Drugs

https://doi.org/10.1007/s40265-019-01078-0

REVIEW ARTICLE

Platelet Glycoprotein IIb/IIIa Receptor Inhibitor Tirofiban in Acute

Ischemic Stroke
Ming Yang1,2,3,4   · Xiaochuan Huo2,3,4 · Zhongrong Miao2,3,4 · Yongjun Wang1,3,4

© Springer Nature Switzerland AG 2019

Abstract
Tirofiban is a non-peptide selective glycoprotein (GP) IIb/IIIa receptor inhibitor that reversibly inhibits fibrinogen-dependent
platelet aggregation and subsequent formation of thrombi, which contribute to the major atherosclerotic complications in
the development, progression, and resolution of ischemic stroke. The adjunctive use of tirofiban has been extensively evalu-
ated in progressive stroke, combined intravenous thrombolysis (IVT), and endovascular treatment (EVT) in both preclinical
and clinical studies. A body of evidence has been accumulated on the risks and benefits associated with tirofiban in terms
of prevention of stroke progression, stent thrombosis, improvement in functional independence, and mortality, especially
among high-risk ischemic stroke patients as a further strategy alongside conventional treatment. In general, tirofiban has a
favorable tolerability and efficacy profile in the improvement of vascular recanalization and long-term functional outcome,
although the optimum dosage, application setting, and precise target patients are not yet well-established. However, its
specific inhibition of ongoing platelet aggregation and thrombus formation rather than absolute thrombolysis suggests that
tirofiban, one of the most widely used GP IIb/IIIa inhibitors, with high affinity and a short plasma/biologic half-life, may
have great potential in the acute treatment of ischemic stroke. Substantial practical progress is likely as our understanding of
the mechanism of action and pharmacological actions of tirofiban in atherosclerotic ischemic disease improves. Therefore,
we classify and summarize the available findings regarding tirofiban in acute ischemic stroke to stimulate and guide further
research and clinical practice.

Key Points 

Tirofiban, a non-peptide selective platelet glycoprotein

* Yongjun Wang (GP) IIb/IIIa receptor inhibitor, reversibly inhibits fibrin-
[email protected] ogen-dependent platelet aggregation and subsequent
Ming Yang formation of thrombi, which contribute to major athero-
[email protected] sclerotic complications in the development, progression,
Xiaochuan Huo and resolution of acute ischemic stroke (AIS).
[email protected]
The adjunctive use of tirofiban with conventional man-
Zhongrong Miao agement has been extensively evaluated in progressive
[email protected]
stroke, combination thrombolysis, and endovascular
1
Department of Neurology, Beijing Tiantan Hospital, Capital treatment in both preclinical and clinical studies.
Medical University, No. 119 Nan Sihuan West Road, Fengtai
District, Beijing 100160, People’s Republic of China
The high affinity of tirofiban for GP IIb/IIIa receptors, its
2
short plasma/biologic half-life, and its specific inhibition
Department of Interventional Neurology, Beijing
Tiantan Hospital, Capital Medical University, Beijing,
of ongoing platelet aggregation and thrombus formation
People’s Republic of China rather than absolute thrombolysis indicate that tirofiban
3
China National Clinical Research Center for Neurological
may have potential in the treatment of AIS.
Diseases, Beijing, People’s Republic of China
4
Center of Stroke, Beijing Institute for Brain Disorders,
Beijing, People’s Republic of China

Vol.:(0123456789)
 M. Yang et al.

1 Introduction placebo-controlled trials, double-blind and open-label tri-

als, and case series that described the GP IIb/IIIa receptor
Antiplatelets have been widely used in the treatment of inhibitor tirofiban in the acute management of AIS. Two
atherosclerotic diseases, including myocardial infarc- reviewers independently screened titles, abstracts, and full
tion (MI) and acute ischemic stroke (AIS). The inhibiting texts for eligibility. We also manually searched the refer-
effects of conventional antiplatelet agents such as aspirin ence lists of included studies to find relevant articles not
and clopidogrel rely on either inhibiting prostaglandin included in the original search.
synthesis or blocking signal transduction pathways [1,
2]. However, other molecular pathways are unaffected by
these drugs, leaving the glycoprotein (GP) IIb/IIIa recep- 2 Rationale for Tirofiban in Ischemic Stroke
tors activated, which is believed to be the final common
pathway to platelet aggregation and subsequent throm- 2.1 Molecular Mechanism of Platelet Aggregation
bus formation [3]. Recently, platelet GP IIb/IIIa recep- Inhibition
tor inhibitors, especially tirofiban, have been increasingly
advocated as putative agents to counteract different stages The GP IIb/IIIa receptor is a prototypic integrin exclusively
of thrombosis mediated by activated platelets. expressed on the membranes of platelets and megakaryo-
The heterogeneous pathogenesis of ischemic stroke and cytes [6]. It acts as a bridging ligand between platelets by
risk of hemorrhagic transformation contribute to the dif- fibrinogen through reconfiguration and mediates thrombosis,
ficulty of introducing both safe and effective antiplatelet which is considered the final common step in the aggrega-
treatment. GP IIb/IIIa receptor inhibitors were first used tion of activated platelets [3]. Following activation, the num-
for high-risk MI patients in combination with thrombolytic ber of GP IIb/IIIa receptors on the platelet surface increases
drugs or percutaneous coronary intervention (PCI) to pro- to 80,000–90,000 [7]. Simultaneously, the coagulation
duce dose-dependent inhibition effects on platelet aggrega- cascade is activated, surrounding aggregated platelets, and
tion and thromboembolism [4, 5]. Based on both theory then recruitment of leukocytes/macrophages mediated by
and findings in ischemic heart disease, researchers have pro-inflammatory mediators results in the leukocyte–plate-
attempted to investigate the applicability of GP IIb/IIIa let aggregation complex [8]. Therefore, the putative therapy
receptor inhibitors in AIS. In this review, we first describe for acute management of ischemic cerebrovascular disease
the physiopathologic mechanism of tirofiban, a representa- would be to counteract the prothrombogenic mechanism.
tive non-peptide platelet GP IIb/IIIa receptor inhibitor, and This therapeutic target has stimulated investigations on
then provide a comprehensive interpretation of the studies platelet GP IIb/IIIa receptor inhibitors.
that have reported on practical applications and evaluated Table  1 presents the characteristics of the three
its efficacy and safety profile in AIS. approved GP IIb/IIIa inhibitors, abciximab, eptifibatide,
Using the keywords “tirofiban” combined with “gly- and tirofiban. Abciximab is a recombinant Fab fragment
coprotein IIb/IIIa receptor”, “animal models”, “progres- of a monoclonal anti-IIb/IIIa antibody with high molecu-
sive stroke”, “intravenous thrombolysis”, “endovascular lar weight, eptifibatide is a small peptide, and tirofiban
treatment” or “mechanical thrombectomy”, we searched is a small non-peptide compound. Abciximab also has
PubMed and EMBASE in July 2018 for randomized cross-reactivity with receptors on endothelial cells and
leukocytes, but tirofiban and eptifibatide are competitively

Table 1  Characteristics of glycoprotein IIb/IIIa inhibitors

Characteristic Abciximab Eptifibatide Tirofiban

Substance type Monoclonal antibody Cyclic peptide Non-peptide

Molecular weight 47,600 832 495
Inhibition modality Nonselective, non-competitive Selective competitive Selective competitive
Binding modality Irreversible Competitive Reversible
Receptor affinity High Low Intermediate
Plasma half-life 10–30 min 2.5 h 2 h
Platelet function recovery time 24–48 h < 4 h 4–8 h
Antigenicity Yes No No
Clearance Proteolytic cleavage Renal (60–70%); biliary Renal (80%)
(20–30%)
Platelet GP IIb/IIIa Receptor Inhibitor Tirofiban in AIS

selective for GP IIb/IIIa receptors [9]. The different bind- 3 Preclinical Studies of Glycoprotein (GP)
ing/inhibition modalities on GP IIb/IIIa receptors and IIb/IIIa Receptor Inhibitors
plasma/biologic half-lives influence the response to med-
ication-induced bleeding. In experimental stroke models, GP IIb/IIIa receptor
Tirofiban, a representative low-molecular-weight non- inhibitors alone or in combination with recombinant tis-
peptide platelet GP IIb/IIIa receptor antagonist (Fig. 1), sue plasminogen activator (rt-PA) have demonstrated effi-
efficiently blocks GP IIb/IIIa receptors with high selec- cacy and safety for platelet inhibition, infarction volume
tivity by preventing fibrinogen binding to platelets and reduction, functional improvement, and so on. As early as
subsequent platelet aggregation at the site of atheroscle- 1989, Coller et al. [16] studied the receptor blockade effect
rosis [3]. Before being used in stroke, tirofiban had been of GP IIb/IIIa antagonists in monkey models of carotid
successfully applied in the prevention of ischemic compli- artery injury in a dose-escalation trial ranging from 0.1 to
cations and recurrent MI during PCI with an acceptable 0.4 mg/kg. Results confirmed its dose-dependent block-
tolerability profile [10, 11]. Since then, a few explora- ing effect on GP IIb/IIIa receptors, in that an intravenous
tory studies have tested it alone or in combination with bolus dose of tirofiban 0.2 mg/kg achieved approximately
intravenous thrombolysis (IVT) or endovascular therapy 70% receptor blockade and complete thrombosis inhibi-
(EVT) as an alternative agent in the acute management tion. Subsequently, similar platelet and fibrin disaggre-
of ischemic stroke, aiming at restoring cerebral perfusion gation effects of GP IIb/IIIa antagonists were tested on
with a broader time period, higher efficacy, and lower risk murine transient middle cerebral artery (MCA) occlusion
of intracranial hemorrhage. models or in vitro blood samples [15, 17, 18]. Therefore,
it was speculated that GP IIb/IIIa antagonists might play
thrombolysis promoter roles, including platelet disaggre-
2.2 Metabolism and Excretion of Tirofiban gation, and downregulation of thrombin and plasminogen
activator inhibitor, especially for fresh thrombi [19]. Early
Pharmacokinetic studies reported that tirofiban achieved evidence of the thrombosis-inhibiting effects of GP IIb/
steady-state plasma concentrations within 1  h after an IIIa antagonists emerged from trials in acute MI that sug-
initial bolus of 5 μg/kg followed by continuous intrave- gested greater improvement in Thrombolysis in Myocar-
nous infusion at 0.05 μg/kg/min [12]. The steady-state dial Infarction (TIMI) scores than with heparin and aspirin
volume of distribution of tirofiban ranged from 21 to 42 L [20].
[12]. The total plasma clearance of tirofiban in volunteers Given these exciting findings, Shuaib et al. [21] tested
ranged from 14.3 to 20.9 L/h regardless of administra- the combination IVT of rt-PA and GP IIb/IIIa antagonists
tion dosage [13]. The metabolism pathway of tirofiban on MCA occlusion models with autologous clots. Results
in humans appears to be limited, with most of the drug showed that GP IIb/IIIa antagonists alone achieved a 33%
eliminated in the urine and feces in prototype. Plasma complete recanalization rate, which increased to 66%
clearance of tirofiban was reported to reduce by > 50% in when combined with rt-PA, without inducing hemorrhagic
patients with severe renal insufficiency (creatinine clear- transformation. Similarly, Ding et al. [22] achieved a 50%
ance < 30 ml/min), so dosage reductions are required in recanalization rate on rat models of embolic stroke with
these patients. the same combination thrombolysis therapy. The reference
Intravenous tirofiban 10  μg/kg bolus followed by value of these preclinical studies is limited because of the
0.10–0.15 μg/kg/min for 16–24 h inhibited ex vivo platelet heterogeneous duration of administration and inadequate
aggregation by > 90% within 5 min. Platelet aggregation animal models of acute stroke. However, these positive
was restored to approximately 50% by 4 h after cessa- results from preclinical trials warrant further clinical stud-
tion and reached near-baseline levels after 8 h. This dose- ies to investigate the feasibility of adjunctive intravenous
dependent blockade effect metabolized rapidly after ces- tirofiban for combined thrombolysis or early antiplatelet
sation of intravenous infusion and implied a short plasma therapy in patients with AIS.
half-life (approximately 2 h) [14, 15]. Table 1 shows the EVT has recently gradually developed into another pri-
metabolic characteristics of tirofiban. mary field of application for tirofiban. Feng et al. [23]
evaluated the efficacy and safety of selective intra-arterial
thrombolysis with tirofiban alone or in combination with
urokinase in a New Zealand rabbit MCA occlusion stroke
model. They used recanalization rates (digital subtrac-
tion angiography [DSA]), infarct volume (magnetic reso-
nance imaging [MRI]), and neurological function deficit
Fig. 1  Chemical structure of tirofiban
 M. Yang et al.

(Bederson’s 5-point scale) [24] to compare tirofiban 5 μg/ syndrome) for at least 24 h; 17 patients with AIS with stable
kg, urokinase 25,000 U/kg, urokinase 15,000 U/kg fol- clinical symptoms served as a control group [32]. All 35
lowed by tirofiban 5  μg/kg, and a control group. The patients received unfractionated heparin (UFH) to maintain
results also suggested that intra-arterial combined throm- the activated partial thromboplastin time (aPTT) at 50–70 s,
bolysis with low-dose tirofiban plus urokinase improved which was standard therapy at that time. The results showed
recanalization and reduced infarct volume compared with no differences on clinical outcomes and intracranial hem-
urokinase alone or control. This and other pharmacody- orrhage between groups. After previously confirming the
namic experiments on tirofiban indicated that combining safety of tirofiban in progressive stroke, Philipps et al. [33]
tirofiban and rt-PA/urokinase enhanced the thrombolysis conducted another observational pilot study to evaluate its
effect and improved microvascular patency by prevent- efficacy. All 35 subjects with stroke were split into one of
ing post-thrombolysis artery reocclusion and platelet two subgroups according to TOAST criteria: large-vessel
aggregation. occlusion (n = 14, including large-artery atherosclerosis and
In addition, ultraselective intra-arterial infusion as an cardioembolism stroke) and small-vessel occlusion (n = 21).
administration method could reduce the dosage of tirofiban Both groups were treated with tirofiban according to the
while increasing local drug concentration surrounding the PRISM-PLUS protocol [4]. Results indicated that tirofiban
infarction site, thereby decreasing the risk of intracranial was well-tolerated in progressive stroke, even in combi-
hemorrhage [25, 26]. This treatment modality has provided nation with aspirin 100 mg, clopidogrel 75 mg, or both,
a basis for clinical medication during EVT, especially for and low-dose heparin; no severe bleeding complications
revascularization-refractory patients. Despite the limita- occurred during tirofiban treatment. However, only patients
tions of the animal experiments and small sample sizes, the in the small-vessel occlusion group experienced significant
encouraging results and theoretical basis have prompted improvement of neurological symptoms after the administra-
extensive clinical research on the safety and efficacy profile tion of tirofiban (NIHSS improvement: 3.4 ± 3.4 for small-
of tirofiban in AIS. vessel occlusion vs. 0.8 ± 4.2 for large-vessel occlusion). As
reported in previous studies, small-vessel occlusion stroke
was prone to secondary neurological deterioration, which
4 Clinical Studies of Tirofiban in Acute was generally attributed to arteriole hyalinosis, intracranial
Ischemic Stroke (AIS) perforating artery atherothrombosis, and endothelial dys-
function [31, 34]. GP IIb/IIIa inhibitors are supposed to
4.1 Monotherapy in the Management of AIS interfere with these underlying mechanisms and ultimately
lead to improved microcirculation. Therefore, existing evi-
In ischemic cerebrovascular disease, tirofiban was initially dence has initially proved the efficacy and safety profile of
studied in progressive stroke, which is mostly defined as tirofiban for patients with progressive stroke, and the spe-
worsening of at least 4 points on the European Stroke Scale cific therapeutic effect varies according to pathogenesis of
(ESS) or on the National Institute of Health Stroke Scale stroke subtypes. However, given the limitations inherent to
(NIHSS) within the first 72 or 96 h of symptom onset [27, the uncontrolled observational design of these pilot stud-
28]. Progressive stroke has always been a treatment chal- ies, the results should be interpreted with caution, because
lenge in clinical practice because of the lack of effective spontaneous improvement, fluctuation of clinical symptoms
evidence-based therapies. Physiopathologic mechanisms in lacunar stroke, and different courses of stroke subtype
of secondary neurological deterioration involve intracra- pathogenesis could have biased the results. Nevertheless, we
nial perforating artery atherosclerosis, collateral circula- believe these preliminary findings have provided theoreti-
tion insufficiency, distal embolism, and hemorrhagic trans- cal and ethical bases for future randomized controlled trials
formation, among others [29, 30]. Studies have indicated (RCTs) (Table 2).
that patients with stroke with large-artery atherosclerosis Torgano et  al. [35] conducted an RCT involving 150
and small-artery disease subtype (according to the TOAST patients with AIS within 6 h from symptom onset. All sub-
classification) were susceptible to progressive stroke [31]. jects were randomized to tirofiban 0.6 μg/kg/min for 30 min
In an early open pilot study of 35 patients with AIS, followed by 0.15 μg/kg/min or intravenous aspirin 300 mg
18 patients with progressive stroke received intravenous daily. Both drugs were administered within 6 h of symptom
tirofiban with a 30-min loading infusion at a rate of 0.4 μg/ onset and for 3 days. Final results indicated that 56% of
kg/min followed by continuous infusion of 0.1 μg/kg/min patients in each group achieved neurological improvement at
(according to the PRISM-PLUS [Platelet Receptor Inhibi- 72 h. At 3-month follow-up, 45% of patients in the tirofiban
tion in Ischemic Syndrome Management in Patients Lim- group and 53% in the aspirin group achieved a modified
ited by Unstable Signs and Symptoms] protocol [4] in Rankin Scale (mRS) score of ≤ 1, mortality was 10.6%
international guidelines for the treatment of acute coronary for both groups, and 1% and 4% of patients experienced
Platelet GP IIb/IIIa Receptor Inhibitor Tirofiban in AIS

Table 2  Previous reported medication regimens with tirofiban in endovascular therapy for acute ischemic stroke
Study (patients) Study design; Administration route Heparin (IU) Recanaliza- Favorable sICH (%) Mortality (%)
medication tion rate outcome (mRS
setting IA (mg) IV (duration) (%) 0–2) (%)

Mangiafico et al. Retrospective; No 24–48 ha 2500–3000 90.9 90.9 0 9.1

[80] proactive use
(n = 11)
Mangiafico et al. Retrospective; No 24–48 ha 24–48 h 80.1 61.9 23.8 28.6
[81] proactive use
(n = 21)
Ihn et al. [82] Retrospective; No 24–48 ha b
84.6 61.5 15.4 15.4
(n = 13) proactive use
Ernst et al. [83] Retrospective; No 10 μg/kg, bolus 2000 IU 80.8 43 (mRS 0–3) 9 27
(n = 37) proactive use
Deshmukh et al. Retrospective; 0.6 10 mg 35 mg/kg 80.1 61.9 (mRS 0–3) 14.3 28.6
[95] rescue therapy
(n = 21)
Kwon et al. [96] Retrospective; 0.35–2.0 No 2000–3000 81.3 50 37.5 18.8
(n = 16) rescue therapy
Kim et al. [97] Retrospective; 0.2–1.0 0.12 μg/kg/min 4000 ± 834.4 IU 75.1 56.3 6.3 12.5
(n = 16) rescue therapy (12–24 h)
b
Kellert et al. Retrospective No 12 h 62.0 14.0 16.0 30.0
[111] (n = 162) controlled;
rescue therapy
b b
Kang et al. [89] Retrospective 0.5–1 No 200–4000 74.3 0
(n = 132) controlled;
rescue therapy
Seo et al. [98] Retrospective; 0.2–0.75 No Catheter flushing 77.7 50 27.8 16.6
(n = 18) rescue therapy
Zhao et al. [109] Prospective 0.25–0.5 0.2–0.25 mg/h ACT at 79 46 11 23
(n = 180) controlled (12–24 h) 250–300 s
observational;
rescue therapy
Chang et al. [93] Retrospective 0.3–1 6–12 h –b 64.6 39.5 16.7 12.5
(n = 148) controlled
observational;
rescue therapy

ACT​activated clotting time, IA intra-arterial, IV intravenous, mRS modified Rankin Scale

a
 PRISM-PLUS regimen [4]: 30-min loading infusion at a rate of 0.4 μg/kg/min followed by a maintenance infusion of 0.10 μg/kg/min
b
 Indicates that detailed information was not reported

symptomatic intracranial hemorrhage, respectively. None medication was continued for 48 h. Results indicated that
of these differences were statistically significant, but the intravenous tirofiban did not significantly induce more cer-
results provided further evidence for the safety and poten- ebral hemorrhagic transformation or parenchymal hemor-
tial efficacy of intravenous tirofiban, even when used for rhage (30 vs. 26.6%; odds ratio [OR] 1.18; 95% confidence
long periods. interval [CI] 0.66–2.06), whereas mortality significantly
The SaTIS (Safety of Tirofiban in Acute Ischemic Stroke) reduced after 5 months of follow-up compared with controls
trial [36] was a placebo-controlled, prospective, open-label, (2.3 vs. 8.7%; OR 4.05; 95% CI 1.1–14.9). No significant
multicenter trial including 260 patients with AIS with a improvement was found in functional outcome at 1 week and
baseline NIHSS score of 4–18. All subjects were refractory 5 months. The SaTIS trial further corroborated the safety of
to or ineligible for intravenous alteplase therapy and were tirofiban in hemorrhagic complications as well as efficacy on
randomly assigned to intravenous tirofiban (PRISM-PLUS mortality reduction, although it was not powered to detect
[4] regimen of 0.4 μg/kg/min for 30 min followed by a con- significant differences in functional improvement.
tinuous infusion of 0.1 μg/kg/min, adapted for creatinine Hypoperfusion and embolism, two underlying physio-
clearance) or placebo within 3–22 h after symptom onset; pathologic mechanisms of ischemic stroke, are often linked
 M. Yang et al.

and interactive. Microvascular occlusion duo to arteriogenic large-vessel reocclusion [44]. Theoretically, early adminis-
embolization may lead to hypoperfusion with impaired clear- tration of antiplatelet agents after IVT might prevent platelet
ance of emboli [37, 38]. Theoretically, GP IIb/IIIa inhibitors aggregation and subsequent vascular reocclusion, thereby
can prevent ongoing microthrombosis and improve micro- improving functional outcomes. However, the ARTIS (Anti-
circulation by blocking fibrinogen-dependent platelet aggre- platelet Therapy in Combination With rt-PA Thrombolysis
gation. Several preclinical trials have confirmed its infarct in Ischemic Stroke) trial concluded that early intravenous
volume reduction effect via decreased microthrombosis [15, administration of aspirin 300 mg shortly after rt-PA did not
17]. Junghans et al. [39] evaluated the inhibition effect of improve outcomes at 3 months but significantly increased
tirofiban for cerebral microembolism in a self-controlled the rate of symptomatic intracranial hemorrhage (sICH)
clinical trial including 24 consecutive symptomatic patients [47]. Based on this and the insignificant clinical benefits
(with recent transient ischemic attack, amaurosis fugax, or from the CLEAR (Combined Approach to Lysis Utilizing
ischemic stroke) with active embolization (> 6 microembolic Eptifibatide and rt-PA in Acute Ischemic Stroke) trial [48],
signals [MES] per hour on initial transcranial doppler [TCD] the 2013 American Heart Association/American Stroke
recording). Results showed that the MES rate dropped dra- Association (AHA/ASA) guidelines for the early manage-
matically, from a median of 38 (range 9–324) to zero in all ment of AIS do not recommend the use of antiplatelet agents
patients after receiving intravenous tirofiban. Furthermore, as an adjunctive treatment within 24 h after IVT (class III,
this inhibitory effect exhibited reversibility after cessation level of evidence C) [49].
of tirofiban infusion, with a significant increase of MES However, given the long-lasting, irreversible and nonse-
(median 13.5, range 0–35). This finding provided therapeutic lective inhibitory effect of aspirin on platelet aggregation,
evidence of tirofiban for inhibiting acute thrombosis forma- as well as the controversial high dosage of aspirin (300 mg)
tion and reducing potential microembolism, especially for in ARTIS, current evidence should not completely rule out
unstable cerebral atherosclerosis disease. all the possible benefits from early antiplatelet therapy after
In general, most of these were pilot studies with small thrombolysis. In fact, Diedler et al. [50] evaluated the safety
samples, and the early preliminary studies used heterogene- profile of IVT under antiplatelets (mostly aspirin) based
ous dosage regimens, so the results should be interpreted on the 11,865 patients from the SITS (Safe Implementa-
with caution. However, Torgano et al. [35] and the SaTIS tion of Treatments in Stroke) registry study. Apart from
trial initially confirmed the relative safety of intravenous patients receiving both aspirin and clopidogrel, no signifi-
tirofiban in the early management of AIS without increasing cant increased risks of sICH, mortality, or poor functional
the risk of intracerebral hemorrhage. Although the majority outcome were found between patients with and without
of exploratory studies have indicated the efficacy of tirofiban antiplatelets, irrespective of antiplatelet type. The results
in AIS, its needs to be confirmed in large prospective RCTs. implied that receiving antiplatelets should not be considered
It should be noted that the existing safety profile of tirofiban a contraindication to IVT when clinically indicated. Accord-
has promoted more clinical research on its application in ingly, it is speculated that early initiation of antiplatelets
progressive ischemic stroke or in combination with revas- after IVT might be clinically applicable. Later, Amaro et al.
cularization therapies in patients with AIS. [51] performed a single-center retrospective analysis of 172
patients with AIS receiving IVT, including 139 patients who
4.2 Combined Application with Intravenous received antiplatelets within 24 h of thrombolysis and 33
Thrombolysis (IVT) patients who received them after 24 h. The early antiplatelet
group showed advantages over the conventional antiplatelet
Alteplase, an rt-PA, initiated within 4.5 h after symptom group in terms of vascular recanalization rates at day 3 and
onset, has been widely proven beneficial for patients with functional outcomes at day 90. Based on previously reported
AIS [40, 41]. The overall recanalization rate is approxi- results from CLEAR [48], the subsequent CLEAR-Enhanced
mately 46% after IVT with alteplase [42]. However, reoc- Regimen [52] and CLEAR-Full Dose Regimen [53] trials
clusion after initial recanalization occurs in 14–34% of confirmed the relative safety of combined thrombolysis with
patients and accounts for 73% of early neurological deterio- reduced dose (0.6 mg/kg) and full-dose (0.9 mg/kg) rt-PA,
ration [43, 44]. The reocclusion has been mainly ascribed respectively, plus eptifibatide 135 μg/kg bolus followed by
to activated platelet aggregation, endothelial damage, and 0.75 μg/kg/min infusion for 2 h compared with intravenous
probably the thrombolytic agent itself [45, 46]. It has been rt-PA alone in patients with AIS. Thus, further larger con-
confirmed that the intravenous thrombolytic agent used for trolled trials on combined thrombolysis therapy are war-
AIS could induce strong and prolonged platelet activation ranted to investigate its safety and efficacy and the optimum
and platelet-related inflammation, which undermines the dose of thrombolytics.
initial thrombolysis effect and leads to secondary throm- Tirofiban has a shorter effective plasma/biologic half-life
bogenesis, distal microcirculation obstruction, or even and exerts parallel inhibiting effects to eptifibatide, which
Platelet GP IIb/IIIa Receptor Inhibitor Tirofiban in AIS

blocks the final pathway to platelet aggregation and throm- thrombolysis group showed less reocclusion at 24 h (2.4
bus formation. The SaTIS trial and a series of preliminary vs. 22.0%; p = 0.025), lower NIHSS score at day 7 or dis-
studies [32, 33, 35, 54] verified the safety profile of tirofiban. charge (1 vs. 6; p = 0.002), and more favorable outcomes at
Hence, tirofiban might offer a promising alternative option 3 months (70.7 vs. 46.2%; p = 0.026).
for combined thrombolysis in certain patients with AIS. Evidence from these preliminary trials suggests that the
Seitz et al. [54], from University Hospital Düsseldorf, veri- safety and efficacy profile of combined IVT, even with full-
fied the efficacy and safety of combined thrombolysis with dose alteplase (0.9 mg/kg) plus adjunctive tirofiban, is supe-
rt-PA plus tirofiban in a retrospective case–control prelimi- rior to that of conventional alteplase thrombolysis. However,
nary study. Researchers divided subjects with AIS within most of these trials were of low evidence quality because of
3 h of symptom onset into low-dose rt-PA plus tirofiban small sample sizes, non-randomized controlled design, or
(rt-PA + T, n = 37), standard rt-PA (0.9 mg/kg, n = 119), lack of long-term follow-up results for further analysis. As to
and controls (n = 41, with contraindication to rt-PA or time the optimal dosage of tirofiban, the PRISM-PLUS regimen
delay > 3 h since stroke onset). Subjects in the rt-PA + T (30-min loading infusion at a rate of 0.4 μg/kg/min followed
group received an intravenous bolus of 24 ± 9  mg and by a continuous infusion of 0.1 μg/kg/min and adapted for
tirofiban 0.4 μg/kg/min for 30 min followed by continu- creatinine clearance), which was initially used for unstable
ous infusion of 0.1 μg/kg/min for 24 h. Results indicated angina and non-Q-wave MI, seems clinically practical and
that 63% of patients receiving rt-PA + T and 55% of those feasible based on safety and efficacy considerations. Via
receiving rt-PA had favorable functional outcomes compared thrombolysis of platelet thrombus and inhibition of platelet
with 16% of controls (p < 0.05). Mortality and intracranial aggregation or subsequent rethrombosis, adjunctive tirofiban
hemorrhage rates were similar between groups. The results might achieve synergistic effects with thrombolytic agents,
indicated that intravenous rt-PA plus tirofiban might be a which are more effective on erythrocyte-rich thrombi [59].
promising combined thrombolysis therapy for acute stroke To the best of our knowledge, experience is now being
within 3 h from stroke onset. Around the same time, Uni- gained with the use of combined thrombolysis as an alter-
versity Hospital Düsseldorf reported another case series of native in selected cases with AIS in some stroke centers
acute basilar artery thrombosis treated with the same com- in China [58]. Combined thrombolysis treatment has been
bined thrombolysis regimen. All four cases achieved com- drawing increasing attention regarding vascular recanaliza-
plete vascular recanalization and good neurological outcome tion and improved clinical outcomes, although specific tar-
without hemorrhagic complications [55]. get patients and detailed optimal dosage need to be further
Later, Seitz et al. [56] conducted another open trial of 47 validated in prospective, dose-escalating RCTs.
patients with AIS in the MCA territory to investigate the
clinical efficacy profile of combined thrombolysis with rt-PA 4.3 Application in Endovascular Treatment
plus tirofiban. Compared with standard rt-PA 0.9 mg/kg,
rt-PA 20 mg + tirofiban 0.4 μg/kg/min for 30 min followed Periprocedural artery reocclusion and distal embolization
by continuous infusion of 0.1 μg/kg/min for 24 h reduced were common complications in the initial period of PCI,
significantly more T2 infarction lesions on day 8 com- leading to further myocardial damage [60]. This subopti-
pared with baseline mean transit time lesions (50 vs. 30%, mal myocardial reperfusion was due to vascular endothe-
p < 0.03) and achieved more neurological improvement, lial traumatic injury and subendothelial matrix exposure,
as evaluated by ESS (59 vs. 15; p < 0.01). No sICH was which resulted in further platelet adhesion, aggregation, and
observed among subjects. Meanwhile, this combined throm- inflammatory mediator release [61, 62]. Adjunctive use of
bolysis regimen was reconfirmed as effective for intracere- GP IIb/IIIa inhibitors, especially when administered in the
bral large-artery occlusive disease. Straub et al. [57] reported early phase of infarction, has been confirmed to reduce the
that 68% of 19 patients with acute MCA occlusion achieved risk of vascular complications and the need for revasculari-
MCA recanalization, which is obviously superior to the 46% zation during PCI [63, 64]. A series of RCTs has established
with conventional IVT [42]. In a recent single-center pro- the safety and efficacy of all three currently available GP IIb/
spective open-labeled trial, Li et al. [58] reinvestigated the IIIa inhibitors in perioperative periods [65, 66]. Thus, GP
safety and efficacy of combination thrombolysis therapy in IIb/IIIa inhibitors are now recommended as routine bailout
41 patients with AIS. The incidence of sICH and mortality therapy for thrombotic complications in ischemic heart dis-
as well as clinical outcomes at discharge or 3 months were ease [67].
similar between the combined thrombolysis group (rt-PA Although EVT advances in AIS have lagged behind those
0.9 mg/kg plus tirofiban 0.4 μg/kg/min for 30 min followed in cardiovascular disease, the AHA/ASA guidelines [68, 69]
by continuous infusion of 0.1 μg/kg/min for at least 24 h) recommend pursuing EVT for improved revascularization
and standard alteplase group (rt-PA 0.9 mg/kg), which was and clinical outcomes with second-generation thrombectomy
a propensity score-matched cohort. However, the combined devices since publication of several large thrombectomy
 M. Yang et al.

RCTs for specific patients with AIS attributable to cerebral combined with intra-arterial thrombolysis inspired more
large-artery occlusion [70–76]. Endovascular recanaliza- exploratory research in EVT. Later the same year, Man-
tion rates varied according to approaches, including intra- giafico et al. [81] reported another retrospective case series
arterial thrombolysis, mechanical thrombectomy (MT), with the same study protocol except that both intravenous
angioplasty, and stent implantation, which can frequently tirofiban and heparin were continued throughout the oper-
bring about endothelial damage, plaque disruption, and ation and for 24–48 h as long as signs of periprocedural
subsequent platelet activation similar to that in PCI, result- bleeding were absent. Of 21 patients, 17 achieved success-
ing in early arterial reocclusion and clinical deterioration. ful recanalization and five experienced ICH, three of which
Reocclusion after successful cerebrovascular recanalization were fatal. At 3-month follow-up, 13 of 21 patients had
occurs in as many as 22–34% of patients, most of whom favorable functional outcomes, and six patients had died.
have disease complicated with underlying high-grade resid- This combined therapy, comprising proactive tirofiban plus
ual stenosis and intracranial atherosclerotic disease [45, 77]. heparin, intra-arterial urokinase, and MT seemed effective in
The endogenous thrombin induced by vascular endothelial improving cerebrovascular revascularization. However, this
damage during endovascular procedures and the attenuated great benefit from artery patency did not completely trans-
antegrade blood flow may synergistically reinforce plate- late into equivalent reductions in mortality and sICH, which
let activity and result in reocclusion of initially recanalized led to debate over the safety of simultaneous proactive use of
artery [45, 78]. Tirofiban, which blocks the final pathway of tirofiban and heparin for long periods during and following
activated platelet aggregation and subsequent thrombus for- an operation. Ihn et al. [82] reinvestigated the safety and effi-
mation, was used in a number of case series and exploratory cacy of intravenous tirofiban as pretreatment combined with
clinical trials during perioperative periods of intra-arterial subsequent intra-arterial urokinase 100,000–800,000 IU and/
thrombolysis, endovascular thrombectomy, angioplasty, or or MT in 13 patients with AIS secondary to major cerebral
emergent permanent stenting, aiming to prevent early arte- artery occlusion. Intravenous infusion of tirofiban 0.4 μg/
rial reocclusion and thromboembolic complications. How- kg/min bolus for 30 min followed by infusion of 0.1 μg/kg/
ever, the individual prognosis must be carefully considered min was started immediately upon confirmation of major
before proceeding with EVT. artery occlusion with CT angiography (CTA) and exclusion
of intracerebral hemorrhage with head CT and continued for
4.3.1 Proactive Use of Tirofiban Before Endovascular 24–48 h. MT mainly referred to percutaneous transarterial
Procedures angioplasty (PTA) with balloon, which was performed on
six patients in the study. At 90 days, recanalization (TIMI
Given the pharmacological effects of GP IIb/IIIa inhibi- grade 2 or 3) had been achieved in 11 of 13 patients, whereas
tors, researchers speculated that pretreatment with tirofiban eight patients had favorable outcomes (mRS 0–2), two expe-
would play a crucial role in improving revascularization rienced sICH, and two had died.
and maintaining microcirculation before, during, and after Comparative analysis of these three exploratory studies
endovascular procedures by preventing platelet aggregation of the proactive use of tirofiban raises several points. First,
and vascular reocclusion [54, 79]. However, whether this the baseline clinical severity was worse than in most other
advantage entirely evolves into paralleled satisfactory clini- clinical studies, for example, the median admission NIHSS
cal outcomes remains to be determined. score ranged from 18 to 21 and internal carotid artery (ICA)
As early as 2005, Mangiafico et al. [80] reported a case T-bifurcation and basilar artery occlusion accounted for
series of proactive administration of intravenous tirofiban two-thirds of all patients. Second, these studies did not use
plus local intra-arterial urokinase 300,000–600,000 IU and advanced MT devices such as a stent retriever or the Penum-
MT for 11 patients with AIS attributable to large cerebral bra System. Third, all subjects were treated with proactive
artery occlusion. Proactive intravenous tirofiban 0.4 μg/kg/ tirofiban before thrombolysis or endovascular procedures
min for 30 min followed by continuous infusion of 0.1 μg/ and continued for over 24 h, without triage based on patho-
kg/min started immediately after the admission head com- genesis classification or temporal recanalization status. Fur-
puted tomography (CT) and continued for 24–48 h. Intrave- thermore, heparin and intra-arterial urokinase were coupled
nous heparin 2500–3000 IU was started concurrently with with tirofiban for the majority of patients, which might also
tirofiban to maintain an activated clotting time (ACT) of increase the risk of symptomatic intracerebral hemorrhage.
200–300 s during interventional procedures. Results showed These characteristics may well account for the discrepan-
that 10 of 11 subjects achieved complete recanalization at cies between excellent recanalization and relatively inferior
24 h after operation and favorable outcomes (mRS 0–2) at clinical outcomes.
3 months; the remaining patient with partial recanalization Considering the specific inhibition effect on platelet
died 3 months later. Neither sICH nor systemic bleeding aggregation and atherothrombosis of GP IIb/IIIa inhibitors,
occurred. These initial clinical experiences of tirofiban researchers began to consider proactive use of tirofiban in
Platelet GP IIb/IIIa Receptor Inhibitor Tirofiban in AIS

certain stroke patients, such as those with large-artery ather- that predict unfavorable clinical outcomes and have always
osclerosis subtype. Ernst et al. [83] retrospectively evaluated been a thorny treatment challenge for interventional neu-
the clinical feasibility of pretreatment with low-dose GP IIb/ rologists. Several rescue measures have been introduced
IIIa inhibitor before EVT in 120 patients with acute verte- clinically for thrombectomy-refractory cases, including
brobasilar occlusive (VBO) stroke (mean admission NIHSS intra-arterial thrombolysis, permanent stent implantation,
score 24). Unlike anterior circulation stroke, acute VBO balloon angioplasty, aspiration-assisted stent retrieval, and
stroke is more relevant with atherothrombotic occlusion or double solitaire thrombectomy [90–93]. Besides endothelial
in situ thrombosis [84]. Of these patients, 37 received intra- damage during endovascular manipulations, stent thrombec-
venous tirofiban 10 μg/kg bolus followed by continued infu- tomy failure and early reocclusion are strongly correlated
sion of 10 μg/kg/h during transport from another hospital or with in situ thrombo-occlusion and severe residual stenosis,
CT/MRI to DSA room, and 93 received another GP IIb/IIIa which are also common complications of ICAS [45, 89].
inhibitor, abciximab. After angiography analysis confirmed Thus, researchers hypothesize that tirofiban could be intrave-
VBO, intra-arterial rt-PA 20 mg/h, maximum dose 40 mg, nously/intra-arterially infused as rescue therapy for eligible
was administered at the site of occlusion via microcathe- patients with endothelial damage or in situ atherosclerotic
ter regardless of the need for subsequent additional PTA/ stenosis at the site of occlusion during EVT. Intra-arterial
stenting or thrombus aspiration, which were introduced for tirofiban has several advantages over intravenous medica-
patients with comorbid underlying > 70% atherosclerotic tion in terms of local drug concentration surrounding tar-
stenosis. Intravenous tirofiban was suspended after admin- get lesions and real-time feedback on angiographic changes
istration of oral antiplatelet agents. Finally, 43% of patients [94]. In turn, intra-arterial administration, as a more invasive
receiving tirofiban had no or moderate disability (mRS procedure, has shortcomings in terms of surgical injuries or
0–3) at 3 months, whereas 27% died and 9% experienced a higher risk of hemorrhagic complications if improperly
sICH. All these endpoints were noninferior to other VBO carried out.
stroke studies [85, 86], indicating that low-dose intravenous Intra-arterial tirofiban and other GP IIb/IIIa inhibitors
tirofiban as a pretreatment strategy may be more specifically were first studied as rescue therapies in 2005 by Deshmukh
suited to acute VBO stroke. et al. [95] in patients with AIS due to large-artery occlu-
In general, pretreatment with low-dose tirofiban could sion who failed to recanalize after intravenous/intra-arterial
effectively improve vascular recanalization for patients rt-PA or endovascular mechanical recanalization. GP IIb/
with large-artery occlusive stroke, but, for safety reasons, IIIa inhibitors, including tirofiban, were delivered either
practical application should proceed prudently, especially locally intra-arterially, intravenously, or both (intra-arterial
when coupled with long-duration heparin infusion and/or tirofiban 0.6 mg followed by intravenous tirofiban 10 mg).
intra-arterial thrombolytic drugs. However, given the small In this preliminary retrospective observational study, 17 of
sample size, heterogeneous specific treatment modalities, the 21 recanalization-refractory patients achieved complete
and uncontrolled experiment designs, caution is compulsory or partial recanalization and 13 patients experienced favora-
when generalizing from these conclusions. As to patients ble functional outcomes (mRS score 0–3). Three patients
complicated with certain underlying pathogenesis, such as experienced non-life-threatening sICH. Kwon et al. [96]
intracranial atherosclerosis (ICAS), proactive use of tirofiban reported another case series including 16 patients with AIS
seems reasonable but awaits further confirmation by RCTs. (mean admission NIHSS score 12.9) within 6 h of symp-
Furthermore, even if its customized benefits are confirmed, tom onset. All patients underwent adjuvant intra-arterial
timely identification of pathogenesis and mechanism of eli- tirofiban therapy after unsuccessful intra-arterial thromboly-
gible ischemic stroke cases before endovascular procedures sis therapy. Tirofiban was administered intra-arterially at a
is another major challenge for emergency neurologists [87]. rate of 1.39 μg/kg/min, with total dose range 0.35–2.0 mg
according to recanalization status. Angiographic recanaliza-
4.3.2 Rescue Treatment with Tirofiban tion was successful in 13 of the 16 patients (81.3%), and six
for Recanalization‑Refractory Patients (37.5%) experienced ICH. Of special note, 50% (8/16) of
patients achieved functional independence, whereas three
MT with a stent retriever or an aspiration device such as patients died after 3 months of follow-up, a polarization
a solitaire/trevo stent or Penumbra System have demon- sign between successful recanalization and poor prognosis/
strated high  safety and efficacy for large-artery occlusive complications. It was postulated that the high sICH and mor-
stroke [71–76, 88]. However, stent-retriever thrombectomy tality rates were mainly ascribed to the high dose of intra-
fails to recanalize infarction-related major arteries in about arterial tirofiban (≥ 25 μg/kg) in six patients, exactly three
29% of patients [71], and instant reocclusion after success- of which had sICH followed by severe disability or death.
ful endovascular recanalization occurs in approximately Later, Kim et al. [97] reported another exploratory study.
20% of patients [45, 89]. Both are therapeutic dilemmas Based on previous experience, advanced MT methods at
 M. Yang et al.

that time, such as stent-retriever thrombectomy, permanent was 30.3% (40/132). The IST group had significantly more
stent implantation, microwire/microcatheter thrombus frag- instant reocclusion after initial recanalization than did the
mentation, and so on, were adopted during EVT. Conven- non-IST group (65% [26/40] vs. 3.3% [3/92]). With the aid
tional intra-arterial infusion of tirofiban (average 0.66 mg, of tirofiban, 74.3% (26/35) of patients with instant reocclu-
range 0.2–1.0) was performed proximal to the thrombi sion during MT achieved Thrombolysis in Cerebral Infarc-
after a first attempt at thrombectomy, followed by continu- tion (TICI) 2b/3, and no sICH was observed. Researchers
ous intravenous infusion of tirofiban for patients with early concluded that patients with IST were prone to instant reoc-
arterial reocclusion or emergent stent implantation only at clusion during MT and that low-dose intra-arterial tirofiban
a lower rate of 0.12 μg/kg/min for 12–24 h. In total, 75.1% substantially improved artery recanalization without induc-
(12/16) of patients reached artery recanalization and 56.3% ing more ICH. The study was limited by its lack of long-term
(9/16) achieved functional independence at 3 months; only follow-up results. Accordingly, we speculate that low-dose
one patient had sICH. Similar recanalization and functional intra-arterial tirofiban followed by continuous intravenous
outcome improvement results were reported for patients with infusion may be an alternative rescue therapy option for
MT-refractory stroke [98]. When thrombectomy with sten- thrombectomy-refractory patients with ICAS, although more
triever failed, adjuvant intra-arterial tirofiban was infused prospective RCTs are essential.
at 0.1 mg/min (average total dose 0.33 mg, range 0.2–0.75). However, even successful cerebrovascular recanaliza-
Results showed that 14 (77.7%) of 18 patients experienced tion is not necessarily permanent: approximately 25% of
successful recanalization and nine (50%) achieved functional patients experience neurological deterioration within the
independence. However, five patients experienced periproce- first 24–48 h from stroke onset. Besides hemorrhagic trans-
dural complications: five emboli distalization and one artery formation and cerebral hyperperfusion syndrome, subacute
perforation. artery reocclusion and futile recanalization are two further
Accordingly, it followed that adjuvant tirofiban might major concerns that require intensive monitoring [102, 103].
be an effective alternative rescue treatment with acceptable Futile recanalization is one of the most underrated compli-
tolerance and that operators should exercise due diligence cations; it was recently reported that up to 47% of patients
while confronting revascularization-refractory cases during who received angiographic recanalization had experienced
endovascular procedures. Besides, these exploratory studies adverse outcomes at 3 months [103, 104]. The incidence of
have provided a basis for clinical practice and future studies subacute reocclusion was reported to range from 3 to 9%
on tirofiban dosages. In fact, dose–response tests regarding within the first 24 h after IVT or EVT [79, 105, 106]. The
the safety and efficacy of tirofiban during PCI proposed a primary mechanism seems to be increased platelet activation
regimen of tirofiban 25 μg/kg bolus followed by continuous due to the release of thrombin after IVT and to endothelial
infusion of 0.15 μg/kg/min [99]. However, no such dose- damage caused by MT [79, 107]. Theoretically, early admin-
tolerance trials have been conducted in EVT of cerebrovas- istration of antiplatelet agents appears to be an effective pre-
cular disease as yet. Further controlled dose-escalation trials vention strategy for subacute reocclusion after successful
for recanalization-refractory patients regarding intra-arterial recanalization. Therefore, Jeong et al. [108] retrospectively
tirofiban with state-of-the-art thrombectomy devices such as analyzed 712 patients with AIS who underwent IVT or
a direct aspiration system and stent retriever are essential for EVT and compared the clinical outcomes of early initia-
generalization and application. tion (< 24 h) of antithrombotics (including antiplatelet and
Most instant reocclusion during MT were ascribed to anticoagulant agents) with conventional strategy (> 24 h).
in situ thrombo-occlusion (IST) [100, 101]. Considering the No significant difference was found in hemorrhage risk
high prevalence of ICAS in Asian populations, some Asian between the two medication strategies. Despite the retro-
researchers hypothesized tirofiban may have a specific role spective design and possible selection bias of this study, the
in atheroembolic major artery occlusion. To evaluate the ASA still modified the recommendation accordingly to that
efficacy of tirofiban in patients with IST, Kang et al. [89] antithrombotic therapy within the first 24 h after IV (with
retrospectively analyzed and categorized 132 patients with or without EVT) can be considered if it provides signifi-
acute large-artery occlusive stroke who underwent MT into cant benefits or if withholding such medication is known to
an IST group and a non-IST group according to the presence bring potential risk (class of recommendation IIb, level of
of underlying ICAS via post-MT magnetic resonance angi- evidence B-NR) [69]. Based on these principles, we deduce
ography or CTA. When encountering instant reocclusion that early administration of a GP IIb/IIIa inhibitor such as
after successful recanalization, the operator would resort to tirofiban for certain patients within the crucial first 24 h may
additional intra-arterial tirofiban (62.5 μg/min, total dose be an effective prevention strategy against subacute cerebro-
0.5–1 mg) and a subsequent re-attempt at thrombectomy, vascular reocclusion.
including forced contact aspiration and stent thrombec- In addition, tirofiban produces dose-dependent block-
tomy. Final analysis indicated that the incidence of IST ade effects on platelet aggregation and thrombosis within
Platelet GP IIb/IIIa Receptor Inhibitor Tirofiban in AIS

5 min, and approximately 50% of platelet aggregation is or favorable outcomes, but instead correlated with fatal
restored at 4 h after cessation, and near-baseline levels are ICH (OR 3.03; 95% CI 1.5–4.05) and poor outcomes (OR
reached after 8 h. Thus, after the loading dose of intra- 6.60; 95% CI 1.06–41.52). Researchers speculated that these
arterial tirofiban for fast-acting and real-time feedback on negative findings may be ascribed to the heterogeneity of the
angiographic changes, subsequent long-duration continuous thrombectomy devices, the higher tirofiban dose, and selec-
intravenous infusion may be crucial for improved microvas- tion bias in that patients receiving tirofiban were prone to
cular patency and prevention of delayed arterial reocclusion. heavier atherosclerotic burden, although no final consensus
Recently, Zhao et al. [109] evaluated the safety and efficacy was reached.
profile of low-dose tirofiban after EVT in patients with AIS Although controversial, in general, we can draw prelimi-
through an observational trial involving 180 patients (mean nary conclusions from the available evidence that rescue
admission NIHSS score 20; 90 subjects each treated with therapy with tirofiban for recanalization-refractory patients
and without tirofiban). Intra-arterial tirofiban 0.25–0.5 mg appears to be well-tolerated and effective for better neu-
during EVT and subsequent continued intravenous infusion rological improvement and lower mortality, especially for
0.2–0.25 mg/h for 12–24 h were prescribed at operators’ patients complicated with in situ atherosclerotic stenosis.
discretion for revascularization-refractory settings such as Tirofiban, with its high efficiency and short platelet inhibi-
balloon angioplasty, instant reocclusion, emergency stent- tion half-life profile, has been attracting increasing attention
ing, and so on. Intravenous tirofiban overlapped with dual from interventional neurologists. As to the specific dosage
antiplatelet therapy for 4 h before cessation. Final analysis of tirofiban in revascularization-refractory patients, exist-
suggested superior outcomes for the tirofiban group versus ing clinical evidence indicates that ≤ 1 mg for intra-arterial
the non-tirofiban group for mortality (23 vs. 44%; p = 0.005) administration and intravenous infusion of 0.1 μg/kg/min for
and long-term functional independence (adjusted OR 4.37; 12–24 h seems feasible, albeit more RCTs are essential to
95% CI 1.13–16.97) without further sICH. However, no eliminate disputes, such as around the optimum dose, com-
significant between-group difference was found for reca- bination with heparin, and so on.
nalization or reocclusion rates. Researchers concluded that
low-dose tirofiban was associated with lower mortality and
improved functional independence for patients with AIS 5 Conclusion
treated with EVT. Likewise, Chang et al. [93] conducted
a multicenter retrospective controlled trial to evaluate the The different pathomechanisms of ischemic stroke and the
clinical significance of rescue stenting for 148 patients for risk of hemorrhagic transformation contribute to the dif-
whom thrombectomy had failed. Results suggested that res- ficulty of introducing antiplatelet treatment that is both
cue stenting may require a GP IIb/IIIa inhibitor, and stent safe and effective. Although GP IIb/IIIa inhibitors have
patency was correlated with administration of GP IIb/IIIa no thrombolytic properties, we must still take precautions
inhibitor (intra-arterial bolus of tirofiban 0.3–1.0 mg or Reo- against the higher bleeding risk, especially when admin-
pro 5–10 mg, followed by intravenous continuous infusion istered within 48  h of stroke onset [112]. The AbESTT
for 6–12 h) without inducing more sICH. (Abciximab in Emergency Treatment of Stroke Trial) trial,
However, the tolerability profile of tirofiban during the which used abciximab, another GP IIb/IIIa inhibitor, was
perioperative period for patients undergoing endovascular suspended because of severe bleeding complications without
thrombectomy remains under debate. Kleinschnitz et al. neurological improvement [112]. Postulated mechanisms of
[110] compared the pathogenic role of GP Ib, VI, and IIb/ its adverse effects included high-dose abciximab and its non-
IIIa receptors in a mouse model of transient MCA occlu- selective irreversible inhibition effects on platelet aggrega-
sion. Results suggested that selective blockade of GP IIb/ tion. In contrast, tirofiban binds more specifically and revers-
IIIa receptors, the final common pathway of platelet aggre- ibly to platelet GP IIb/IIIa receptors, with a shorter plasma
gation, with a special antiplatelet antibody exerted no posi- and biologic half-life (Table 1), which may contribute to
tive influences on infarct volume and favorable outcomes, its lower rate of hemorrhagic complications regardless of
instead increasing the incidence of intracerebral hemorrhage whether it is used alone or in combination with thrombo-
and mortality. Similarly, a retrospective controlled study of lytics or endovascular procedures. However, it should be
tirofiban administration in patients with AIS treated with further noted that the bleeding risk with GP IIb/IIIa inhibi-
MT also reported similarly negative results [111]. In this tors, including tirofiban, increased when combined with anti-
study, tirofiban was used as rescue therapy for patients coagulants such as heparin, especially over long durations
with stent implantation and those with suspected endothe- [80, 81, 113].
lial damage according to local standards, but no detailed Another major concern with tirofiban is reversible
medication information was provided. Final results sug- thrombocytopenia, which was reported more in large-scale
gested that tirofiban did not improve artery recanalization clinical trials in ischemic heart disease [4, 114] but rarely
 M. Yang et al.

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Funding  This study was supported by a grant from National Key R&D microvascular patency in experimental acute focal cerebral
Program of China (grant number: 2016YFC1301500) and National ischemia. Stroke. 2000;31:1402–1409 (discussion 1409–1410).
Science and Technology Major Project of China (grant number: 16. Coller BS, Folts JD, Smith SR, Scudder LE, Jordan R. Abolition
2015BAI12B02 and 2017YFC1310901). of in vivo platelet thrombus formation in primates with mono-
clonal antibodies to the platelet gpiib/iiia receptor. Correlation
Conflict of interest  Ming Yang, Xiaochuan Huo, Zhongrong Miao and with bleeding time, platelet aggregation, and blockade of gpiib/
Yongjun Wang have no conflicts of interest that are directly relevant to iiia receptors. Circulation. 1989;80:1766–1774.
the contents of this article. 17. Choudhri TF, Hoh BL, Zerwes HG, Prestigiacomo CJ, Kim
SC, Connolly ES Jr, et al. Reduced microvascular thrombosis
and improved outcome in acute murine stroke by inhibiting gp
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