Utility of tPA Administration in Acute Treatment of Internal Carotid Artery Occlusions

Abstract

Background

Intravenous tissue plasminogen activator (IV-tPA) remains part of the guidelines for acute ischemic stroke treatment, yet internal carotid artery occlusions (ICAO) are known to be poorly responsive to IV-tPA. It is unknown whether bridging thrombolysis (BT) is beneficial in such cases.

Purpose

We sought to evaluate whether the use of IV-tPA improved overall clinical outcomes in patients undergoing endovascular thrombectomy (EVT) for ICA occlusions.

Methods

Data from 1367 consecutive stroke cases treated with EVT from 2012-2019 were prospectively collected from a single center. Univariate and multivariate logistic regression were used to assess the relationship between IV-tPA administration and clinical outcome.

Results

153 patients were found to have carotid terminus and tandem ICAO who received EVT and presented within 4.5h of last seen well. 50% (n = 82) received IV tPA. There were no differences between the groups with respect to age, NIHSS, time to EVT and ASPECTS score. 53% had tandem ICA-MCA occlusions. Rate of recanalization (≥ TICI 2B) and sICH did not significantly differ between the two groups. Regression analysis demonstrated no effect of IV-tPA on modified Rankin Score (mRS) at 90 days and overall mortality. Factors significantly associated with reduced mortality included lower age, lower NIHSS, and better rate of recanalization.

Conclusions

There was no significant difference in clinical outcomes in those receiving BT vs. direct EVT for ICAO. For centers with optimal door-to-puncture times, bypassing IV-tPA may expedite recanalization times and potentially yield more favorable outcomes. Patients with higher NIHSS and tandem lesions may have better outcomes with BT.

Introduction

Intravenous tissue plasminogen activator (IV-tPA) remains an integral part of the guidelines for acute ischemic stroke (AIS) treatment for patients presenting within 4.5 hours of last seen well (LSW) regardless of the vessel territory at risk. Internal carotid artery occlusions (ICAO) pose a particular challenge as they are resistant to IV-tPA.^1-4 Compared to middle cerebral artery (MCA) occlusions, the rates of ICAO recanalization are lower and post-treatment National Institute of Health Stroke Scale (NIHSS) are higher.^2,5,6 Earlier studies found bridging thrombolysis (BT)—administering IV-tPA prior to endovascular treatment (EVT)—improved clinical outcomes without increasing risk of complications.^7-9 A recent publication utilizing the National Inpatient Sample also determined BT was associated with favorable outcomes ¹⁰ . Notably, more contemporary data suggests that patients with ICAO who proceed directly to EVT (dEVT) have equally favorable outcome. ⁷ Other studies report BT increases the rate of both symptomatic (sICH) and asymptomatic intracranial hemorrhage (asICH), but this risk is offset by an average absolute increase in disability-free survival and overall favorable outcome.^9,11,12 The most current results from the DEVT, DIRECT-MT, and MR CLEAN NO-IV, and SKIP randomized controlled trials demonstrated non-inferiority of dEVT vs BT in the former two, but not in the latter two (although SKIP utilized a reduced dose of 0.6 mg/kg of IV-tPA).^13-16

Moreover, substantial heterogeneity currently exists between those who undergo dEVT compared to those with BT. Recent analyses comparing tPA eligible and ineligible patients found that tPA ineligible patients are treated later, and have more comorbidities, such as a history of atrial fibrillation and prior stroke. Despite this even among IV-tPA eligible patients, dEVT has shown equal angiographic results and long-term outcomes. ¹⁷ Despite the existence of this data, reports are lacking regarding the utilization of BT upon isolated ICAO.

Our aim was to evaluate whether the use of BT improved functional outcomes (mRS ≤ 2) in those undergoing EVT for isolated extracranial ICA occlusions (ICAO), terminal ICAO, and tandem intracranial MCA occlusions. Our secondary aim was to assess the effect of BT on length of hospital stay and overall cost.

Materials and Methods

After Institutional Review Board approval, we performed a retrospective analysis of a prospectively maintained database of AIS patients receiving EVT between 2012 – 2019. Demographic characteristics, clinical and radiological data, treatment and procedural information were extracted and analyzed. Data used to prepare this manuscript may be made available upon reasonable request.

Patient Selection

AIS patients who presented to or were transferred to our two comprehensive stroke centers and underwent EVT during the study period were analyzed. Occlusion location was confirmed by computed tomography angiography (CTA), magnetic resonance angiography (MRA) and/or cerebral angiography. Decision to pursue EVT was determined by a vascular neurologist and treating neuro-interventionalist, after detailed discussion with the patient and their family. Patients included in the study were those who presented within 4.5 hours of LSW and received EVT for angiographically confirmed occlusions of the ICA terminus, isolated extracranial, and tandem intracranial MCA.

Baseline Characteristics

Baseline demographic (age, sex), clinical (stroke severity, time from symptom onset, risk factor profile), radiographic (pre-treatment Alberta Stroke Programme Early CT Score [ASPECTS], occlusion location) information and procedural technique and efficiency (Thrombolysis in Cerebral Infarction Scale [TICI]) were collected and analyzed by a vascular neurologist blinded to patient characteristics. Patients were divided into 2 groups- patients who received IV-tPA versus patients who did not.

Outcomes

Efficacy outcomes included early neurological improvement (NIHSS at 24 hours 0 – 1 or ≥ 8-point improvement in NIHSS at 24 hours) and functional independence at 90 days (Modified Rankin Scale [mRS] 0 – 2). Safety outcomes included early neurological deterioration (END, ≥ 4 point worsening of NIHSS at 24 hours), parenchymal hemorrhage (PH1 or PH2), sICH (≥ 4 point NIHSS worsening with PH1/2), and mortality at 90 days. Additionally, length of stay (LOS) and mean cost of hospital admission were assessed.

Statistical Analyses

Continuous variables are reported as mean ± standard deviation or median with inter quartile range (as appropriate) and categorical variables are reported as proportions. Between groups comparison for continuous variables was performed using Student’s t-test and categorical variables using Chi-square test or Fisher Exact Test, as appropriate. Univariable analysis was performed for baseline characteristics between IV-tPA and non-IV-tPA groups. Multi-variable logistic regression analysis was performed to identify predictors of mRS 0 – 2 at 90 days. Variables with a P value of < 0.2 on univariable analysis were used for multivariable logistic regression. Associations are presented as odds ratio with 95% CI. Significance was defined as P ≤ 0.05. Statistical analysis was performed using IBM SPSS Statistics 23 (IBM-Armonk, NY).

Results:

Data from 1367 consecutive stroke cases treated with EVT from 2012 – 2019 were reviewed. A total of 153 patients were found to have isolated extracranial ICAO, isolated terminus ICAO, and tandem ICAO, who presented within 4.5 hours of LSW. Amongst the 153 patients included in the study, 50% (82) received IV-tPA. There were no significant differences between the groups with respect to age, gender, NIHSS upon admission and 24 hours, ASPECTS, and presence of tandem occlusions. The BT group had significantly lower rates of history of prior stroke (9.8 vs 28.9%; Table 1). Reasons for not receiving tPA included (Figure 1): historical contraindication (prior intraparenchymal hemorrhage, recent surgery, bleeding diathesis, and recent ischemic stroke, [30%]), taking a direct oral anticoagulant (17%), high INR (15%), low ASPECTS (5%) mild symptoms (5%), concern for hemorrhage on imaging (2%), family declined (2%), and other (e.g. outside hospital unable to prepare tPA prior to transfer [1%]).

Table 1.

Baseline Characteristics and Outcomes

	Overall (n = 153)	tPA (n = 82)	No tPA (n = 83)	P value
Age, median yrs (SD)	71 (14)	69.7 (14)	69.7 (15)	0.996
Female (%)	78 (51.0)	39 (47.6)	46 (55.4)	0.419
Prior stroke (%)	29 (19.0)	8 (9.8)	24 (28.9)	0.002
Atrial fibrillation history (%)	64 (41.8)	31 (37.8)	37 (44.6)	0.325
Baseline NIHSS, median (SD)	19 (6.4)	19 (6.5)	19 (6.4)	0.673
24 hour NIHSS, mean (SD)	12 (7.6)	11 (7.8)	12 (7.4)	0.283
ASPECTS median (SD)	9 (1.3)	8.7 (1.5)	8.9 (1.1)	0.481
Tandem (%)	81 (52.9)	47 (57.3)	41 (49.4)	0.260
No Stent		2% (1)	7% (3)	0.29
Acute Stent		91% (43)	80% (33)
Non acute Stent		6% (3)	12% (5)
TICI ≥ 2b (%)	136 (90.7)	73 (90.1)	63 (91.3)	1.000
sICH (%)	3 (2.0)	2 (2.4)	1 (1.2)	1.000
mRS ≤ 2 (%)	48 (31.4)	30 (38.5)	18 (27.3)	0.214
Mortality at 90 days (%)	43 (29.9)	21 (26.9)	22 (33.3)	0.466

Figure 1.

Reasons for not receiving IV tPA

Time to treatment, puncture-to-recanalization (data available for 131 patients, 72 who received tPA), rate of recanalization (≥TICI2B), sICH, inpatient LOS, functional outcomes (mRS ≤ 2), and mortality did not significantly differ between the two groups. (Tables 1 and 2).

Table 2.

Procedural Outcomes, Length of Stay, and Cost with or without IV-tPA administration

	tPA	No tPA	P value
Puncture-to-recanalization, mean mins (SD)	47.97 (27.56)	54.86 (32.58)	0.192
Time to EVT, mean mins (SD)	151 (66)	144 (74)	0.529
LOS, mean days (SD)	6.57 (5.95)	7.28 (6.70)	0.488
Cost, mean US $ (SD)	21,829.32 (12,933.85)	19,522.69 (13,666.21)	0.348

Regression analysis demonstrated no effect of BT on mRS at 90 days [OR 0.4 (0.1 – 1.3) P = 0.14] and overall mortality [OR 1.4 (0.3 – 6.9), P = 0.64]. Additionally, stenting (acute or non-acute) did not have any significant impact upon outcome, regardless of tPA administration (P = 0.29). Factors significantly associated with reduced mortality included lower NIHSS, and ASPECTS. The only factor significantly associated with better functional outcome was lower baseline NIHSS.

Additional analyses were performed for patients with high NIHSS score. Among patients with NIHSS ≥ 15 (n = 109) (31.7% vs 18.4%, P = 0.12) and with NIHSS ≥ 10 (n = 136) (37.8% vs 25.8%, P = 0.14), patients receiving BT had statistically non-significant higher rates of 90-day mRS 0 – 2 compared to dEVT patients. Similarly, shift analysis for 90-day mRS score revealed non-statistical differences between groups (NIHSS ≥ 15: P = 0.32, NIHSS ≥ 10: P = 0.47)

Amongst patients who had tandem occlusions, those that underwent BT trended to have higher rates of favorable outcomes and lower mortality (46.7% vs 27.3% and 22.2% vs 33.3%, respectively; Table 3). Patients who did not harbor tandem occlusions had equivalent rates of favorable outcomes and mortality (27.3% and 33.3%, respectively; Table 3).

Table 3.

Functional Outcome and Mortality with or without Tandem Occlusion

	Tandem			Without Tandem
	IV-tPA (45)	No IV-tPA (33)	P value	IV-tPA (33)	No IV-tPA (33)	P value
mRS 0-2 (%)	21 (46.7)	9 (27.3)	0.102	9 (27.3)	9 (27.3)	1
Mortality (%)	10 (22.2)	11 (33.3)	0.31	11 (33.3)	11 (33.3)	1

Cost and Length of Stay

Hospitalization cost data was available for 77% (118) of the patients, of which 60 received BT. Average cost was higher in the BT group, but was not statistically significant ($21,829.32 vs $19,522.69, P = 0.348; Table 2). Similarly, LOS was also comparable between the two groups (BT: 6.5 ± 5.9 days vs dEVT: 7.2 ± 6.6 days, P = 0.48) (Table 2).

Discussion:

In our patient population who underwent EVT for large vessel occlusions (LVO) involving the ICA (isolated extracranial carotid, terminus, or tandem), BT did not impact functional outcomes. Several studies have reported similar results in patients who undergo EVT for LVO, with or without BT; however, these studies included all anterior circulation LVO, not solely ICAO. ³ ICARO-3 evaluated these two treatment modalities for ICAOs; however, their purpose was to probe the superiority of intra-arterial therapy (intra-arterial thrombolysis and/or EVT) over IV-tPA (not specifically evaluating BT vs. dEVT). While their study did not meet its primary outcome, they did report a trend towards favorable outcome for the IAT group. ¹⁸ Similarly, other studies reported favorable outcomes in patients treated with BT vs dEVT alone, but for all anterior circulation LVOs.^19-21

Reported benefits of BT include softening the dense clot burden and dissolving distal thrombi after large vessel recanalization, potentially shortening procedure and recanalization time. ²² This may be of particular importance in ICAO, as it has been reported that recanalization, either spontaneous or related to thrombolytic or interventional therapies, is less likely. ²³ Two large studies looked at patients treated with BT for ICAO and yielded mixed results with one reporting poor outcomes compared to similar groups with MCA occlusions, while the other describing favorable outcomes compared to controls.^24-25

With our population, patients who presented with higher NIHSS fared better with BT. Furthermore, our patients who harbored tandem occlusions trended to have favorable outcomes. Our institution has higher overall rates of reperfusion after EVT of about 91% compared to older studies (54%), which may explain why our patients with higher NIHSS and tandem occlusions had favorable outcomes. ¹³ Multiple studies have shown that effective reperfusion is a key predictor of overall functional outcome.^26-28. Notably, there was a 7-minute increase in time from presentation to EVT, which was similarly seen in DIRECT-MT and MR CLEAN NO-IV^14-15; however, there still was no significant difference between both groups.

With burgeoning health care costs and predicted growth in expenditure, there is a demonstrable focus on controlling costs. ²⁹ Two studies examining the direct and indirect cost of stroke estimated healthcare expenditure to be $73.7 billion in 2010 and $103.5 billion in 2016.^30-31 In treatment of AIS, administration of tPA within the established time windows has proven to be cost-effective, along with IAT as an adjunct for treatment of LVOs.^32-33 A more contemporary study compared EVT vs IV-tPA in LVO patients finding a cost benefit for EVT over IV-tPA; however, this study did not compare BT vs dEVT. ³⁴ In our population, costs were insignificantly higher in the group that received tPA.

Presently, IV-tPA is the standard of care for AIS patients, including those with LVO who present within 4.5 hours of LSW. A recent publication by the Society of Vascular and Interventional Neurology Guidelines and Practice Standards Committee recommends BT for eligible patients. ³⁵ In our selected population with LVO involving ICAO, the addition of BT did not result in favorable outcomes nor did it increase the rate of complications. Notably, in a selected group who presented with higher NIHSS and tandem occlusions, BT did improve functional outcomes. Current randomized controlled trials examining fibrinolytic alternatives (TIMELESS) and comparing groups who receive BT vs dEVT (SWIFT DIRECT) may provide more insight into this ongoing clinical dilemma.^36-37

Conclusions

There was no significant difference in clinical outcomes in those receiving BT vs. dEVT for carotid artery occlusions. For centers with optimal door-to-puncture times, dEVT may expedite recanalization times and potentially yield more favorable outcomes while patients with higher NIHSS and tandem lesions may have better outcomes with BT. Larger studies are warranted to further elucidate this question.

ORCID iD

Kavit Shah https://orcid.org/0000-0001-8378-8224