Outcomes of Emergent Stenting with Antiplatelet Therapy in Patients with Large Vessel Occlusion Stroke with or without Intravenous Tissue Plasminogen Activator

Abstract

Objective: This study aimed to investigate the difference in outcomes after emergent stenting with antiplatelet therapy for large vessel occlusion (LVO) stroke in patients with and without prior intravenous tissue plasminogen activator (IV tPA).

Methods: Patients who arrived at our hospital within 4.5 h of symptom onset and underwent endovascular therapy (EVT) for LVO between January 2015 and March 2023 were analyzed retrospectively. Patients were included if they underwent stenting for atherosclerotic lesions or arterial dissection with antiplatelet therapy during EVT. The safety and clinical outcomes were compared between patients who received IV tPA before EVT (IV tPA group) and those who did not (no-IV tPA group). The primary outcome was symptomatic intracranial hemorrhage (SICH) within 48 h of EVT.

Results: Overall, 54 patients were included in the analysis, with a median age of 72 years (interquartile range [IQR]: 53–74); 41 (76%) were women. The median pre-stroke modified Rankin Scale (mRS) score was 0 (IQR: 0–2), and the median National Institutes of Health Stroke Scale (NIHSS) score was 7 (IQR: 1–21). These patients underwent emergent stenting with antiplatelet therapy during EVT, with stenting performed in the cervical carotid artery and intracranial artery in 38 and 16 patients, respectively. Thirty-one of 54 patients received IV tPA before EVT. Sex, age, NIHSS score on admission, or Alberta Stroke Program Early Computed Tomographic Score on non-contrast CT did not differ significantly between the IV tPA and no-IV tPA groups. Final modified thrombolysis in cerebral infarction scores ≥2b were achieved more frequently in the IV tPA group than in the no-IV tPA group (97% vs. 87%; p = 0.30). SICH (13% vs. 0%; p = 0.13) and any intracranial hemorrhage (ICH) (29% vs. 8.7%; p = 0.09) occurred more frequently in the IV tPA group than in the no-IV tPA group. The rate of achieving mRS scores of 0–2 at 3 months after stroke onset was lower in the IV tPA group [11 (35%) vs. 13 (57%); p = 0.17].

Conclusion: Among patients who received emergent stenting with antiplatelet therapy, successful reperfusion was achieved more frequently in the IV tPA group than in the no-IV tPA group, although the former exhibited a higher SICH rate and worse functional outcomes. These findings suggest that prior IV tPA administration may increase the risk of hemorrhagic complications in cases requiring emergent stenting with antiplatelet therapy.

Introduction

Intravenous (IV) tissue plasminogen activator (tPA) is effective in patients with acute ischemic stroke (AIS).¹⁾ The safety and efficacy of antithrombotic therapy, including antiplatelet therapy, during or early after receiving IV tPA remain unclear, as some studies have reported a higher incidence of bleeding complications,^2,3) whereas others have reported no significant increase in the risk of bleeding complications.^4,5)

Nevertheless, in clinical practice, emergent stenting may be performed during endovascular therapy (EVT) in cases of large vessel occlusion (LVO) due to intracranial atherosclerotic disease, tandem occlusion requiring carotid artery stenting (CAS), or procedure-related dissection, and in such cases, antiplatelet therapy is necessary to maintain recanalization.^6,7)

However, whether the risk of hemorrhagic complications or prognosis after emergent stenting with antiplatelet therapy differs depending on the presence or absence of prior IV tPA remains unclear. Hyperperfusion and reperfusion injury following emergent stenting may contribute to an increased risk of intracranial hemorrhage (ICH) in patients who have received IV tPA.^8,9) Therefore, this study aimed to investigate the difference in outcomes after emergent stenting with antiplatelet therapy for LVO in patients with and without prior IV tPA.

Materials and Methods

Patients

This is a single-center, retrospective study conducted in a regional referral hospital. For the present study, we reviewed the data of consecutive patients who underwent EVT for LVO stroke between January 2015 and March 2023 from an electronic database, and those who met the following criteria were enrolled: 1) patients who were transported to our hospital within 4.5 h of symptom onset; 2) patients who underwent stenting for atherosclerotic lesions, acute arterial dissection, and iatrogenic arterial dissection; and 3) patients who received antiplatelet therapy during EVT for the LVO stroke. LVO included occlusions of the extracranial and intracranial internal carotid artery (ICA), M1 segment of the middle cerebral artery (MCA), basilar artery, and vertebral artery. Tandem occlusion was defined as the simultaneous presence of high-grade stenosis or occlusion of the cervical ICA and thromboembolic occlusion of the intracranial terminal ICA or its branches, usually the MCA.¹⁰⁾

This study was approved by the Institutional Review Board of Kobe City Medical Center General Hospital, which waived the requirement of written informed consent (#zn240315).

Treatment protocol for LVO

All patients underwent CT to rule out ICH and CTA to evaluate the presence and location of vessel occlusion. Mechanical thrombectomy (MT) was performed promptly after the diagnosis of LVO. IV tPA was not administered if the patient had absolute contraindications to its use. In cases where relative contraindications were identified, including advanced age, certain medical histories, neurological symptoms, or clinical findings, IV tPA was administered at the discretion of the attending physician.¹¹⁾ Additionally, if the possibility of stent placement was considered, the decision to administer IV tPA was made based on clinical judgment.

In eligible patients, IV tPA was administered prior to MT. Intraoperative heparin was administered in all cases, and activated clotting time (ACT) measurements were performed intraoperatively. The modified Thrombolysis in Cerebral Infarction (mTICI) scale was used to evaluate reperfusion status.¹²⁾ The Warfarin–Aspirin Symptomatic Intracranial Disease criteria for the intracranial artery and the North American Symptomatic Carotid Endarterectomy Trial criteria for the cervical carotid artery were used to calculate the degree of residual stenosis.^13,14) The 1st-line treatment consisted of antiplatelet agent administration, followed by percutaneous transluminal angioplasty (PTA), in cases where recanalization could not be achieved with MT or residual stenosis of the cervical ICA or MCA was present. Antiplatelet agents were administered orally or through a nasogastric tube after excluding ICH on cone-beam CT.

Patients with >50% residual stenosis or flow stagnation beyond the stenotic area, even after PTA, underwent additional CAS or off-label intracranial stenting. The regimen typically consisted of dual-loading antiplatelet therapy; however, only a single-loading antiplatelet agent was used in patients who were already on antiplatelet medication (aspirin, clopidogrel, or prasugrel) and were considered to be at a higher risk of bleeding. The retrograde approach (MT before CAS) was used in cases of tandem occlusion.

Data collection

The following clinical data were collected: age, sex, pre-stroke modified Rankin Scale (mRS) score, onset-to-door time, vascular risk factors (hypertension, diabetes mellitus, and dyslipidemia), congestive heart failure, chronic kidney disease, prior antithrombotic medication (anticoagulant or antiplatelet agents, or both), National Institutes of Health Stroke Scale (NIHSS) score on admission, and stroke classification.¹⁵⁾ The Alberta Stroke Program Early Computed Tomographic Score (ASPECTS) on non-contrast CT was used to grade the extent of ischemic changes in the MCA territory.¹⁶⁾

Study outcomes

The primary outcome was symptomatic intracranial hemorrhage (SICH) within 48 h of EVT. SICH was defined as any ICH associated with a decline in the NIHSS by 4 or more points.¹⁷⁾ ICH was assessed according to the Heidelberg bleeding classification.¹⁸⁾ The secondary outcomes were any ICH, final mTICI ≥2b, and mRS scores of 0–2 at 3 months after stroke onset.

Statistical analysis

JMP software version 15.1.0 (SAS Institute, Cary, NC, USA) was used for all statistical analyses, with 2-tailed p-values <0.05 indicating statistical significance. Categorical and continuous variables are presented as numbers (percentages) and medians (interquartile ranges [IQR]), respectively. We compared the patient characteristics and outcomes between the IV tPA and no-IV tPA groups. Fisher’s exact test and the Mann–Whitney U-test were used to analyze the categorical and continuous variables, respectively.

Results

Baseline characteristics

A total of 625 patients diagnosed with LVO underwent EVT between January 2015 and March 2023 at our institute. Of these, 406 presented to our hospital within 4.5 h of symptom onset (Fig. 1). Among them, 54 patients [median age: 72 years (IQR: 53–74 years); 41 women (76%)] underwent emergent stenting with antiplatelet therapy during EVT (cervical carotid artery, n = 38; intracranial artery, n = 16). The median pre-stroke mRS score, onset-to-door time, NIHSS score, and CT-ASPECTS were 0 (IQR: 0–2), 1.3 h (IQR: 0.76–2.3), 7 (IQR: 1–21), and 10 (IQR: 9–10), respectively. Thirty-one of 54 patients received IV tPA before EVT, while 23 did not. Table 1 summarizes the baseline characteristics of patients who received IV tPA and those who did not. The reasons for the lack of IV tPA administration included absolute contraindications, relative contraindications, possibility of stenting, and others in 4, 12, 4, and 3 patients, respectively. The no-IV tPA group tended to be younger [66 years (IQR: 61–81) vs. 78 (65–82); p = 0.21] and had a higher frequency of chronic kidney disease in their medical history [5 (22%) vs. 2 (6.4%); p = 0.12].

Fig. 1 Flowchart of patient inclusion in the study. EVT, endovascular therapy; IV tPA, intravenous tissue plasminogen activator; LVO, large vessel occlusion; PTA, percutaneous transluminal angioplasty

Table 1 Baseline characteristics of patients who received IV tPA and those who did not

	IV tPA (n = 31)	No-IV tPA (n = 23)	p-value
Age, years, median (IQR)	78 (65–82)	66 (61–81)	0.21
Female sex, n (%)	24 (77)	17 (74)	>0.99
mRS 0–1 before onset, n (%)	26 (84)	20 (87)	>0.99
History of hypertension, n (%)	19 (61)	13 (57)	0.78
History of diabetes mellitus, n (%)	8 (26)	5 (22)	>0.99
History of dyslipidemia, n (%)	11 (35)	8 (35)	0.72
History of congestive heart failure, n (%)	6 (19)	3 (13)	0.53
History of chronic kidney disease, n (%)	2 (6.4)	5 (22)	0.12
Prior antithrombic medication, n (%)	12 (39)	7 (30)	0.58
Onset-to-door time (min), median (IQR)	92 (44–147)	74 (47–120)	0.80
NIHSS on admission, median (IQR)	9 (2–23)	7 (1–13)	0.17
ASPECTS on admission, median (IQR)	10 (9–10)	10 (10–10)	0.15
Etiology of stroke, n (%)			0.40
Cardioembolic	2 (6.5)	4 (17)
Atherothrombotic	25 (81)	14 (61)
Cryptogenic	2 (6.5)	2 (8.7)
Others	2 (6.5)	3 (13)
Occluded vessel, n (%)			0.76
ICA	10 (32)	10 (43)
MCA	8 (26)	6 (26)
Tandem	12 (39)	6 (26)
CCA	1 (3.2)	1 (4.4)
VA-BA	0	0

ASPECTS, Alberta Stroke Program Early CT Score; CCA, common carotid artery; ICA, internal carotid artery; IQR, interquartile range; IV tPA, intravenous tissue plasminogen activator; MCA, middle cerebral artery; mRS, modified Rankin Scale; NIHSS, National Institute of Health Stroke Scale; VA-BA, vertebral artery–basilar artery

Procedural data

Thrombectomy was performed in 33 of 54 patients; a stent retriever alone and a stent retriever with aspiration were used in 19 and 14 patients, respectively. PTA was performed in 24 patients. Fifty-four patients underwent emergent stenting with antiplatelet therapy during EVT (cervical carotid artery, n = 38; intracranial artery, n = 16). The etiologies were atherosclerosis, dissection, and iatrogenic dissection in 46, 3, and 5 patients, respectively. The antiplatelet regimen included dual therapy with aspirin 200 mg and clopidogrel 300 mg in 36 cases, aspirin 200 mg and prasugrel 20 mg in 13 cases, and monotherapy with aspirin 200 mg, clopidogrel 300 mg, and prasugrel 20 mg in 2, 2, and 1 case, respectively.

Table 2 summarizes the procedural data of patients who received IV tPA and those who did not. Compared with the no-IV tPA group, the IV tPA group underwent thrombectomy more frequently [21 (68%) vs. 12 (52%); p = 0.27] and showed a trend toward more frequent use of the stent retriever alone [13 (42%) vs. 6 (26%); p = 0.51]. The intraoperative heparin dosage was significantly higher in the no-IV tPA group, [5000 (4000–6000) vs. 7000 (6000–9000) units; p <0.0001] as was the maximum ACT [225 (199–270) vs. 278 (234–335) s; p = 0.01]. Additionally, the use of argatroban was significantly more frequent in the no-IV tPA group [3 (9.7%) vs. 9 (39%); p = 0.019]. No significant differences were evident in the other parameters between the 2 groups.

Table 2 Procedural data of patients who received IV tPA and those who did not

	IV tPA (n = 31)	No-IV tPA (n = 23)	p-value
Thrombectomy, n (%)	21 (68)	12 (52)	0.27
Thrombectomy technique, n (%)			0.51
Stent retriever	13 (42)	6 (26)
Stent retriever with aspiration	8 (26)	6 (26)
Aspiration	0	0
PTA, n (%)	14 (45)	10 (43)	>0.99
Types of stent, n (%)			0.81
Carotid stent	22 (71)	16 (70)
Intracranial stent	9 (29)	7 (30)
Antiplatelet regimen, n (%)			0.90
Dual antiplatelet therapy	28 (90)	21 (91)
Single antiplatelet therapy	3 (9.7)	2 (8.7)
Indications for stenting, n (%)			0.94
Atherosclerotic	26 (84)	20 (87)
Dissection	2 (6.6)	1 (4.4)
Iatrogenic dissection*	3 (9.7)	2 (8.7)
Intraoperative heparin dosage (units), median (IQR)	5000 (4000–6000)	7000 (6000–9000)	<0.0001
Maximum ACT (s), median (IQR)	225 (199–270)	278 (234–335)	0.01
Argatroban use	3 (9.7)	9 (39)	0.019

*Iatrogenic dissections occurred due to balloon angioplasty or stent retriever

ACT, activated clotting time; IQR, interquartile range; IV tPA, intravenous tissue plasminogen activator; PTA, percutaneous transluminal angioplasty; s, seconds

Outcomes

SICH was encountered in 4 patients in the IV tPA group (Heidelberg bleeding classification 2 and 3c in 2 cases each) and in no patient in the no-IV tPA group [4 (13%) vs. 0 (0%); p = 0.13]. The median age of patients with SICH was 83 years (IQR: 80–85), 3 of whom were women, and their NIHSS scores were significantly higher while their ASPECTS scores were lower compared with those in the no-SICH group [29 (IQR: 13–40) vs. 6 (IQR: 1–21), p = 0.015; 8 (IQR: 5–10) vs. 10 (IQR: 9–10), p = 0.019]. The etiology was atherosclerosis in all SICH cases, with 3 cases of tandem occlusion. CAS was performed in all of these 3 cases. While successful reperfusion was achieved with an mTICI score of 3 in all 4 patients, their mRS score at 3 months were 5 or 6. Additionally, any ICH tended to be more frequent in the IV tPA group [9 (29%) vs. 2 (8.7%); p = 0.092]. Successful recanalization with a final mTICI score ≥2b was achieved in almost all cases in the IV tPA group, while the proportion was slightly lower in the no-IV tPA group [30 (97%) vs. 20 (87%); p = 0.30]. Despite this, the proportion of patients who achieved mRS scores of 0–2 at 3 months after stroke onset tended to be lower in the IV tPA group compared with the no-IV tPA group [11 (35%) vs. 13 (57%); p = 0.17; Table 3].

Table 3 Outcomes of patients who received IV tPA and those who did not

	IV tPA (n = 31)	No-IV tPA (n = 23)	p-value
Primary outcome
Symptomatic ICH, n (%)	4 (13)	0	0.13
Secondary outcome
Any ICH, n (%)	9 (29)	2 (8.7)	0.092
Final mTICI ≥2b, n (%)	30 (97)	20 (87)	0.30
mRS scores 0–2 at 90 days, n (%)	11 (35)	13 (57)	0.17

ICH, intracranial hemorrhage; IV tPA, intravenous tissue plasminogen activator; mRS, modified Rankin Scale; mTICI, modified thrombolysis in cerebral infarction

Discussion

This study revealed that among patients who underwent emergent stenting with antiplatelet therapy during EVT for LVO, those who received prior IV tPA exhibited a trend toward higher successful reperfusion rates compared to those who did not receive prior IV tPA; however, they also had higher incidences of SICH and any ICH, along with a tendency for worse functional outcomes.

SICH is an adverse event following IV tPA for AIS, with a reported incidence of 6.4%.¹⁹⁾ One study reported that antiplatelet therapy could increase the risk of early neurological deterioration due to SICH by a factor of 3.7 in patients receiving IV tPA.²⁰⁾ In this study, SICH occurred in 4 (13%) of 31 patients who received IV tPA, followed by emergent stenting with antiplatelet therapy. This incidence was comparable to the previously reported rate of hemorrhage (1/12 or 8.3%) in a series of patients with AIS, who received an emergent loading dose of antiplatelet agents (aspirin 300 mg and clopidogrel 300 mg) with emergent stenting after IV tPA.²¹⁾ These incidence rates (13% in this study and 8.3% in the previous study) were slightly higher than the previously reported incidence of SICH (6%–7%) following EVT after IV tPA.²²⁾

The higher incidence of SICH observed in our study (4 cases, 13%) might be explained by the advanced age and severe medical conditions (as evidenced by the high NIHSS scores in all 4 cases), both recognized risk factors for hemorrhage following IV tPA. Compared to the patient population in the previously cited large-scale registry study,²²⁾ in which the median age was lower and baseline stroke severity milder, our cohort may have included patients with higher baseline risk scenarios. In such high-risk scenarios, factors that further increase the likelihood of hemorrhage, such as antiplatelet loading, hyperperfusion due to CAS, and reperfusion injury associated with intracranial stent placement, probably contribute to the occurrence of SICH.^8,9) Herein, all 4 patients with SICH had poor functional outcomes, with an mRS score of 5 or 6 at 3 months, suggesting that SICH led to a poor functional prognosis in the IV tPA group. Moreover, despite the higher recanalization rate with final mTICI scores ≥2b, the low proportion of patients with mRS 0–2 suggests that while IV tPA may contribute to successful recanalization, the associated risk of hemorrhagic complications may negate these benefits, potentially leading to poorer functional outcomes. Our findings suggest the need to carefully assess the balance between the risks and benefits of combined IV tPA and antiplatelet therapy in patients with LVO who are at high risk of bleeding.

Limitations

This study has some limitations. First, multiple conditions such as atherosclerotic lesions, dissecting lesions, and iatrogenic dissections were indications for stenting. The inclusion of patients with such diverse backgrounds in a single study population detracts from the uniformity of the results, potentially diminishing the accuracy of the interpretation. Second, the present analysis included observational data from a single center, and the sample size was small. Therefore, further investigation with a larger sample size derived from multiple centers is necessary.

Conclusion

Among patients who received emergent stenting with antiplatelet therapy, successful reperfusion was achieved more frequently in the IV tPA group than in the no-IV tPA group, although the former exhibited a higher SICH rate and worse functional outcomes. These findings suggest that prior IV tPA administration may increase the risk of hemorrhagic complications in cases requiring emergent stenting with antiplatelet therapy.

Disclosure Statement

The authors declare that they have no conflicts of interest.

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