The Efficacy and Safety of Tirofiban Use in Endovascular Thrombectomy for Intravenous Thrombolysis Applicable Patients with Large Vessel Occlusion Stroke—a Post Hoc Analysis from the Direct-MT Trial

Tirofiban, a non-peptide selective glycoprotein IIb/IIIa receptor inhibitor, can inhibit fibrinogen-dependent platelet aggregation and subsequent thrombosis [1]. It has been routinely applied in percutaneous coronary intervention for prevention of recurrent myocardial infarction and ischemic complications before its wide application in neurointervention [2, 3]. Tirofiban inhibits platelet aggregation in a dose-dependent manner and exerts the antiplatelet effect from 30 min after loading dose, with normalization of platelet function within no more than 4 h after treatment stop [4].

Tirofiban has been gradually accepted as an adjunctive therapy to thrombectomy for emergent large vessel occlusion (LVO) stroke, although its general efficacy and safety remained controversial [5‐8]. In cases of intracranial atherosclerotic stenosis (ICAS)-related LVO stroke, tirofiban is effective and well-tolerated [9]. On the other hand, tirofiban, as an antiplatelet agent, can theoretically increase hemorrhagic risk after rt-PA infusion. However, tirofiban administration was reported for no increase in the occurrence of intracranial hemorrhage after intravenous thrombolysis (IVT) [10, 11]. The safety of tirofiban administration after IVT in stroke patients undergoing endovascular thrombectomy (EVT) is still indecisive. Meanwhile, with the progress of thrombectomy techniques, the successful recanalization rate has reached to over 80%, whether the tirofiban use might further improve the efficacy of thrombectomy is unclear.

Recently, the Endovascular Treatment With vs Without Tirofiban for Patients with Large Vessel Occlusion Stroke (RESCUE BT) trial revealed no difference in the 90 days modified Rankin Scale (MRS) distribution between two groups, but suggested a possible benefit of tirofiban use in the large artery atherosclerosis (LAA) subgroup [12]. The RESCUE BT trial enrolled patients undergoing EVT between 4.5 h and 24 h after symptoms onset, and patients with IVT were excluded. The question for the efficacy and safety of tirofiban use in IVT applicable patients was not answered by the RESCUE BT trial.

The Direct-MT trial was the first randomized controlled trial to prove the non-inferiority of thrombectomy alone to bridging therapy (intravenous thrombolysis before thrombectomy) for emergent LVO stroke of anterior circulation in endovascular treatment capable centers [13]. Patients within 4.5 h after stroke symptom onset were enrolled and assigned to thrombectomy-alone group or bridging therapy group randomly. In such a context, the effect of tirofiban use can be critically evaluated in thrombectomy-alone patients and in bridging therapy patients with comparable baseline data. This post hoc analysis aimed to provide reference to the efficacy and safety of tirofiban use in thrombectomy for emergent LVO stroke of IVT applicable patients.

Taking LVO stroke patients as a whole group, the efficacy and safety of tirofiban use in thrombectomy remained controversial. An observational study based on a single-center prospective registry study in China showed that tirofiban was not associated with higher sICH and leads to lower odds of deaths and better odds of long-term functional independence [23]. A multicenter registry from Korea revealed the safety of tirofiban use during endovascular therapy after IVT but failed to prove its efficacy [24]. In our study, tirofiban use showed no improvement in 90 days MRS distribution in LVO stroke patients undertaking thrombectomy with or without IVT. Also, it failed to bring benefit in successful recanalization rate enhancement and final infarct volume reduction. In Direct-MT trial, general successful recanalization rate reached at the level of 80%. If tirofiban brought potential contributions to the improvements in recanalization rate, it is really hard to be recognized with significance. Recently, a meta-analysis indicated that the use of tirofiban during IVT bridging thrombectomy might reduce the risk of re-occlusion of the treated vessel and 90 days mortality without increasing the risk of sICH and any ICH [25]. But no difference in re-occlusion rate after tirofiban use was detected in thrombectomy-alone group or in bridging therapy group according to our study. Given that we had adjusted confounding factors, such as the cause of stroke and emergent stenting, the additional benefit of tirofiban use in terms of preventing vessel re-occlusion other than in cases of LAA-related LVOs and of stent angioplasty was not claimed.

Several large-scale studies have investigated the efficacy and safety of tirofiban use in EVT for LVOs of LAA etiology. In a multicenter prospective study, 649 patients with LAA stroke were enrolled to evaluate the efficacy and safety of tirofiban use. Tirofiban was found to be associated with superior clinical outcomes in anterior circulation stroke and major stroke (NIHSS > 5) patients but with no cerebral hemorrhage increase [26]. In another study with 503 patients of LVOs retrospectively examined, intravenous tirofiban was associated with high recanalization rate and good outcome in both the whole cohort and the LAA subgroup [27]. Intravenous tirofiban infusion can also decrease the risk of early re-occlusion of the treated arteries with no increased risk of hemorrhage after angioplasty and stenting in ICAS-related LVOs [28].

As for the safety outcome, this post hoc analysis proved that tirofiban use increased ICH risk in neither group. No interaction effect existed between tirofiban and rt-PA. These results are consistent with the findings of a meta-analysis which included 722 patients with IVT bridging therapy from three trials, and 846 patients with IVT alone from seven studies published between 2001 and 2021. Pooled results showed that early tirofiban administration with IVT or bridging therapy did not increase the risks of sICH and ICH [29]. However, it was demonstrated that tirofiban, as an adjunct to thrombectomy, increased fatal bleeding risk in a dose-dependent manner [30]. In another nonrandomized study, tirofiban treatment increased risk of major ICH after endovascular thrombectomy, which might be the consequence of the sole intra-arterial administration of tirofiban [31]. Later, sole intra-arterial tirofiban was verified the association with higher hemorrhage rate and death rate as an adjunct to EVT [27]. In RESCUE BT trial, tirofiban was prescribed in a “routine” manner before EVT instead of in a flexible manner. Although no significant difference in the incidence of sICH between two groups (numerically higher for tirofiban group), the incidence of any ICH was increased in the tirofiban group [12]. In real-world practice, several noteworthy factors might influence the risk of cerebral hemorrhage after adjunctive tirofiban use during EVT. The first one is the actual time window of endovascular reperfusion. The hemorrhage risk increases with time period from symptom onset to reperfusion [32]. The second one is the severity of stroke, as the higher baseline NIHSS score can predict sICH risk after EVT independently [33]. The third one is the route and dosage of tirofiban use, which for now still lack consensus. In Direct-MT trial, the time period from symptom onset to reperfusion was strictly controlled, and tirofiban was administrated based on specific demand at a relatively low dosage level and mainly by transvenous route. Precise prescription of tirofiban in LVO stroke patients with acceptable hemorrhagic risk should be explored profoundly in the future.

Our study had several limitations. First, for now, neuro-interventionists still lack international guidelines for tirofiban use in the endovascular recanalization for LVOs. However, all of the operators from selected enrollment centers were of full experience in EVT, and the prescribed dosage of tirofiban in Direct-MT trial was within the range of the recommendations from 2019 Chinese expert consensus on clinical application of tirofiban in atherosclerotic cerebrovascular disease. Second, according to the design of Direct-MT trial, stent retriever was the primary device, and aspiration devices could be used as a secondary option if the initial reperfusion failed. This analysis, to some degree, represents the situation of tirofiban use in stent retrieval thrombectomy, in which the endothelial damages are regarded as unavoidable. Third, Direct-MT trial is a study based on Chinese population for whom the ICAS-related LVO is more common, but in western population, tirofiban is typically used in extracranial stenting evolved in tandem occlusion. The results of this analysis should not be generalized to all population. Fourth, given the nature of post hoc analysis, bias should be unavoidable. Well-designed prospective randomized controlled trials are needed to address this issue in the future. But we can still provide insight into the clinical practice and future research of tirofiban use in thrombectomy for IVT applicable patients with emergent LVO stroke.

Based on data from Direct-MT trial, tirofiban is a safe medication for IVT applicable patients with LVO stroke undergoing thrombectomy. However, no matter with or without IVT, tirofiban use showed no benefits in achieving favorable outcomes.