J Neurol Res
Journal of Neurology Research, ISSN 1923-2845 print, 1923-2853 online, Open Access
Article copyright, the authors; Journal compilation copyright, J Neurol Res and Elmer Press Inc
Journal website https://www.neurores.org


Volume 10, Number 5, October 2020, pages 147-149

Large Vessel Strokes: Is Bridging With Intravenous Thrombolysis Still Beneficial in the Era of Endovascular Treatment?

Harshit Shaha, Shruti Digheb, Ashkan Mowlac, d

aDepartment of Neurosciences, AHN Saint Vincent Hospital, Alleghany Health Network, Erie, PA, USA
bDepartment of Cancer Prevention, Roswell Park Comprehensive Cancer Center, State University of New York at Buffalo, Buffalo, NY, USA
cDivision of Endovascular Neurosurgery, Department of Neurological Surgery, Keck School of Medicine, University of Southern California (USC), Los Angeles, CA, USA
dCorresponding Author: Ashkan Mowla, Division of Endovascular Neurosurgery, Department of Neurological Surgery, Keck School of Medicine, University of Southern California (USC), 1200 North State St., Suite 3300, Los Angeles, CA 90033, USA

Manuscript submitted June 8, 2020, accepted June 15, 2020, published online August 12, 2020
Short title: Large Vessel Strokes’ EVT
doi: https://doi.org/10.14740/jnr621

The year 2020 marks the silver jubilee of the landmark National Institute of Neurological Disorders and Stroke (NINDS) trial which made intravenous tissue plasminogen activator (IV tPA) the only Food and Drug Administration (FDA)-approved treatment for acute ischemic stroke (AIS) management thus far [1]. Over the years, the use of IV tPA has become safer and ubiquitous [2-8]. 2020 also marks the fifth anniversary of the five large randomized clinical trials (RCTs) which revolutionized acute stroke care by endorsing the benefits of concomitant use of IV tPA and endovascular treatment (EVT) with stent retrievers over IV tPA alone in large vessel strokes [9]. EVT with stent retrievers have demonstrated to improve the overall functional outcome and reduce mortality in large vessel strokes, with or without IV tPA [9]. While the efficacy of IV tPA in AIS has been well validated, recently and in the era of effective EVT, its use in AIS with large vessel occlusion (LVO) has been debated. We are at a critical juncture in the ever evolving and exciting field of AIS care, the question on every neurologist’s mind remains whether to bypass IV tPA for EVT in AIS with LVO. Is it the end of the road for IV tPA in AIS with LVO?

It has been largely recognized that IV tPA has a low rate of recanalization in AIS with LVO. In a computed tomography (CT) angiogram-based retrospective study, only 21% of the AIS patients with LVO who received IV tPA within 4.5 h of symptom onset achieved complete recanalization [10]. The same study noted much lower rates of recanalization in the case of proximal internal carotid artery and basilar artery occlusions, approximately 4% [9]. Rai et al concluded that administration of IV tPA before EVT for large vessel strokes single handedly increased the total length of hospital stay and the health care costs [11]. It is well known that early recanalization of an occluded intracranial large vessel leads to better functional outcome. Combination therapy increases the door to groin puncture time of EVT that may lead to delayed recanalization time and subsequently worse functional outcomes [12]. Furthermore, the results of the recently published SKIP trial [13], comparing EVT with versus without IV tPA in AIS with internal carotid artery (ICA) and M1 occlusions, showed a lower rate of intracranial hemorrhage in the EVT only group (34% vs. 50%, P = 0.02). There is also a concern that IV tPA administration might fragment a blood clot targeted for extraction and potentially propagate the fragments downstream, making it non-amenable to EVT [14]. Kamal et al [15] also reported the possibility of recurrent AIS early after IV tPA administration due to disintegration of a pre-existing intracardiac, valvular or aortic thrombus and subsequent systemic embolization. Since health care providers usually think of intracranial hemorrhage as the cause of neurological deterioration during or shortly after IV thrombolysis (IVT), this might cause a delay in the timely diagnosis of recurrent AIS and subsequently EVT in the case of large vessel stroke.

Despite the concerns associated with IV tPA administration before EVT in large vessel strokes, it continues to remain as the standard of care. Current American Heart Association/American Stroke Association (AHA/ASA) guidelines set against withholding IV tPA administration in eligible patients regardless of the LVO status [16]. The Highly Effective Reperfusion Evaluated in Multiple Endovascular Stroke Trials (HERMES) collaborative group performed a pooled data analysis of the five landmark LVO stroke trials and showed that patients who underwent EVT after IV tPA administration had better functional outcomes and less mortality [9]. In a prospective observational study, Ferrigno et al [17] showed that IV tPA plus EVT group had higher chance of having a favorable outcome compared to EVT only group (35% vs. 22%, P = 0.007) along with lower rate of mortality at 3 months (32% vs. 14%, P < 0.0001) in the case of anterior circulation large vessel strokes. In addition, a post-hoc analysis of the ASTER trial [18], which included 381 patients, showed that 90-day mortality rate in the IV tPA plus EVT group was lower compared to EVT alone (fully-adjusted risk ratio: 0.59; 95% confidence interval (CI): 0.39 - 0.88). Both studies showed a trend towards better chance of achieving thrombolysis in cerebral infarction (TICI) scale 2b - 3 for patients in IVT plus EVT group [17, 18].

The current goal of our healthcare system and emergency medical services (EMS) is early identification of AIS patients and a faster delivery of IV tPA. Typically, a patient is brought in by the EMS to the nearest stroke center, where IV tPA can be administered. If an LVO is identified, the patient will be transferred to a stroke center with the capability to perform EVT in case the initial admitting facility does not have the capability of doing EVT. Such a model is now called “drip and ship”. This approach is most beneficial if the patient is far away from an EVT-capable hospital. In such cases, IV tPA can aid LVO recanalization while the patient is being transferred to a facility with higher level of care. Additionally, if the patient is deemed ineligible for EVT after arrival at a stroke center with EVT capability due to various reasons [19], previously administered IV tPA, at the least, will give the patient a chance of recanalization. Of note, the door-in to door-out time is crucial in the “drip and ship” model. Logistical and transport delays can prolong this duration. It is well known that longer durations are associated with poor functional outcomes [20].

Although the direct EVT approach without IV tPA in large vessel strokes sounds like an attractive approach, we believe that there is a need for a large-scale multi-center RCT, comparing the functional outcome of direct EVT in IV tPA eligible large vessel strokes, with a group who receive IVT followed by EVT. Results from such a study may help to provide guidance towards implementing changes in our systems of care. Meanwhile, IVT prior to EVT for eligible large vessel strokes will continue to remain the standard of care.


None to declare.

Financial Disclosure

Authors have no relevant financial disclosure to report.

Conflict of Interest

None to declare.

Author Contributions

All authors have contributed to the theoretical formalism, designing the study, data collection, data analysis and writing the manuscript.

Data Availability

The authors declare that data supporting the findings of this study are available within the article.

  1. Mowla A, Kamal H, Mehla S, Shirani P, Sawyer RN. Rate, Clinical Features, Safety Profile and Outcome of Intravenous Thrombolysis for Acute Ischemic Stroke in Patients With Negative Brain Imaging. J Neurol Res. 2020;10(4):144-145.
  2. Mowla A, Singh K, Mehla S, Ahmed MK, Shirani P, Kamal H, Krishna C, et al. Is acute reperfusion therapy safe in acute ischemic stroke patients who harbor unruptured intracranial aneurysm? Int J Stroke. 2015;10(Suppl A100):113-118.
    doi pubmed
  3. Singh K, Mowla A, Mehla S, Ahmed MK, Shirani P, Zimmer WE, Sawyer RN, et al. Safety of intravenous thrombolysis for acute ischemic stroke in patients with preexisting intracranial neoplasms: a case series. Int J Stroke. 2015;10(3):E29-30.
    doi pubmed
  4. Mowla A, Shah H, Lail NS, Shirani P. Successful intravenous thrombolysis for acute stroke caused by polycythemia vera. Arch Neurosci. 2017;4(4):e62181.
  5. Shahjouei S, Tsivgoulis G, Goyal N, Sadighi A, Mowla A, Wang M, Seiffge DJ, et al. Safety of intravenous thrombolysis among patients taking direct oral anticoagulants: A Systematic Review and Meta-Analysis. Stroke. 2020;51(2):533-541.
    doi pubmed
  6. Mowla A, Kamal H, Lail NS, Vaughn C, Shirani P, Mehla S, Rajabzadeh-Oghaz H, et al. Intravenous thrombolysis for acute ischemic stroke in patients with thrombocytopenia. J Stroke Cerebrovasc Dis. 2017;26(7):1414-1418.
    doi pubmed
  7. AbdelRazek MA, Mowla A, Hojnacki D, Zimmer W, Elsadek R, Abdelhamid N, Elsadek L, et al. Prior asymptomatic parenchymal hemorrhage does not increase the risk for intracranial hemorrhage after intravenous thrombolysis. Cerebrovasc Dis. 2015;40(5-6):201-204.
    doi pubmed
  8. Mowla A, Shah H, Lail NS, Shirani P. Acute pancreatitis in the setting of acute ischemic stroke. Arch Neurosci. 2017;4(2):e42957.
  9. Goyal M, Menon BK, van Zwam WH, Dippel DW, Mitchell PJ, Demchuk AM, Davalos A, et al. Endovascular thrombectomy after large-vessel ischaemic stroke: a meta-analysis of individual patient data from five randomised trials. Lancet. 2016;387(10029):1723-1731.
  10. Bhatia R, Hill MD, Shobha N, Menon B, Bal S, Kochar P, Watson T, et al. Low rates of acute recanalization with intravenous recombinant tissue plasminogen activator in ischemic stroke: real-world experience and a call for action. Stroke. 2010;41(10):2254-2258.
    doi pubmed
  11. Rai AT, Boo S, Buseman C, Adcock AK, Tarabishy AR, Miller MM, Roberts TD, et al. Intravenous thrombolysis before endovascular therapy for large vessel strokes can lead to significantly higher hospital costs without improving outcomes. J Neurointerv Surg. 2018;10(1):17-21.
    doi pubmed
  12. Mowla A, Doyle J, Lail NS, Rajabzadeh-Oghaz H, Deline C, Shirani P, Ching M, et al. Delays in door-to-needle time for acute ischemic stroke in the emergency department: A comprehensive stroke center experience. J Neurol Sci. 2017;376:102-105.
    doi pubmed
  13. Suzuki K, Kimura K, Takeuchi M, Morimoto M, Kanazawa R, Kamiya Y, Shigeta K, et al. The randomized study of endovascular therapy with versus without intravenous tissue plasminogen activator in acute stroke with ICA and M1 occlusion (SKIP study). Int J Stroke. 2019;14(7):752-755.
    doi pubmed
  14. Rajah G, Saber H, Lieber B, Kappel A, Smitt M, Chamiraju P, Narayanan S, et al. A moving target? The fate of large vessel occlusion strokes pretreated with intravenous tissue plasminogen activator in the era of mechanical thrombectomy. World Neurosurg. 2020.
    doi pubmed
  15. Kamal H, Mowla A, Farooq S, Shirani P. Recurrent ischemic stroke can happen in stroke patients very early after intravenous thrombolysis. J Neurol Sci. 2015;358(1-2):496-497.
    doi pubmed
  16. Powers WJ, Rabinstein AA, Ackerson T, Adeoye OM, Bambakidis NC, Becker K, Biller J, et al. Guidelines for the early management of patients with acute ischemic stroke: 2019 update to the 2018 guidelines for the early management of acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2019;50(12):e344-e418.
  17. Ferrigno M, Bricout N, Leys D, Estrade L, Cordonnier C, Personnic T, Kyheng M, et al. Intravenous recombinant tissue-type plasminogen activator: influence on outcome in anterior circulation ischemic stroke treated by mechanical thrombectomy. Stroke. 2018;49(6):1377-1385.
    doi pubmed
  18. Gariel F, Lapergue B, Bourcier R, Berge J, Barreau X, Mazighi M, Kyheng M, et al. Mechanical thrombectomy outcomes with or without intravenous thrombolysis. Stroke. 2018;49(10):2383-2390.
    doi pubmed
  19. Mokin M, Ansari SA, McTaggart RA, Bulsara KR, Goyal M, Chen M, Fraser JF, et al. Indications for thrombectomy in acute ischemic stroke from emergent large vessel occlusion (ELVO): report of the SNIS Standards and Guidelines Committee. J Neurointerv Surg. 2019;11(3):215-220.
    doi pubmed
  20. Jeong HS, Kwon HJ, Song HJ, Koh HS, Kim YS, Lee JH, Shin JE, et al. Impacts of rapid recanalization and collateral circulation on clinical outcome after intraarterial thrombolysis. J Stroke. 2015;17(1):76-83.
    doi pubmed

This article is distributed under the terms of the Creative Commons Attribution Non-Commercial 4.0 International License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Journal of Neurology Research is published by Elmer Press Inc.


Browse  Journals  


Journal of clinical Medicine Research

Journal of Endocrinology and Metabolism

Journal of Clinical Gynecology and Obstetrics


World Journal of Oncology

Gastroenterology Research

Journal of Hematology


Journal of Medical Cases

Journal of Current Surgery

Clinical Infection and Immunity


Cardiology Research

World Journal of Nephrology and Urology

Cellular and Molecular Medicine Research


Journal of Neurology Research

International Journal of Clinical Pediatrics



Journal of Neurology Research, bimonthly, ISSN 1923-2845 (print), 1923-2853 (online), published by Elmer Press Inc.             
The content of this site is intended for health care professionals.
This is an open-access journal distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License, which permits unrestricted
non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Creative Commons Attribution license (Attribution-NonCommercial 4.0 International CC-BY-NC 4.0)

This journal follows the International Committee of Medical Journal Editors (ICMJE) recommendations for manuscripts submitted to biomedical journals,
the Committee on Publication Ethics (COPE) guidelines, and the Principles of Transparency and Best Practice in Scholarly Publishing.

website: www.neurores.org   editorial contact: editor@neurores.org
Address: 9225 Leslie Street, Suite 201, Richmond Hill, Ontario, L4B 3H6, Canada

© Elmer Press Inc. All Rights Reserved.