When acute ischemic stroke occurs, the patient’s outcome depends on rapid clearance of the thrombus. Two of the primary treatments for stroke are IV thrombolysis with alteplase (rt-PA) and thrombectomy via endovascular therapy (EVT). Time is brain. What do you choose?

What are the latest guidelines on the time window for IV thrombolysis with rt-PA?

What are the inclusion and exclusion criteria for administering rt-PA?

Is the patient’s age a factor in deciding whether to administer rt-PA?

What are the two major complications from IV thrombolysis, and how should you manage them?

Can you perform EVT on a patient who has been given rt-PA? Should you?

What are the circumstances when thrombectomy is a better choice than IV thrombolysis?

How has the evidence for EVT evolved?

What are the best uses of CT angiography and CT perfusion in assessing patients with acute ischemic stroke?

1. Part 1: Intravenous Thrombolysis in Acute Ischemic Stroke
2. Part 2: Endovascular Therapy in Acute Ischemic Stroke
3. Abbreviation List
4. Abbreviations of Clinical Trials

Part 1: Intravenous Thrombolysis in Acute Ischemic Stroke

1. Introduction
2. Inclusion and Exclusion of Intravenous Thrombolysis: A Changing Landscape
   1. Hematologic Disorders and Previous Antithrombotic Treatment
   2. Seizures
   3. Minor Stroke
   4. Cerebral Microbleeds
   5. Glucose Disorders
   6. Myocardial Infarction and Other Cardiological Disorders
   7. Additional Recommendations
3. Intravenous Thrombolysis in Clinical Practice
4. Intravenous Thrombolysis Complications
   1. Hemorrhagic Transformation
      • Radiological Classification
      • Clinical Implications of Hemorrhagic Transformation
   2. Orolingual Angioedema
   3. “Wake-up” Stroke – Changing the Paradigm
5. New Thrombolysis Agents and Techniques
6. Conclusion
7. Tables and Figures
   1. Table 1. Eligibility Criteria and Exclusion Criteria for Intravenous Thrombolysis
   2. Table 2. American Heart Association Definitions of Classification of Recommendations
   3. Table 3. Management of Orolingual Angioedema Post Intravenous Thrombolysis
   4. Figure 1. Types of Hemorrhagic Transformation
8. References

Introduction

Stroke is the fifth leading cause of death in the United States and an important cause of long-term disability.¹ Approximately 795,000 people suffer from stroke each year (610,000 primary strokes and 185,000 recurrent strokes),¹ with ischemic stroke representing the vast majority of all stroke types (87%).² The cornerstone of acute ischemic stroke treatment relies on rapid clearance of an offending thrombus in the cerebrovascular system.³ Advanced neuroimaging and clinical trials, together with continuous adjustments of inclusion/exclusion criteria, have helped emergency clinicians to rapidly and more accurately identify the patients who will benefit from acute stroke treatment.

Alteplase (recombinant tissue plasminogen activator [rt-PA]) was the first drug approved by the United States Food and Drug Administration (FDA) for treatment of acute ischemic stroke. rt-PA is a protease derived by recombinant DNA technology that activates fibrin-bound plasminogen, leading to plasmin formation and the disintegration of fibrin clots.^4,5 In 1995, the National Institute of Neurological Disorders and Stroke (NINDS) Recombinant Tissue Plasminogen Activator trial showed that patients suffering from ischemic stroke who received intravenous (IV) rt-PA in a dose of 0.9 mg/kg within 3 hours of symptom onset had a more favorable outcome at 3 months than those who received placebo (odds ratio [OR] 1.7; 95% confidence interval [CI], 1.2 to 2.6; P = .008).⁶ Since then, other studies and randomized controlled trials have confirmed the safety and efficacy of IV thrombolysis (IVT).^7-12

In 2008, the ECASS III study¹³ showed a statistically significant benefit in selected patients treated with IV rt-PA between 3 hours and 4.5 hours from symptom onset. Additional studies have supported the use of IVT in a time window as late as 4.5 hours after symptom onset.^14-16 The IST-3 trial attempted to extend the time window for IVT administration beyond the 4.5-hour time window, but was unable to show a meaningful improvement in outcome beyond that time point.¹⁷ However, the recently published EXTEND trial reveals promising results for extending the time window up to 9 hours, in selected populations.¹⁸ The benefit of IVT in favorable neurologic outcome has been demonstrated to persist at both 3 and 12 months after stroke occurrence.^6,19

Tables and Figures

References

Evidence-based medicine requires a critical appraisal of the literature based upon study methodology and number of subjects. Not all references are equally robust. The findings of a large, prospective, randomized, and blinded trial should carry more weight than a case report.

To help the reader judge the strength of each reference, pertinent information about the study, such as the type of study and the number of patients in the study is included in bold type following the references, where available.

1. Benjamin EJ, Virani SS, Callaway CW, et al. Heart disease and stroke statistics-2018 update: a report from the American Heart Association. Circulation. 2018;137(12):e67-e492. (Guidelines)
2. Roger VL, Go AS, Lloyd-Jones DM, et al. Heart disease and stroke statistics--2011 update: a report from the American Heart Association. Circulation. 2011;123(4):e18-e209. (Guidelines)
3. Bivard A, Lin L, Parsonsb MW. Review of stroke thrombolytics. J Stroke. 2013;15(2):90-98. (Systematic review)
4. Collen D, Dewerchin M, Rapold HJ, et al. Thrombolytic and pharma-cokinetic properties of a conjugate of recombinant single-chain urokinase-type plasminogen activator with a monoclonal antibody specific for cross-linked fibrin in a baboon venous thrombosis model. Circulation. 1990;82(5):1744-1753. (Basic research)
5. Marder VJ, Novokhatny V. Direct fibrinolytic agents: biochemical attributes, preclinical foundation and clinical potential. J Thromb Haemost. 2010;8(3):433-444. (Systematic review)
6. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke N Engl J Med. 1995;333(24):1581-1587. (Randomized double-blind trial; Part 1: 291 patients, Part 2: 333 patients)
7. Saver JL. Number needed to treat estimates incorporating effects over the entire range of clinical outcomes: novel derivation method and application to thrombolytic therapy for acute stroke. Arch Neurol. 2004;61(7):1066-1070. (Randomized controlled trial)
8. Wardlaw JM, Murray V, Berge E, et al. Thrombolysis for acute ischaemic stroke. Cochrane Database Syst Rev. 2014(7):CD000213. (Cochrane review; 27 trials, 10,187 patients)
9. Hacke W, Donnan G, Fieschi C, et al. Association of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials. Lancet. 2004;363(9411):768-774. (Pooled analysis; 3 trials)
10. Wardlaw JM, Murray V, Berge E, et al. Recombinant tissue plasminogen activator for acute ischaemic stroke: an updated systematic review and meta-analysis. Lancet. 2012;379(9834):2364-2372. (Systematic review and meta-analysis; 12 trials, 7012 patients)
11. Wahlgren N, Ahmed N, Davalos A, et al. Thrombolysis with alteplase for acute ischaemic stroke in the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST): an observational study. Lancet. 2007;369(9558):275-282. (Observational study; 6483 patients)
12. Hacke W, Kaste M, Fieschi C, et al. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. The European Cooperative Acute Stroke Study (ECASS). JAMA. 1995;274(13):1017-1025. (Randomized double-blind placebo-controlled clinical trial; 109 patients)
13. Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med. 2008;359(13):1317- 1329. (Randomized double-blind controlled trial; 821 patients)
14. Wahlgren N, Ahmed N, Davalos A, et al. Thrombolysis with alteplase 3-4.5 h after acute ischaemic stroke (SITS-ISTR): an observational study. Lancet. 2008;372(9646):1303-1309. (Prospective study; 12,529 patients)
15. Bluhmki E, Chamorro A, Davalos A, et al. Stroke treatment with al-teplase given 3.0-4.5 h after onset of acute ischaemic stroke (ECASS III): additional outcomes and subgroup analysis of a randomised controlled trial. Lancet Neurol. 2009;8(12):1095-1102. (Randomized double-blind controlled trial; 418 patients)
16. Ahmed N, Wahlgren N, Grond M, et al. Implementation and outcome of thrombolysis with alteplase 3-4.5 h after an acute stroke: an updated analysis from SITS-ISTR. Lancet Neurol. 2010;9(9):866-874. (Observational study; 23,942 patients)
17. IST Collaborative Group, Sandercock P, Wardlaw JM, et al. The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (the Third International Stroke Trial [IST-3]): a randomised controlled trial. Lancet. 2012;379(9834):2352-2363. (Multicenter randomized open-treatment trial; 3035 patients)
18. Ma H, Campbell BCV, Parsons MW, et al. Thrombolysis guided by perfusion imaging up to 9 hours after onset of stroke. N Engl J Med. 2019;380(19):1795-1803. (Multicenter randomized placebo-controlled trial; 225 patients)
19. Fischer U, Mono ML, Zwahlen M, et al. Impact of thrombolysis on stroke outcome at 12 months in a population: the Bern stroke project. Stroke. 2012;43(4):1039-1045. (Prospective study; 807 patients)
20. Powers WJ, Rabinstein AA, Ackerson T, et al. 2018 guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/ American Stroke Association. Stroke. 2018;49(3):e46-e110. (Guidelines)
21. Wechsler LR. Intravenous thrombolytic therapy for acute ischemic stroke. N Engl J Med. 2011;364(22):2138-2146. (Systematic review)
22. Jauch EC, Saver JL, Adams HP Jr, et al. Guidelines for the early man-agement of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2013;44(3):870-947. (Guidelines)
23. Tsivgoulis G, Katsanos AH, Mavridis D, et al. Intravenous thrombolysis for ischemic stroke patients on dual antiplatelets. Ann Neurol. 2018;84(1):89-97. (Retrospective analysis of prospectively collected data; 2086 patients)
24. De Silva DA, Manzano JJ, Chang HM, et al. Reconsidering recent myocardial infarction as a contraindication for IV stroke thrombolysis. Neurology. 2011;76(21):1838-1840. (Systematic review)
25. Patel MR, Meine TJ, Lindblad L, et al. Cardiac tamponade in the fibrinolytic era: analysis of >100,000 patients with ST-segment elevation myocardial infarction. Am Heart J. 2006;151(2):316-322. (Meta-analysis; 102,060 patients)
26. Kremen SA, Wu MN, Ovbiagele B. Hemopericardium following intravenous thrombolysis for acute ischemic stroke. Cerebrovasc Dis. 2005;20(6):478-479. (Case report)
27. Emberson J, Lees KR, Lyden P, et al. Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of individual patient data from randomised trials. Lancet. 2014;384(9958):1929-1935. (Meta-analysis; 9 trials, 6756 patients)
28. Meretoja A, Strbian D, Mustanoja S, et al. Reducing in-hospital delay to 20 minutes in stroke thrombolysis. Neurology. 2012;79(4):306-313. (Retrospective analysis of prospectively collected data; 1860 patients)
29. Meretoja A, Weir L, Ugalde M, et al. Helsinki model cut stroke throm-bolysis delays to 25 minutes in Melbourne in only 4 months. Neurology. 2013;81(12):1071-1076. (Retrospective analysis of prospectively collected data; 48 patients)
30. White-Bateman SR, Schumacher HC, Sacco RL, et al. Consent for intravenous thrombolysis in acute stroke: review and future directions. Arch Neurol. 2007;64(6):785-792. (Systematic review)
31. Larrue V, von Kummer RR, Muller A, et al. Risk factors for severe hemorrhagic transformation in ischemic stroke patients treated with recombinant tissue plasminogen activator: a secondary analysis of the European- Australasian Acute Stroke Study (ECASS II). Stroke. 2001;32(2):438-441. (Secondary analysis of randomized controlled trial; 450 patients)
32. Paciaroni M, Agnelli G, Corea F, et al. Early hemorrhagic transformation of brain infarction: rate, predictive factors, and influence on clinical outcome: results of a prospective multicenter study. Stroke. 2008;39(8):2249-2256. (Prospective multicenter study; 1125 patients)
33. Thomalla G, Sobesky J, Kohrmann M, et al. Two tales: hemorrhagic transformation but not parenchymal hemorrhage after thrombolysis is related to severity and duration of ischemia: MRI study of acute stroke patients treated with intravenous tissue plasminogen activator within 6 hours. Stroke. 2007;38(2):313-318. (Retrospective analysis of prospectively collected data; 152 patients)
34. Barber PA, Demchuk AM, Zhang J, et al. Validity and reliability of a quantitative computed tomography score in predicting outcome of hyperacute stroke before thrombolytic therapy. ASPECTS Study Group. Alberta Stroke Programme Early CT Score. Lancet. 2000;355(9216):1670-1674. (Prospective study; 203 patients)
35. Demchuk AM, Hill MD, Barber PA, et al. Importance of early ischemic computed tomography changes using ASPECTS in NINDS rt-PA Stroke Study. Stroke. 2005;36(10):2110-2115. (Prospective study; 608 CT scans)
36. Lou M, Safdar A, Mehdiratta M, et al. The HAT score: a simple grading scale for predicting hemorrhage after thrombolysis. Neurology. 2008;71(18):1417-1423. (Grading scale development)
37. Strbian D, Engelter S, Michel P, et al. Symptomatic intracranial hemorrhage after stroke thrombolysis: the SEDAN score. Ann Neurol. 2012;71(5):634-641. (Grading scale development; 974 patients)
38. Mazya M, Egido JA, Ford GA, et al. Predicting the risk of symptomatic intracerebral hemorrhage in ischemic stroke treated with intravenous alteplase: safe Implementation of Treatments in Stroke (SITS) symptomatic intracerebral hemorrhage risk score. Stroke. 2012;43(6):1524- 1531. (Prospective study; 31,627 patients)
39. Asuzu D, Nystrom K, Amin H, et al. TURN: a simple predictor of symptomatic intracerebral hemorrhage after IV thrombolysis. Neurocrit Care. 2015;23(2):166-171. (Retrospective analysis of prospectively collected data; 1336 patients, validation cohort 983 patients)
40. Strbian D, Michel P, Seiffge DJ, et al. Symptomatic intracranial hemorrhage after stroke thrombolysis: comparison of prediction scores. Stroke. 2014;45(3):752-758. (Retrospective analysis of prospectively collected data; 3012 patients)
41. Anderson CS, Robinson T, Lindley RI, et al. Low-dose versus standard-dose intravenous alteplase in acute ischemic stroke. N Engl J Med. 2016;374(24):2313-2323. (Randomized controlled trial; 1607 patients)
42. Goldstein JN, Marrero M, Masrur S, et al. Management of thrombol-ysis-associated symptomatic intracerebral hemorrhage. Arch Neurol. 2010;67(8):965-969. (Retrospective analysis of prospectively collected data; 311 patients)
43. French KF, White J, Hoesch RE. Treatment of intracerebral hemorrhage with tranexamic acid after thrombolysis with tissue plasminogen activator. Neurocrit Care. 2012;17(1):107-111. (Case report)
44. Yaghi S, Eisenberger A, Willey JZ. Symptomatic intracerebral hemorrhage in acute ischemic stroke after thrombolysis with intravenous recombinant tissue plasminogen activator: a review of natural history and treatment. JAMA Neurol. 2014;71(9):1181-1185. (Systematic review)
45. Albers GW, Bates VE, Clark WM, et al. Intravenous tissue-type plasminogen activator for treatment of acute stroke: the Standard Treatment with Alteplase to Reverse Stroke (STARS) study. JAMA. 2000;283(9):1145-1150. (Prospective mulitcenter study; 389 patients)
46. Engelter ST, Fluri F, Buitrago-Tellez C, et al. Life-threatening orolingual angioedema during thrombolysis in acute ischemic stroke. J Neurol. 2005;252(10):1167-1170. (Observational study; 120 patients)
47. Hill MD, Lye T, Moss H, et al. Hemi-orolingual angioedema and ACE in-hibition after alteplase treatment of stroke. Neurology. 2003;60(9):1525- 1527. (Prospective study; 176 patients)
48. Myslimi F, Caparros F, Dequatre-Ponchelle N, et al. Orolingual angioedema during or after thrombolysis for cerebral ischemia. Stroke. 2016;47(7):1825-1830. (Prospective study; 923 patients)
49. Pahs L, Droege C, Kneale H, et al. A novel approach to the treatment of orolingual angioedema after tissue plasminogen activator adminis-tration. Ann Emerg Med. 2016;68(3):345-348. (Case report)
50. Mackey J, Kleindorfer D, Sucharew H, et al. Population-based study of wake-up strokes. Neurology. 2011;76(19):1662-1667. (Population-based study; 1854 patients)
51. Fink JN, Kumar S, Horkan C, et al. The stroke patient who woke up: clinical and radiological features, including diffusion and perfusion MRI. Stroke. 2002;33(4):988-993. (Prospective study; 364 patients)
52. Michel P, Ntaios G, Reichhart M, et al. Perfusion-CT guided intravenous thrombolysis in patients with unknown-onset stroke: a randomized, double-blind, placebo-controlled, pilot feasibility trial. Neuroradiol-ogy. 2012;54(6):579-588. (Randomized double-blind pilot trial; 12 patients)
53. Michel P, Odier C, Rutgers M, et al. The Acute STroke Registry and Analysis of Lausanne (ASTRAL): design and baseline analysis of an ischemic stroke registry including acute multimodal imaging. Stroke. 2010;41(11):2491-2498. (Registry design; 1633 patients)
54. Nogueira RG, Gupta R, Jovin TG, et al. Predictors and clinical relevance of hemorrhagic transformation after endovascular therapy for anterior circulation large vessel occlusion strokes: a multicenter retrospective analysis of 1122 patients. J Neurointerv Surg. 2015;7(1):16-21. (Retrospective analysis; 1122 patients)
55. Albers GW, Marks MP, Kemp S, et al. Thrombectomy for stroke at 6 to 16 hours with selection by perfusion imaging. N Engl J Med. 2018;378(8):708-718. (Multicenter randomized open-label trial with blinded outcome assessment; 182 patients)
56. Thomalla G, Simonsen CZ, Boutitie F, et al. MRI-guided thrombolysis for stroke with unknown time of onset. N Engl J Med. 2018;379(7):611- 622. (Randomized controlled trial; 503 patients)
57. Huang X, Cheripelli BK, Lloyd SM, et al. Alteplase versus tenecteplase for thrombolysis after ischaemic stroke (ATTEST): a phase 2, randomised, open-label, blinded endpoint study. Lancet Neurol. 2015;14(4):368-376. (Randomized open-label blinded endpoint study; 104 patients)
58. Parsons M, Spratt N, Bivard A, et al. A randomized trial of tenecteplase versus alteplase for acute ischemic stroke. N Engl J Med. 2012;366(12):1099-1107. (Randomized phase 2 trial; 75 patients)
59. Haley EC, Jr, Thompson JL, Grotta JC, et al. Phase IIB/III trial of te-necteplase in acute ischemic stroke: results of a prematurely terminated randomized clinical trial. Stroke. 2010;41(4):707-711. (Randomized double-blind controlled phase 2B/3 trial; 112 patients)
60. Logallo N, Novotny V, Assmus J, et al. Tenecteplase versus alteplase for management of acute ischaemic stroke (NOR-TEST): a phase 3, randomised, open-label, blinded endpoint trial. Lancet Neurol. 2017;16(10):781-788. (Randomized open-label blinded endpoint study; 1100 patients)
61. Campbell BCV, Mitchell PJ, Churilov L, et al. Tenecteplase versus alteplase before thrombectomy for ischemic stroke. N Engl J Med. 2018;378(17):1573-1582. (Randomized open-label, blinded outcome study; 202 patients)
62. No authors listed. Randomised controlled trial of streptokinase, aspirin, and combination of both in treatment of acute ischaemic stroke. Multicentre Acute Stroke Trial--Italy (MAST-I) Group. Lancet. 1995;346(8989):1509-1514. (Randomized controlled trial; 662 patients)
63. Multicenter Acute Stroke Trial--Europe Study Group, Hommel M, Cornu C, et al. Thrombolytic therapy with streptokinase in acute ischemic stroke. N Engl J Med. 1996;335(3):145-150. (Randomized controlled trial; 310 patients)
64. Donnan GA, Davis SM, Chambers BR, et al. Streptokinase for acute ischemic stroke with relationship to time of administration: Australian Streptokinase (ASK) Trial Study Group. JAMA. 1996;276(12):961-966. (Randomized double-blind placebo-controlled trial; 340 patients)
65. Hacke W, Furlan AJ, Al-Rawi Y, et al. Intravenous desmoteplase in patients with acute ischaemic stroke selected by MRI perfusion-diffusion weighted imaging or perfusion CT (DIAS-2): a prospective, randomised, double-blind, placebo-controlled study. Lancet Neurol. 2009;8(2):141-150. (Randomized double-blind placebo-controlled trial; 186 patients)
66. Hacke W, Albers G, Al-Rawi Y, et al. The Desmoteplase in Acute Isch-emic Stroke Trial (DIAS): a phase II MRI-based 9-hour window acute stroke thrombolysis trial with intravenous desmoteplase. Stroke. 2005;36(1):66-73. (Randomized double-blind placebo-controlled phase 2 trial; 104 patients)
67. von Kummer R, Mori E, Truelsen T, et al. Desmoteplase 3 to 9 hours after major artery occlusion stroke: the DIAS-4 Trial (efficacy and safety study of desmoteplase to treat acute ischemic stroke). Stroke. 2016;47(12):2880-2887. (Randomized double-blind placebo-controlled phase 3 trial; 270 patients)
68. Albers GW, von Kummer R, Truelsen T, et al. Safety and efficacy of desmoteplase given 3-9 h after ischaemic stroke in patients with occlusion or high-grade stenosis in major cerebral arteries (DIAS-3): a double-blind, randomised, placebo-controlled phase 3 trial. Lancet Neurol. 2015;14(6):575-584. (Randomized double-blind placebo-controlled phase 3 trial; 492 patients)
69. Pancioli AM, Broderick J, Brott T, et al. The combined approach to lysis utilizing eptifibatide and rt-PA in acute ischemic stroke: the CLEAR stroke trial. Stroke. 2008;39(12):3268-3276. (Randomized double-blind dose escalation and safety study; 94 patients)
70. Nacu A, Kvistad CE, Naess H, et al. NOR-SASS (Norwegian Sonothrombolysis in Acute Stroke Study): randomized controlled contrast-enhanced sonothrombolysis in an unselected acute ischemic stroke population. Stroke. 2017;48(2):335-341. (Randomized double-blind controlled trial; 183 patients)

Part 2: Endovascular Therapy in Acute Ischemic Stroke

1. The Evolution of Medical and Endovascular Management of Acute Ischemic Stroke
2. Current Evidence for Endovascular Thrombectomy
3. Patient Selection
   1. Age
   2. Duration of Symptoms
   3. Stroke Severity
   4. Premorbid Functional Status
   5. Occlusion Location
      • Tandem Occlusion
4. Imaging
   1. Computed Tomography
   2. Computed Tomographic Angiography
   3. Computed Tomographic Perfusion
   4. Magnetic Resonance Imaging
5. rt-PA Status
6. Technique
   1. Vascular Access
   2. Catheter System Setup
   3. Balloon Guide Catheters
   4. Thrombectomy Devices
7. Future Directions and Systems of Care
8. Figures
   1. Figure 1. Application of CT Perfusion in Management of a Patient With Acute Stroke
   2. Figure 2. Distal Anterior Cerebral Artery Thrombectomy
   3. Figure 3. Evaluation of Ischemic Changes on Brain CT Scan
   4. Figure 4. CT Perfusion Modalities and Their Interpretation in Acute Stroke
   5. Figure 5. Trans-Radial Approach for Acute Thrombectomy
   6. Figure 6. Challenging Arterial Anatomy for Thrombectomy in a Patient With Acute Stroke
9. References

The Evolution of Medical and Endovascular Management of Acute Ischemic Stroke

The studies that heralded the 1996 United States Food and Drug Administration (FDA) approval of recombinant tissue plasminogen activator (rt-PA; also known as alteplase) as the first medication for the treatment of acute ischemic stroke set the stage for a new age of hyperacute stroke interventions.^1,2 In spite of the impact of intravenous (IV) rt-PA on the treatment of acute ischemic stroke, some patients do not respond to the drug, particularly those patients who harbor an embolus lodged in a vessel that is too large for the medication to lyse. There are studies showing that large-vessel occlusions may respond to rt-PA in only some patients.¹ In addition, many patients are ineligible for IV rt-PA because treatment requires that the patient receive the drug within 3 hours from the time of stroke onset (4.5 hours in selected patients).² Many patients are excluded from IV rt-PA due to medical and surgical exclusion criteria.

The first trial of intra-arterial thrombolytic treatment was published in 1998 when the PROACT I study demonstrated the safety and efficacy of intra-arterial (IA) prourokinase (pro-UK) in the treatment of patients with a large-vessel occlusion of the middle cerebral artery (MCA).³ In this study, patients were randomized to treatment with either a continuous infusion of IV heparin alone or heparin plus treatment with pro-UK, infused intra-arterially via an endovascularly placed catheter. Patients in the pro-UK arm were found to have higher recanalization rates compared with the control group, although in patients treated with pro-UK, there was a non–statistically significant trend toward a higher rate of intracerebral hemorrhage.

One of the earliest mechanical devices aimed at endovascular lysis of a cerebrovascular clot was the EKOS MicroLysis^® Micro-infusion (EKOS corporation, Bothell, WA), which implemented a combination of mechanical disruption and ultrasound for clot lysis.⁴ Another early device, the MERCI^® Retriever (Concentric Medical, CA) is a corkscrew-like device that engages and retrieves the target clot.⁵ Penumbra (Penumbra, Inc., Alameda, CA) introduced its first separator aspiration-based systems in 2007, which break down the clot locally by mechanical disruption, then aspirate the fragments via large-bore catheters.⁶ Each of these devices has been evaluated in single-arm studies that have shown modest recanalization rates and better functional outcomes compared to their nonrandomized matched patients from the National Institute of Neurological Disorders and Stroke (NINDS) rt-PA study.^4,5,7,8

In 2013, IMS-III, SYNTHESIS, and MR RESCUE, 3 long-anticipated randomized controlled trials of endovascular management of stroke, were published and demonstrated no additional benefit of endovascular therapy (EVT) over medical treatment.^9-11 In hindsight, there were many factors that contributed to the failure of these studies to demonstrate a benefit for EVT in the treatment of large-vessel occlusion. By the time of the conclusion of IMS-III, the majority of the devices used in it were considered obsolete by practice standards of the day.

Retrievable stents, also known as stent-retrievers or stentrievers (eg, Solitaire [ev3/Covidien, Irvine, CA, USA] and Trevo [Stryker, Kalamazoo, MI, USA]) and large-bore aspiration catheters (eg, Penumbra aspiration system [Penumbra, Inc., Alameda, CA]) have demonstrated superiority in achieving vessel recanalization in head-to-head trials with older devices such as EKOS and the Penumbra separator.¹² Broussalis et al demonstrated that the rates of successful recanalization in patients treated with stentrievers was 82% compared with only 62% in patients treated with MERCI retrievers (P = .016).¹² A major critique of the IMS-III trial was poor patient selection, because patients were enrolled on the basis of clinical stroke severity rather than on direct confirmation of the presence of a large-vessel occlusion using noninvasive computed tomographic (CT) angiography imaging. The most critical lesson learned from those trials is that clinical benefit is highly dependent on timely recanalization. In the IMS-I and IMS-II populations, every 30-minute delay in recanalization was associated with a 10% decrease in the chance of functional independence (defined as a modified Rankin scale [mRS] score of ≤ 2).

Figures

References

Evidence-based medicine requires a critical appraisal of the literature based upon study methodology and number of subjects. Not all references are equally robust. The findings of a large, prospective, randomized, and blinded trial should carry more weight than a case report.

To help the reader judge the strength of each reference, pertinent information about the study, such as the type of study and the number of patients in the study is included in bold type following the references, where available.

1. Linfante I, Llinas RH, Selim M, et al. Clinical and vascular outcome in internal carotid artery versus middle cerebral artery occlusions after intravenous tissue plasminogen activator. Stroke. 2002;33(8):2066-2071. (Retrospective; 36 patients)
2. Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med. 2008;359(13):1317- 1329. (Randomized double-blind controlled trial; 821 patients)
3. del Zoppo GJ, Higashida RT, Furlan AJ, et al. PROACT: a phase II randomized trial of recombinant pro-urokinase by direct arterial delivery in acute middle cerebral artery stroke. PROACT Investigators. Prolyse in Acute Cerebral Thromboembolism. Stroke. 1998;29(1):4-11. (Prospective randomized controlled trial; 46 patients)
4. The Interventional Management of Stroke (IMS) II study. Stroke. 2007;38(7):2127-2135. (Prospective randomized trial; 81 patients)
5. Smith WS, Sung G, Starkman S, et al. Safety and efficacy of mechanical embolectomy in acute ischemic stroke: results of the MERCI trial. Stroke. 2005;36(7):1432-1438. (Prospective randomized controlled trial; 151 patients)
6. The Penumbra Pivotal Stroke Trial Investigators. The penumbra pivotal stroke trial: safety and effectiveness of a new generation of mechanical devices for clot removal in intracranial large vessel occlusive disease. Stroke. 2009;40(8):2761-2768. (Prospective randomized controlled trial; 125 patients)
7. IMS Study Investigators. Combined intravenous and intra-arterial recanalization for acute ischemic stroke: the Interventional Management of Stroke Study. Stroke. 2004;35(4):904-911. (Prospective randomized trial; 80 patients)
8. Smith WS, Sung G, Saver J, et al. Mechanical thrombectomy for acute ischemic stroke: final results of the Multi MERCI trial. Stroke. 2008;39(4):1205-1212. (Prospective randomized controlled trial; 164 patients)
9. Ciccone A, Valvassori L. Endovascular treatment for acute ischemic stroke. N Engl J Med. 2013;368(25):2433-2434. (Prospective randomized controlled trial; 362 patients)
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Abbreviation List

Abbreviations of Clinical Trials