrombolysis. In this study, in order to minimize the occurrence of the hemorrhagic transformation and ensure the safety of the research, we abandoned the standard dose of the rt-PA (0.9 mg/kg) combined with tirofiban, on the contrary, the low-dose rt-PA (0.6 mg/kg) combined with tirofiban was selected for the patients with non-cardiogenic stroke. In the study, the NIHSS scores of the two groups showed a downward trend in 24 hours and 7 days after the treatment. Although the improvement in NIHSS score at 24 hours was not statistically significant, it showed that in the acute phase of the stroke, the neurological function of the two groups of patients improved, and the rt-PA + T group had a more obvious improvement. At 90 days, 83.3% of patients in the rt-PA + T group had favorable functional outcomes compared with 60.0% of patients with the favorable functional outcomes in the rt-PA group (P = 0.045) which showed that the early tirofiban use was associated with the neurological improvement at 3 months.
Reviewing several previous studies10–12, 34, we found that the results confirmed the clinical efficacy of the rt-PA and tirofiban combination in the treatment of the AIS, and this outcome was consistent with the results of this study. But to our knowledge, this study is the first to be studied on low-dose rt-pa combined with tirofiban for the treatment of non-cardiogenic ischemic stroke. Combining the results of this study, it is speculated that the tirofiban combined with the low-dose rt-PA thrombolytic therapy can improve the recanalization rate and reduce the neurological deficit at an early stage as well as improve the long-term functional outcomes.
The hemorrhagic transformation (HT) after the IVT is a pathological process of increased permeability of the blood-brain barrier caused by many factors, such as ischemic injury, reperfusion injury, and coagulation disturbance. The rt-PA and plasminogen can destroy the blood-brain barrier and interact with the matrix metalloproteinases (MMP) through the signal transduction pathways such as lipoprotein receptor-1, which aggravates the imbalance of the MMP function and accelerates the matrix degradation35. All in all, the above interventions lead to the transformation of hemorrhage after the intravenous thrombolysis with the rt-PA. Clinical statistics show that 3–6% of the patients following the rt-PA may have HT during the thrombolytic therapy36,37. The incidence of the symptomatic hemorrhage was 1.7%-8.8% and the sICH was 2.4%-4.9% after the IVT with the standard dose rt-PA (0.9 mg/kg), most of which occurred within the first 36 hours, the sICH led to the deterioration of the neurological function and affected the outcome. As a result, the severe disability or the fatality rate of the patients was as high as 90%20. However, the tirofiban caused severe thrombocytopenia, but the incidence of the HT caused by severe thrombocytopenia was only 0.5–2%. The half-life of the tirofiban is about 2 hours, and the prolonged bleeding time induced by the tirofiban can return to normal within 3 hours after the drug withdrawal38. In this study, early low-dose rt-PA combined with the tirofiban used in patients did not increase the risk of the sICH, ICH, severe systemic bleeding, and mortality compared with the patients who were treated with the standard dose rt-PA. It may be related to the inclusion of more patients with mild ischemic stroke in the study, and it may also be one of the reasons for the high rate of good prognosis in the results. There was no significant difference in the incidence of the adverse events between the two groups, and this indicated that the safety of the low-dose rt-PA combined with the tirofiban in the treatment of the AIS can be guaranteed compared with the standard dose rt-PA alone, a number of previous studies had also confirmed similar result10,39,40, in addition, compared to previous studies, we used low-doses of rt-PA for a higher safety profile.
However, there are several limitations of this study. First, the sample size of this study was less, the results need to be interpreted with caution. Second, we did not use neuroimaging to further confirm the type of arterial occlusion. Instead, we used clinical assessment as a surrogate measure, which may have room for errors. Third, due to the limitation of the time window, cardiogenic stroke was initially excluded only by electrocardiogram and previous medical history, future randomized clinical trials are warranted to validate the present results.