12 Strokes: A Case-based Guide to Acute Ischemic Stroke Management

This comprehensive, case-based resource provides the state-of-the-art knowledge that can help readers improve access and optimize delivery of stroke thrombectomy.  Improving access to stroke is of particular importance because patients often misinterpret their symptoms or cannot speak for themselves if they have aphasia.  More importantly, access needs to be organized because stroke therapies are all extremely time-sensitive.  Scalable, choreographed protocols are necessary for emergency medical systems to ‘capture’ stroke patients and automatically transport and triage to time-sensitive treatments.  Many of the chapters in the first section on Fundamentals and Systems provide valuable insight in improving access to stroke care.   Replete with illustrative case studies and emphasizing that treatment approaches to stroke should not be comprised of a one-size-fits-all approach, this illuminating title provides the complete thought, detail, insight and organization that will help readers meet the needs of stroke patients with large vessel occlusions.  12 Strokes: A Case-based Guide to Acute Ischemic Stroke Management examines the primary technical principles that underlie the current thrombectomy approaches.  Instead of continuing the conceptual dichotomy of stent vs. aspiration, many of the chapters look at underlying principles and then discuss ways in which the currently available devices and approaches can best exploit them.  The variety, creativity and detail in many of these chapters will help the reader develop a deeper understanding that might assist their ability to successfully take care of their next patient that ‘doesn’t follow the textbook.’  In addition, the anatomic and pathophysiologic classification of the core Twelve Chapters will help readers organize their thinking and approach.  This knowledge, particularly because it is organized based on common, challenging syndromes, will arm the reader to quickly recognize patterns and deftly adapt their management approaches to the needs of the patient. 

An invaluable contribution to the clinical literature, 12 Strokes:  A Case-based Guide to Acute Ischemic Stroke Management will be of great interest to not only neurosurgeons and neurologists but other specialists, primary care providers, and trainees as well.

• Language: English
• Publisher: Springer
• Release date: Jan 11, 2021
• ISBN: 9783030568573

Book preview

Part IFundamentals and Systems

© Springer Nature Switzerland AG 2021

F. K. Hui et al. (eds.)12 Strokeshttps://doi.org/10.1007/978-3-030-56857-3_1

1. Evidence on Mechanical Thrombectomy in Acute Ischemic Stroke

Matias Negrotto¹   and Sami Al Kasab²

(1)

Hospital Maciel, Montevideo, Uruguay

(2)

Medical University of South Carolina, Department of Neurology, and Neurosurgery, Charleston, SC, USA

Keywords

Stroker-tPA treatmentLarge vessel occlusionsEndovascular

Goals of This Chapter

1.

Review the literature that forms the basis of mechanical thrombectomy in acute ischemic stroke for large vessel occlusion.

2.

Critically analyze steps to follow on stroke protocol and the decision to make endovascular treatment.

3.

Critically analyze the importance of imaging studies in this pathology.

Landmark Papers

Langhorne P1, Williams BO, Gilchrist W, Howie K. Do Stroke Units Save Lives? Lancet. 1993 Aug 14; 342(8868): 395–8

This seminal paper initiated the fertile ground for stroke treatment. This paper clearly demonstrated the newly introduced meta-analysis technique and identified that stroke units improved patient outcomes.

The authors performed a statistical overview of randomized controlled trials reported between 1962 and 1993 in which the management of stroke patients in a specialist unit was compared with that in general wards. They identified ten trials, eight of which used a strict randomization procedure. 1586 stroke patients were included: 766 allocated to a stroke unit and 820 to general wards. The odds ratio (stroke unit vs. general wards) for mortality within the first 4 months (median follow-up of 3 months) after the stroke was 0.72 (95% CI 0.56–0.92), consistent with a reduction in mortality of 28% (2p < 0.01). This reduction persisted (odds ratio 0.79, 95% CI 0.63–0.99, 2p < 0.05) when calculated for mortality during the first 12 months. The conclusion was that management of stroke patients in a stroke unit was associated with a sustained reduction in mortality.

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): 1581–7

r-tPA treatment: In 1995 the first study with a positive impact was published, being statistically significant regarding the use of IV r-tPA in ischemic stroke: NINDS2. It showed, at n = 333, that patients treated with IV r-tPA compared to placebo within 3 hours of onset of symptoms had at least 30% better outcome in terms of disability at 3 months. The patients with IV r-tPA had a 3-month mortality rate of 17% vs. 21% (p = 0.30); however, the percent hemorrhage was 6.4% vs. only 0.6 in control (p < 0.001). The findings were statistically significant with a clear benefit of IV r-tPA treatment, with a required number of treatment (NNT) of eight to obtain favorable results.

Hacke W, Kaste M, Bluhmki E, Brozman M, Dávalos A, Guidetti D, et al.; ECASS Investigators. Thrombolysis with Alteplase 3 to 4.5 Hours After Acute Ischemic Stroke. N Engl J Med 2008; 359 (13): 1317–29

In 2008, the second statistically significant study was published that supported treatment with IV r-tPA: ECASS III. This work increased the therapeutic window, extending the use of IV r-tPA within the first 4.5 hours of symptom onset. There was no difference in mortality, but it was favorable in terms of morbidity with an NNT of 14 for favorable results. Thus, from the results of these two seminal works, we have begun to implement this technique, with a level of evidence class 1A in the guidelines of the American Heart Association/American Stroke Association (AHA/ASA) of 2013/2014. Restoration of blood flow in patients with ischemic stroke is effective in reducing long-term morbidity. For patients meeting national and international eligibility guidelines, IV r-tPA improves functional outcomes at 3 and 6 months when given within the first 4.5 hours. It should be delivered as soon as possible, with better results shown the early it is given. Therefore, its administration must be initiated whenever there is a correct indication. This approach will help minimize start-to-treat times, a key efficacy factor for r-tPA [11, 12].

Acute large vessel ischemic strokes pose a significant challenge to intravenously administered thrombolytic therapy. Large vessel occlusion (LVO) is defined as the presence of occlusion of a large intracranial vessel (including both the anterior and posterior circulations) with a corresponding perfusion deficit on CT perfusion imaging indicative of an acute ischemic stroke that would be technically eligible for IA endovascular intervention. Specific segments (intracranial internal carotid artery (ICA), M1 and M2 segments of the middle cerebral artery, A1 and A2 anterior cerebral segments of the anterior cerebral artery, the basilar artery, V4 segment of the vertebral artery, and P1 and P2 segments of the posterior cerebral artery) are included [13].

Presence of an LVO is a significant predictor of outcome in patients undergoing stroke therapy, and unless recanalized, these patients do poorly [14, 15]. IV r-tPA has not been shown to be effective for recanalization of these proximal vessels [16] due to a large thrombus burden [17]and hence has limited efficacy in impacting outcomes [18].

Large vessel occlusions (LVOs) are responsible for significant proportions of AIS [19]and portend a dismal prognosis [20]. They are a major source of morbidity, mortality, and healthcare cost, and developing a focused treatment strategy for these patients was important. The data presented below strongly support endovascular therapy as a significant independent predictor of outcome compared with IV thrombolysis alone for large vessel occlusions.

Endovascular Treatment

The EVT of AIS has rapidly evolved rapidly over the past 20 years [21–23]. The first three multicenter, prospective, randomized, controlled trials (IMS III, SYNTHESIS, MR RESCUE) using first-generation devices (MERCI system) failed to show benefit of intra-arterial revascularization. In 2015, controlled clinical trials with a level of evidence class 1A (MR CLEAN, ESCAPE, EXTEND-IA, SWIFT PRIME, REVASCAT) forever changed the treatment paradigm for ischemic stroke. These studies demonstrated clear efficacy of endovascular treatment by mechanical thrombectomy in patients with ischemic stroke of less than 6 hours of evolution, with occlusion of large vessels of the anterior circulation. It was not only a crucial point in history of stroke but also in the history of medicine. For those who have lived through the transition from having no proven acute intervention to the introduction of thrombolytic and now endovascular therapy, this was an unforgettable moment. It was the most important event in stroke since the introduction of tPA in 1995.

Broderick JP, Palesch YY, Demchuk AM, Yeatts SD, Khatri P, Hill MD, et al. Endovascular Therapy After Intravenous t-PA versus t-PA Alone for Stroke. N Engl J Med. 2013;368:893–903 (IMS 3)

In March 2013, in a single issue the New England Journal of Medicine published three studies that evaluated the efficacy of endovascular treatment for ischemic stroke (IMS III, MR RESCUE, SYNTHESIS). In IMS III, a total of 656 participants underwent randomization (434 participants to endovascular therapy and 222 to intravenous tPA alone) at 58 study centers between August 25, 2006, and April 17, 2012 in the United States, Canada, Australia, and Europe. Eligibility criteria included receipt of intravenous tPA within 3 hours after symptom onset and a moderate-to-severe neurologic deficit (defined as an NIHSS score ≥10 or, after approval of amendment 3, a score of 8 to 9 with CT angiographic evidence of an occlusion of the first segment of the middle cerebral artery [M1], internal carotid artery, or basilar artery at institutions where CT angiographic imaging at baseline was the standard of care for patients with acute stroke). Participants randomly assigned to the endovascular-therapy group underwent angiography as soon as possible, either at the hospital that initiated treatment with intravenous tPA or at another participating hospital. Participants who had no angiographic evidence of a treatable occlusion received no additional treatment, and those with a treatable vascular occlusion received endovascular intervention. The angiographic procedure had to begin within 5 hours and be completed within 7 hours after the onset of stroke.

Reperfusion rates, as measured by a TICI score of 2b (partial reperfusion of half or more of the vascular distribution of the occluded artery) to 3, were 38% for an occlusion in the internal carotid artery, 44% for an occlusion in M1, 44% for a single M2 occlusion, and 23% for multiple M2 occlusions.

The trial was stopped early because of futility, according to the prespecified criteria. There was no significant difference between the endovascular-therapy and intravenous tPA groups in the overall proportion of participants with a modified Rankin score of 2 or less. It failed to show a benefit in functional outcome with the use of additional endovascular therapy, as compared with the standard therapy of intravenous tPA alone. The safety profiles were similar in the two treatment groups.

In MR RESCUE, 127 patients were randomized to embolectomy and studied clinical outcomes in subgroups with and without a penumbral pattern on MRI or CT of each treatment arm. They did not observe better revascularization, tissue reperfusion, and clinical outcomes in the embolectomy group compared to the standard care group.

The other trial, SYNTHESIS, compared the efficacy of thrombolytic treatment with respect to endovascular treatment with stent during the first 4.5 h. It included 362 patients (181 in each group). The study did not show significant differences in the rate of good prognosis (30.4% endovascular vs. 34.8% intravenous), in the hemorrhagic complications or mortality.

Numerous concerns regarding various aspects of these trials were raised by the neurointerventional community. First, only one of the three trials, MR RESCUE, routinely identified LVO with either computed tomography or magnetic resonance angiography (CTA or MRA, respectively). In IMS III, CTA was performed in only 47% of patients, and approximately 20% of patients in the interventional arm either did not have an LVO or had an inaccessible, distally located thrombus. In SYNTHESIS Expansion, approximately 10% of patients in the interventional arm did not have a LVO. Moreover, modern devices, such as retrievable stents (stentrievers) and the Penumbra System (Penumbra, Inc., Alameda, California, USA), were used in only a minority of patients. The use of older, less effective endovascular technology resulted in significantly low rates of successful recanalization, defined as thrombolysis in cerebral infarction (TICI) grade 2b or 3. The rates of TICI 2b or 3 recanalization were 40% in IMS III, 27% in MR RESCUE, and not reported in SYNTHESIS Expansion. In the IMS III trial, Solitaire was used in 5 of 434 patients randomized to endovascular treatment. In the SYNTHESIS Expansion trial, Solitaire (ev3/Covidien) and Trevo (Concentric/Stryker) were used in 23 of the 181 patients assigned to endovascular treatment. In MR RESCUE, no patient was treated with Solitaire or Trevo retriever. The low rates of Solitaire or Trevo use in all the abovementioned studies could partially explain the relatively low rates of partial or complete recanalization seen in these studies. Furthermore, patients with minor ischemic deficits were included, so these trials demonstrated that the benefit of endovascular treatment may be seen in patients with major ischemic deficits and not in those with minor ischemic stroke. Last but not least, patients in the interventional arm of SYNTHESIS Expansion were not administered IV-tPA, the use of which is supported by class I evidence, and were treated in a delayed fashion compared to the medical arm.

Despite the negative results, these studies pointed the way for new trials that justified this treatment modality (Table 1.1).

Table 1.1

Characteristics of trials mentioned above

O. Bekhemer, F. Beumer, V. Berg, H Lingsma, Y. Schonewile, V. Nederkoom: The Randomized Trial of Intraarterial Treatment for Acute Ischemic Stroke (MR CLEAN). The New England Journal of Medicine, January 2015, vol 372

The MR CLEAN was the first positive trial to be published in January 2015. It included 500 patients (233 intervention and 267 control group), aged more than 18 years and whose NIHSS was more than 2, with less than 6 hours of evolution since the onset of symptoms to treatment, confirming proximal vascular occlusion by CT angiography, with ASPECTS score of 7–10. IV r-tPA was performed on 90% of the patients (87% intervention vs. 91% control) with the disadvantage of a wait between the initiation of IV thrombolytic and endovascular therapy. No significant changes were observed in terms of mortality; however, there was a statistically significant decrease in morbidity with an mRS of 0–2: 33% with endovascular treatment vs. 19% control group. It had a relatively low reperfusion rate (59% TICI 2b/3), which was also explained by delayed onset of endovascular therapy.

One concern is that the sample size was rather small (500 patients); however, it allowed to estimate the primary effect parameter with sufficient precision. The use of multiple IAT modalities per patient was not restricted. This is a limitation of the trial design, because it will restrict the possibilities of comparing different treatment modalities and only allowed to give a global judgment whether or not IAT is effective. On the other hand, this pragmatism allows us to follow current practice closely and allows new mechanical devices and treatment strategies into the trial.

Time since onset is a serious concern. The arguments for a 6- or even 8-hour time window from onset of stroke symptoms to treatment are mostly based on tradition (previous studies of IAT also used this window) and the absence of an association of complications and treatment effect with time since onset in previous, mostly neutral trials [5].

M. Goyal, A. Demchuk, B. Menon, M. Eesa, J. Rempel, J. Thornton, D. Roy: Randomized Assay of Rapid Endovascular Treatment of Ischemic Stroke (ESCAPE). The New England Journal of Medicine, February 2015

ESCAPE included a total of 315 patients (165 intervention vs. 150 control), with an NIHSS of more than 12, an ASPECTS of more than 5, and a therapeutic window of 12 hours, with diagnosis of proximal occlusion by CT angiography and perfusion for evaluation of circulation. IV r-tPA was made in 76% of the patients (72.7% intervention vs. 78.6% control group). This study was stopped early because of the clear benefit and efficacy of endovascular treatment in the control group. A TICI 2b/3 reperfusion rate of 72% was observed, with a favorable outcome mRS of 0–2 of 53% with intervention vs. 29% control group (NNT = 4) and a decrease in mortality of 10% vs. 19% in the control group.

The trial was based on the premise that patients with large vessel occlusion of the anterior circulation with small to moderate infarct core and moderate to good collaterals identified on computed tomography (CT)-based imaging would benefit most from endovascular treatment if reperfusion was achieved quickly after imaging. In the ESCAPE trial, achieving a short imaging-to-reperfusion time significantly improved the chance of achieving a functionally independent outcome. Speed of treatment can be achieved in dedicated stroke centers with teamwork, parallel workflow, and a focus on quality improvement. Endovascular-capable hospitals should identify eligible patients by using quick and reliable imaging techniques and focus on achieving reperfusion as quickly and efficiently as possible [24].

B. Campbell, P. Mitchell, T. Kleinig, H. Dewey, L. Churilov, N. Yassi: Endovascular Therapy for Ischemic Stroke with Perfusion-Imaging Selection (EXTEND -IA). The New England Journal of Medicine, February 2015

EXTEND-IA was the smallest trial with n = 70 (35 intervention vs. 35 control). The selection criteria were based on perfusion images in patients with LVO, no age limits, no NIHSS limits, and time to treatment of less than 4.5 hours. RAPID software imaging was used for all the patients. IV r-tPA was done in 100% of patients; a TICI 2b/3 reperfusion rate of 86% was observed, with a favorable outcome mRS of 0–2 of 71% with intervention vs. 40% control group and a decrease in mortality of 9% vs. 20% in the control group.

They concluded that early endovascular thrombectomy with Solitaire FR after IV r-tPA resulted in greater reperfusion and early neurologic recovery than r-tPA alone in a population with LVO and salvageable tissue on CT perfusion imaging.

J. Saver, M. Mayank, A. Bonafe, M. Diener, P. Elad, I. Levy: Stent-Retriever Thrombectomy After Intravenous t-PA vs. t-PA Alone in Stroke (SWIFT PRIME). The New England Journal of Medicine, February 2015

In SWIFT PRIME, 196 cases were recruited (98 intervention vs. 98 control), aged 18–80 years, with an NIHSS of between 8 and 29 and ASPECTS of more than 6. 98% received IV r-tPA before 4.5 hours. Large vessel occlusion was diagnosed by CT angiography or MR angiography. RAPID software imaging was used for 80% of patients. A TICI 2b/3 reperfusion rate of 88% was achieved, with a favorable outcome mRS of 0–2 of 60% with intervention vs. 36% control group, with no significant changes in symptomatic intracranial hemorrhage (0% vs. 3%, P = 0.12).

There was no significant decrease in mortality.

In the SWIFT PRIME publication, the rate of functional independence, defined as a modified Rankin scale (mRS) score of 0 to 2, in the intervention group was 60% which was higher than that in MR CLEAN (33%) and similar to that observed in the ESCAPE trial (53%) and the EXTEND-IA trial (71%).

The better outcome results probably reflect the earlier start of the intervention, the exclusion of patients with large core infarcts on the basis of imaging, and the greater reperfusion rate in this trial.

Jovin, A. Chamorro, E. Cobo, M. Miquel, C. Molina, A. Rovira: Thrombectomy Within 8 Hours After Symptom Onset in Ischemic Stroke (REVASCAT). The New England Journal of Medicine, February 2015

REVASCAT assessed the efficacy of mechanical thrombectomy within 8 hours of symptom onset. 206 patients were included (103 vs. 103), aged between 18 and 80 years, with an NIHSS of more than 6, diagnosis of proximal occlusion by CT angiography, and ASPECTS of greater than 7. 73% received IV r-tPA; TICI 2b/3 was 66%, with clear favorable outcome mRS of 0–2 of 44% with intervention vs. 28% control group, with no significant changes in mortality. This study contributed evidence to support the efficacy of neurovascular thrombectomy in patients with anterior circulation stroke who could be treated within 8 hours after the onset of symptoms.

THE REVASCAT was stopped before formal stopping boundaries were reached, because of ethical considerations.

The magnitude of the observed benefit in the abovementioned trials was dramatic. The findings clearly show a superior outcome following treatment with IV thrombolysis and thrombectomy using modern thrombectomy devices compared with best medical treatment alone. The successes from these RCTs have been mostly attributed to improved thrombectomy devices with faster and higher rates of recanalization and better study protocols with documentation of vessel occlusion before randomization.

Raul G. Nogueira, MD; Ashutosh P. Jadhav, MD, PhD; Diogo C. Haussen, MD; Alain Bonafe, MD; Ronald F. Budzik, MD; Parita Bhuva, MD; et al. Thrombectomy 6 to 24 Hours After Stroke with a Mismatch Between Deficit and Infarct. N Engl J Med. January 4, 2018

The DAWN Trial is the first to evaluate the late-window and wake-up stroke patient population. This was a multicenter, prospective, randomized, open-label trial with a Bayesian adaptive-enrichment design and with blinded assessment of end points. This study supports the use of the Trevo retriever beyond the 8-hour time limit in wake-up, unclear-onset, and late-presenting ischemic stroke subjects.

The investigators selected patients arriving after 6 hours from symptom onset for inclusion in the trial by using imaging and clinical scores to identify those with target mismatch – a small core infarct volume but a large area of brain at risk for ischemia yet still potentially salvageable. RAPID software imaging was used for all the patients.

From September 2014 through February 2017, a total of 206 patients were enrolled in the trial; 107 were randomly assigned to the thrombectomy group and 99 to the control group.

For the DAWN trial, patients with a large vessel occlusion stroke presenting between 6 and 24 hours (average of 13 hours) underwent computed tomographic (CT) perfusion or magnetic resonance diffusion-weighted imaging. Patients were selected for inclusion and randomization to thrombectomy or control if they had a small infarct core in relation to their National Institutes of Health Stroke Scale (NIHSS) score. The exact requirements varied with age.

Patients had to have a mismatch between the severity of the clinical deficit and the infarct volume, which was defined according to the following criteria: Patients aged over 80 had to have an NIHSS score of over 10 and a core volume of less than 21 mL. For patients younger than 80 years, requirements were an NIHSS score of over 10 and a core volume of less than 31 mL or an NIHSS score of over 20 and a core volume of less than 51 mL.

Results showed a 2-point difference in the 90-day weighted modified Rankin scale (mRS) score in favor of the thrombectomy group, which translated into a 73% relative reduction of dependency in activities of daily living. In addition, there was a 35% absolute increase in the number of patients achieving functional independence (mRS score, 0 to 2), with a number needed to treat for this end point of 2.8.

The results of this trial expanded the population of patients who can benefit from mechanical thrombectomy for stroke, to significantly reduce functional impairment in the mostly severely affected patients.

The DAWN trial also showed that patients treated earlier had better outcomes, so the concept time is brain is unchanged, it is just that eligibility for treatment should not be restricted by time windows.

G.W. Albers, M.P. Marks, S. Kemp, S. Christensen, J.P. Tsai, S. Ortega-Gutierrez, et al. Thrombectomy for Stroke at 6 to 16 Hours with Selection by Perfusion Imaging. The New England Journal of Medicine, January 24, 2018

DEFUSE 3 was a multicenter, randomized, open-label trial, with blinded outcome assessment, of thrombectomy in patients 6 to 16 hours after they were last known to be well and who had remaining ischemic brain tissue that was not yet infarcted.

From May 2016 through May 2017, a total of 182 patients underwent randomization (92 to the endovascular-therapy group and 90 to the medical-therapy group) at 38 centers in the United States (Fig. 1.1).

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Fig. 1.1

DAWN and DEFUSE 3 selection criteria

Patients with proximal middle-cerebral-artery or internal-carotid-artery occlusion, an initial infarct size of less than 70 ml, and a ratio of the volume of ischemic tissue on perfusion imaging to infarct volume of 1.8 or more were randomly assigned to endovascular therapy (thrombectomy) plus standard medical therapy (endovascular-therapy group) or standard medical therapy alone (medical-therapy group). RAPID software imaging was used for all the patients.

The primary outcome was the ordinal score on the modified Rankin scale (range, 0 to 6, with higher scores indicating greater disability) at day 90. Endovascular therapy plus standard medical therapy was associated with a more favorable distribution of disability scores on the modified Rankin scale at 90 days than standard medical therapy alone. Mortality at 90 days was 14% in the endovascular-therapy group and 26% in the medical-therapy group (P = 0.05). The rate of symptomatic intracranial hemorrhage did not differ significantly between the two groups.

Recommendations and Level of Evidence

Pre-hospital stroke management: Stroke patients are dispatched at the highest level of care available in the shortest time possible. Travel time is equivalent to trauma or myocardial infarction calls [25].

Emergency evaluation and diagnosis of acute ischemic stroke: The evaluation and initial treatment of patients with stroke should be performed expeditiously. Because time is critical, a limited number of essential diagnostic tests are recommended [25].

Early diagnosis and brain and vascular imaging: An emergency brain imaging study is recommended prior to initiating any specific treatment for acute stroke (class I, level of evidence A) [26].

Noninvasive intracranial vascular study: If endovascular therapy is contemplated, this study is strongly recommended during the initial imaging evaluation of the acute stroke patient but should not delay intravenous r-tPA if indicated (class I, level of evidence A) [26].

When evaluating patients with AIS within 6 hours of last known normal with LVO and an Alberta Stroke Program Early Computed Tomography Score (ASPECTS) of ≥6, selection for mechanical thrombectomy based on CT and CTA or MRI and MRA is recommended in preference to performance of additional imaging such as perfusion studies (class I, level of evidence B) [26].

When selecting patients with AIS within 6 to 24 hours of last known normal who have LVO in the anterior circulation, obtaining CTP or DWI-MRI, with or without MRI perfusion, is recommended to aid in patient selection for mechanical thrombectomy, but only when patients meet other eligibility criteria from one of the RCTs that showed benefit from mechanical thrombectomy in this extended time window (class I, level of evidence A) [26].

Intravenous r-tPA (0.9 mg/kg, maximum dose 90 mg) is recommended for administration to eligible patients who can be treated in the time period of 3 to 4.5 hours after stroke onset (class I, level of evidence B) [26].

Patients eligible for intravenous r-tPA should receive intravenous r-tPA even if endovascular treatments are being considered (class I, level of evidence A) [27].

Observing patients after intravenous r-tPA to assess for clinical response before pursuing endovascular therapy is not required to achieve beneficial outcomes and is not recommended (class III, level of evidence B-R) [26].

Endovascular treatment 0 to 6 hours after onset: Patients should receive this therapy if they meet the following criteria (class I, level of evidence A) [26]:

(a)

Prestroke mRS score 0 to 1.

(b)

Acute ischemic stroke receiving intravenous r-tPA within 4.5 hours of onset according to guidelines from professional medical societies.

(c)

Large vessel occlusion.

(d)

Age ≥ 18 years.

(e)

NIHSS score of ≥6.

(f)

ASPECTS of ≥6.

(g)

Treatment can be initiated (groin puncture) within 6 hours of symptom onset.

Endovascular treatment 6 to 24 hours after onset: Patients should receive this therapy if they meet the following criteria (class I, level of evidence A) [26]:

(a)

In selected patients with AIS within 6 to 16 hours of last known normal who have LVO in the anterior circulation and meet other DAWN or DEFUSE 3 eligibility criteria, mechanical thrombectomy is recommended (class I, level of evidence A).

(b)

In selected patients with AIS within 16 to 24 hours of last known normal who have LVO in the anterior circulation and meet other DAWN eligibility criteria, mechanical thrombectomy is reasonable (class IIa, level of evidence B-R).

The technical goal of the thrombectomy procedure should be a TICI 2b/3 angiographic result to maximize the probability of a good functional clinical outcome (class I, level of evidence A) [26].

A finding of intracranial large vessel occlusion(s) during the initial diagnostic evaluation is strongly associated with worse functional outcome and higher mortality rate. Patients with emergent large vessel occlusion (ELVO) are a heterogeneous group requiring rapid and effective revascularization with the likelihood of benefit decreasing over time elapsed from symptom onset [27].

As already mentioned, endovascular treatment in cases not meeting strict criteria is allowable. Each patient should be discussed quickly, analyzing the level of occlusion, NIHSS at presentation, vascular anatomy, established infarct core, Alberta Stroke Program Early CT Score (ASPECTS), age, baseline functional status, and collateral circulation.

The role of mechanical thrombectomy could be significantly expanded if patients are selected based on risk of severe disability and favorable parenchymal/collateral imaging findings, instead of time and occlusion location [28].

Type of device: The use of retrievable stents is recommended with the highest level of evidence by American Heart Association (AHA), Canadian Stroke Best Practices (CSBP), and European Stroke Organisation (ESO) guidelines, with lower levels of recommendations given to consider other devices based on local protocols. An analysis of the MR CLEAN data showed that choice of device did not influence outcomes in that data set. The majority were treated with the Trevo device at 53%, Solitaire device at 13%, and other devices at 17% [29]. The other devices which can be used for mechanical thrombectomy is the aspiration Penumbra System (Penumbra, Inc., California, USA). Two randomized controlled trials compared the safety and efficacy of aspiration thrombectomy compared to stentriever and showed similar safety and efficacy profiles between the two techniques. The ASTER trial concluded that among patients with ischemic stroke in the anterior circulation undergoing thrombectomy, first-line thrombectomy with contact aspiration compared with stent retriever did not result in an increased successful revascularization rate at the end of the procedure [30]. The second trial is the COMPASS trial which confirmed the findings in ASTER [31, 32].

Interestingly, COMPASS showed that the use of aspiration first-line technique was associated with lower cost of approximately 4551 USD compared to stentriever.

Type of anesthesia: Conscious sedation is preferred over general anesthesia (unless medically indicated) by both AHA and CSBP recommendations, albeit with reduced levels of evidence (class IIb level C and level B, respectively), whereas the ESO guideline leaves this as an individual patient decision. Several RCTs are underway to address this issue [33].

Time – RAPID Software to Select Patients for Late-Window Endovascular Therapy

The substantial clinical benefits of late-window thrombectomy that were recently documented in the DAWN and DEFUSE 3 studies led to expansion of the treatment window for thrombectomy from 6 to 24 hours in the 2018 American Heart Association stroke guidelines.

DEFUSE and DAWN trials had a great impact on how ischemic stroke patients who present between 6 and 24 hours are assessed and treated. They had profound implications for treatment of stroke due to LVO, because they validate the biological (rather than chronological) approach to patient selection for endovascular therapy. They also allow many more patients with LVO stroke to be treated with mechanical thrombectomy.

The new clinical trial data and guidelines have led a large number of stroke centers to begin using advanced imaging with computed tomography perfusion (CTP) or magnetic resonance imaging (MRI) to evaluate patients who present with a possible large vessel occlusion in an extended time window. These techniques can provide quantitative estimates of ischemic core and penumbra without user input and have excellent interobserver agreement [34].

The new AHA guidelines recommend that DAWN or DEFUSE 3 eligibility should be strictly adhered to in clinical practice; therefore, it is important to understand how these trials selected eligible patients as it is explained in Fig. 1.1. The only imaging modalities that have been shown to be effective for selecting patients for late-window thrombectomy are CTP and MRI. Both trials used the Rapid Processing of Perfusion and Diffusion (RAPID) automated software platform (iSchemaView, Menlo Park, CA) to determine imaging eligibility for all patients. Imaging selection for patients in both DEFUSE 3 and DAWN required either CTP or MRI, with the majority being selected by CTP. As it was mentioned above, RAPID was also used in EXTEND-IA and SWIFT PRIME trials. RAPID software provides automated analysis in less than 2 minutes. In evidence-based trials, RAPID imaging technology has given healthcare professionals the data needed to make more informed treatment decisions, becoming an extremely valuable tool in the treatment of acute stroke.

Summary

1.

The understanding of the natural history of ischemic stroke and its treatment relies on multiple landmark papers. Endovascular thrombectomy is of benefit to most patients with acute ischemic stroke caused by occlusion of the proximal anterior circulation, irrespective of patient characteristics. Medical systems of care must be equipped to provide this life-saving treatment in a timely fashion to patients with acute ischemic stroke due to large vessel occlusion.

2.

We think that the concept time is brain is unchanged but we should have in mind the concept of penumbra is brain. Eligible patients should still be treated as quickly as possible; it is just that eligibility for treatment should not be restricted by time windows. No matter the time, if we have salvageable tissue in imaging studies, endovascular treatment should be done. We have to validate the biological (rather than chronological) approach to patient selection for endovascular therapy.

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