Our study found that intravenous tirofiban treatment within 24 hours after urokinase thrombolysis did not increase the risk of bleeding, and the NIHSS score was lower at 14 days in patients with AIS at 4–6 hours after onset, while no significant difference was found in mRS Score at 3 months. Long-term neurological improvement ratios of patients were inconsistent in the subgroups of patients with stroke or hypertension.
Previous studies on the safety of tirofiban are similar to those in this paper. A meta-analysis including 17 studies with 2914 AIS patients showed tirofiban via intra-arterial administration was associated with increased risk of fatal ICH (OR, 2.90; 95% CI, 1.12–7.55; p = 0.03), while intravenous administration was not[13]. In patients with thrombolysis of alteplase plus tirofiban, J Zhao et al. also found tirofiban did not increase the risk of any ICH and mortality [14]. Moreover, tirofiban administered at 2–12 hours after alteplase thrombolysis were beneficial and safe[15]. A small randomized controlled study found that thrombolysis of urokinase plus tirofiban could improves self-care ability in AIS patients without clear criminal vessels by relieving the level of inflammatory factors[16]. Considering the pharmacokinetics of tirofiban, which has a short half-life of 2 hours and platelet aggregation was restored to approximately 50% by 4 h after drug withdrawal, tirofiban is safe for AIS patients after intravenous thrombolysis. Our study verified its safety in AIS patients with urokinase thrombolysis within 4–6 hours of onset and explored the application scenarios of tirofiban.
The safety of urokinase plus tirofiban was proved; however, long-term functional improvements in this study do not differ between the two groups. The Safety of Tirofiban in Acute Ischemic Stroke trial also corroborated the safety of tirofiban in hemorrhagic complications without significant differences in functional improvement[17]. Chunrong Tao et al. reached the same conclusion when comparing tirofiban and dual antiplatelet in non-thrombolytic AIS patients by prospective non-randomized study[18]. In patients with AIS without large or medium-sized vessel occlusion, the percentage of patients with a score of 0 or 1 on the mRS at 90 days was 29.1% with tirofiban and 22.2% with aspirin (P = 0.02). Both patients with stroke of recent onset and with progression of stroke symptoms were included causing heterogeneity in the studies [19]. In patients who were not undergoing alteplase thrombolysis or endovascular thrombectomy therapy at the early stage, the proportion of favorable functional outcomes was higher in the tirofiban group (79.1%) than that in the control group (67.8%) at 90 days (p = 0.0155)[20]. In our study, the inconsistency between the NHISS at day 14 and mRS at 3 months in this study may be due to the participants most of which had mild strokes. In addition, our control group patients took dual antiplatelet therapy rather than aspirin monotherapy.
Tirofiban inhibits the final common pathway to platelet aggregation by reversibly blocking fibrin binding receptors, aspirin and clopidogrel rely on either inhibiting prostaglandin synthesis or blocking signal transduction pathways[7, 21]. If the NIHSS scores of 24 hours, 48 hours and 72h after thrombolysis had been collected previously, it would be helpful to identify the short-term effect of tirofiban and whether it can reduce early reocclusion rate. Given the retrospective nature of this analysis and missing data of above in the medical records, our results might underestimate the expected effect of tirofiban. So far, the recommended dosage of tirofiban is 30-min loading infusion at a rate of 0.4 µg/kg/min followed by a continuous infusion of 0.1 µg/kg/min[22]. No uniform time standard for the use of tirofiban after thrombolysis at has been established. We conducted subgroup analyses for the duration of tirofiban treatment (24h, 48h, 72h) and found it was not associated with prognosis (NIHSS at 14 days : F = 0.481, P = 0.620). As for the timing of tirofiban initiation, one study explored the efficacy of tirofiban starting at different times after alteplase thrombolysis. Patients were divided into three groups according to the time points of tirofiban administration: Group A (2 h), Group B (2–12 h), Group C (12–24 h). The efficacy in Group A was better than that in Group C (P = 0.006) and no significant difference in the efficacy was found between Groups A and B (P = 0.268)[13].
The types of stroke suitable for tirofiban treatment are small vascular disease, rather than large vascular occlusion, and progressive stroke[6]. The characteristics of applicable patients are the premise of precision medicine. In the subgroups of patients with previous cerebral infarction or without hypertension, the OR values of less than 1 indicate a poor long-term prognosis for patients received tirofiban. However, the 95% CI of the OR values contain 1, which means that the results are not exact. Therefore, the specific target patients and detailed optimal dosage need to be further validated in prospective, dose-escalating RCTs.