Abstract
Acute ischemic stroke is one of the leading causes of death and long-term disability in the United States. Intravenous thrombolysis with recombinant tissue-type plasminogen activator (rt-PA) has been the mainstay of acute therapy. However, multiple randomized clinical trials have been published that have shown higher rates of recanalization and improved functional outcomes with endovascular therapy compared with intravenous rt-PA in patients with ischemic stroke from large vessel occlusion. This article provides an update and discusses the role of endovascular therapy in management of acute ischemic stroke.
Introduction
Stroke is the leading cause of serious long-term disability and the fifth most common cause of death in the U.S. Ischemic stroke accounts for approximately 87% of all strokes in the U.S.1 For almost two decades, prompt administration of intravenous fibrinolytic treatment with recombinant tissue plasminogen activator (rt-PA), within 4.5 hours of the onset of symptoms in eligible patients, has been the standard of care in management of acute ischemic stroke.2 Despite improvement in functional outcomes at three to six months in patients who receive rt-PA, 3–5 the efficacy of IV rt-PA in achieving recanalization continues to be limited (Table 1). Limitations of rt-PA include - a narrow therapeutic time window (within 3 – 4.5 hours), resistance of an old or large thrombus to fibrinolysis, risks of systemic and cerebral hemorrhage and lower rates of recanalization in patients with proximal vessel occlusion. 4,7,12,13 This led to evolution of endovascular approaches devised to reduce clot burden, improve vessel recanalization, and hence improve functional outcomes. Table 2 describes the most commonly used terms in endovascular management of acute ischemic stroke.
Table 1.
Rate of recanalization | 20 – 46%6 |
Rate of death or disability | 47 – 61%4,7–10 |
Percentage of eligible patients who fail to receive rt-PA | 18–25%11 |
rt-PA – Recombinant tissue plasminogen activator
Table 2.
Time Last Known well | The time prior to hospital arrival at which the patient was last known to be without the signs and symptoms of the current stroke or at his or her baseline state of health. |
Endovascular Treatment | Catheter based approach that may include administration of intra-arterial thrombolytic, and/or mechanical clot retrieval (thrombectomy). |
The National Institute of Health Stroke Scale (NIHSS) | A 42-point score that objectively quantifies severity of neurological impairment from acute stroke. |
Recanalization | Complete or partial restoration of cerebral blood flow as determined on pre and post cerebral angiography. |
Alberta Stroke Program Early CT Score (ASPECTS) | A 10-point quantitative topographic CT scan score to determine early ischemic changes (<3 hours from symptoms onset) in anterior circulation stroke. |
Modified Rankin Score (mRS) | A 6-point disability score most widely used in stroke clinical trials to document outcome measure. |
Functional Independence | Defined by a mRS score of 0 – 2 |
Symptomatic Intracerebral Hemorrhage (sICH) | Radiographic appearance of hemorrhage associated with neurological deterioration post thrombolytic/endovascular therapy. |
Clinical Evidence
In 2013 three randomized controlled trials of endovascular treatment of acute ischemic stroke with primarily intra-arterial (IA) fibrinolysis and/or first generation-mechanical embolectomy devices were published: The Interventional Management of Stroke III (IMS III), 13 Magnetic Resonance and Recanalization of Stroke Clots Using Embolectomy (MR RESCUE)14 and Local versus Systemic Thrombolysis for Acute Ischemic Stroke (SYNTHESIS EXPANSION).15 The results showed that endovascular therapy was non superior to the standard treatment with intravenous rt-PA alone with similar safety outcomes and no significant differences in functional independence. On further analysis it was observed that patient selection criteria used in the these trials (included patients with minor ischemic stroke with NIHSS < 6), lack of arterial occlusion confirmation on imaging (CT or MR angiography), delayed time of endovascular intervention, mechanical thrombectomy as a sole endovascular treatment option and use of old generation thrombectomy devices/stent retrievers; may have contributed towards a lack of clinical benefit of endovascular therapy as compared to medical management.16
Learning from the shortcomings of these trials, in 2015 five landmark randomized controlled trials demonstrated improved clinical outcomes and rates of recanalization of occluded artery with use of new generation mechanical thrombectomy devices (stent retrievers) in acute ischemic stroke with large vessel occlusion in the anterior circulation (Table 3). This led to a paradigm shift in the management of acute ischemic stroke and formed the basis for updating the American Heart Association (AHA)/American Stroke Association guidelines in 2015, establishing the use of endovascular therapy in patients with acute ischemic stroke with a large vessel occlusion.2 Later a meta-analysis, comprising data from 1,287 patients was performed by the Highly Effective Reperfusion Evaluated in Multiple Endovascular Stroke Trials (HERMES) collaborators.22 The results showed that the proportion of patients achieving functional independence at 90 days (defined as modified Rankin Score of 0–2) was 46.0% in the intervention group (mechanical thrombectomy) compared with 26.5% in the control group (odds ratio: 2.35; 95% confidence interval [CI]: 1.85 to 2.98; p <0.0001). These findings further emphasized the benefit of endovascular treatment for management of acute ischemic stroke in anterior circulation large vessel occlusion over medical management and helped paved the way for establishing endovascular therapy as a standard of care for management of acute ischemic stroke in select patient population.
Table 3.
MR CLEAN17 | ESCAPE18 | SWIFT PRIME19 | EXTEND-IA20 | REVASCAT21 | |
---|---|---|---|---|---|
No of patients | 500 | 316 | 196 | 70 | 206 |
Age (years) | ≥18 | ≥18 | 18–80 | ≥18 | 18–85 |
NIHSS inclusion criteria | ≥2 | >5 | 8–29 | None | ≥6 |
Treatment Arm | IV rt-PA + IA UK/rt-PA/device | Stent retriever ± IV rt-PA | Stent retriever ± IV rt-PA | Stent retriever ± IV rt-PA | Stent retriever ± IV rt-PA |
Control Arm (Standard care) | ± IV rt-PA | ± IV rt-PA | ± IV rt-PA | ± IV rt-PA | ± IV rt-PA |
IV rt-PA use | 87% | 72.7% | 100% | 100% | 68% |
Median time from stroke onset to groin puncture (min) | 260 | 200 | 224 | 210 | 269 |
Use of Stent retriever | 81.5% | 86.1% | 89% | 77% | 95% |
Rate of recanalization [TICI 2b/3a] | 59% | 72.4% | 88% | 86% | 66% |
Functional Independence (mRS 0–2) | 32.6% vs. 19.1% | 53.0% vs. 29.3% | 60.0% vs. 35% | 71% vs. 40% | 43.7% vs. 28.2% |
Mortality/sICH | No significant difference in death or sICH | Mortality at 90 days: 10.4% (treatment arm) vs. 19% (control arm). No significant difference in sICH | No significant difference in death or sICH | No significant difference in death or sICH | No significant difference in death or sICH |
MR CLEAN - Multicenter Randomized Control Trial of Endovascular treatment for Acute Ischemic Stroke; ESCAPE - Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion With Emphasis on Minimizing CT to Recanalization Times; SWIFT PRIME- Solitaire FR With the Intention for Thrombectomy as Primary Endovascular Treatment of Acute Ischemic Stroke; EXTEND-IA - Extending the Time for Thrombolysis in Emergency Neurological Deficits–Intra-Arterial; REVASCAT - Randomized Trial of Revascularization With Solitaire FR Device Versus Best Medical Therapy in the Treatment of Acute Stroke Due to Anterior Circulation Large Vessel Occlusion Presenting Within 8 Hours of Symptom Onset; NIHSS - National Institutes of Health Stroke Scale; IV rt-PA - intravenous tissue plasminogen activator; IA - intra-arterial; UK – urokinase; TICI - Thrombolysis in Cerebral Infarction scale; mRS - modified Rankin scale; sICH – Spontaneous intracerebral hemorrhage.
Neuroimaging
As a rule, all patients suspected of having acute ischemic stroke should obtain neuroimaging on first arrival to a hospital before initiating any specific therapy. As per the 2019 AHA/ASA guidelines, both non-contrast CT (NCCT) and magnetic resonance (MR) imaging (MRI) is effective to exclude underlying hemorrhage and determine whether the patients with acute ischemic stroke are candidates for thrombolytic or endovascular therapy.23 However, NCCT head is preferred as the initial imaging test due to low cost, wide spread availability and faster speed of acquisition of images. The Alberta Stroke Program Early CT Score (ASPECTS)- a 10-point quantitative, topographic CT score is a simple and reliable method of assessing the extent of ischemic changes on NCCT which aids in rapid identification of patients who would benefit from endovascular therapy.24 Furthermore, for patients who meet criteria for endovascular therapy, a non-invasive intracranial vascular study – CT angiogram (CTA) or MR angiogram (MRA) of the head and neck; is strongly recommended during the initial imaging evaluation of acute stroke patients, without delaying administration of intravenous rt-PA (Figure 1).23 Obtaining CTA or MRA of head and neck allows rapid identification of large vessel occlusion, presence of collaterals, clinically significant vascular disease (e.g., atherosclerotic stenosis) as well as the aortic arch and great vessel anatomy. When evaluating patients with acute ischemic stroke within 6 hours of last known normal with large vessel occlusion 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 obtaining additional imaging such as perfusion studies. However, in selected patients with AIS within 6 to 24 hours of last known normal who have large vessel occlusion (LVO) in the anterior circulation; obtaining CT perfusion (CTP), Diffusion Restriction Imaging (DWI-MRI), or MRI perfusion (MR-perfusion) is recommended to aid in patient selection for mechanical thrombectomy, but only when patients meet eligibility criteria from one of the trials (DAWN or DEFUSE)25,26 [Table 3] that showed benefit from mechanical thrombectomy in this extended time window [Class of recommendation I, Level of Evidence A].23 With recent advances in the management of acute ischemic stroke, multi-modal CT protocols including CT, CTA, and CTP are being made available increasingly in many centers which can help in quick decision making before attempting endovascular therapy.
Patient Selection Criteria
As per the most recent American Heart Association (AHA)/American Stroke Association guidelines published in 2019,23 selected patients with acute ischemic stroke with onset of symptoms between 0–6 hours, should undergo mechanical thrombectomy (with a stent retriever) if they meet all of the following criteria [Class of recommendation I, Level of Evidence A]:
Pre-stroke modified Rankin Score (mRS) of 0 to 1 (functional independence)
Patients ≥ 18 years
Stroke severity on NIHSS ≥ 6
Computed tomography (CT) brain without evidence of large infarct suggested by Alberta Stroke Program Early CT Score (ASPECTS) of ≥ 6
Imaging proven causative occlusion of the Internal carotid artery (ICA) or proximal segment (M1) of middle cerebral artery (MCA).
Treatment can be initiated (groin puncture) within 6 hours of symptom onset.
In 2018 two major randomized controlled trials were published: DAWN (DWI or CTP Assessment with Clinical Mismatch in the Triage of Wake-Up and Late Presenting Strokes Undergoing Neurointervention with Trevo), 25 and DEFUSE 3 (The Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke); 26 which showed encouraging findings resulting in extending the time window for endovascular therapy in acute ischemic stroke within 6–24 hours from symptom onset. The DAWN trial used clinical-core mismatch, which is a mismatch between the severity of clinical deficit (NIHSS) and infarct volume on diffusion-weighted magnetic resonance imaging (MRI) or perfusion CT imaging (CTP), as an eligibility criteria to select patients with large anterior circulation vessel occlusion for treatment with mechanical thrombectomy between 6 and 24 hours from last known normal. The study demonstrated a benefit in functional outcome at 90 days in the treatment group (mechanical thrombectomy plus standard care) as compared to standard care alone (mRS score 0–2, 49% vs 13%; adjusted difference, 33% [95% CI, 21–44]. Whereas, the DEFUSE-3 trial used perfusion-core mismatch and maximum core size as imaging criteria to select patients with large anterior circulation occlusion 6 to 16 hours from last known normal for mechanical thrombectomy. The results showed a benefit in functional outcome at 90 days in the endovascular-therapy group as compared to the medical-therapy group alone (mRS score 0–2, 44.6% versus 16.7%; RR, 2.67 [95% CI, 1.60–4.48]; P<0.0001). Current guidelines recommend mechanical thrombectomy (preferably with a stent retriever) in selected patients with acute ischemic stroke within 6 to 16 hours of last known normal who have large vessel occlusion in the anterior circulation and meet other DAWN or DEFUSE 3 eligibility criteria (Table 4) [Class of recommendation I, level of evidence A].
Table 4.
DAWN Criteria (6 to 24 hours)25 | DEFUSE-3 (6 to 16 hours)26 |
---|---|
|
|
DAWN - DWI or CTP Assessment with Clinical Mismatch in the Triage of Wake-Up and Late Presenting Strokes Undergoing Neurointervention with Trevo; DEFUSE 3 - The Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke; NIHSS - National Institute of Health Stroke Scale; mRS - Modified Rankin Scale; MCA - Middle Cerebral Artery; ICA -Internal Carotid Artery; MRA - Magnetic Resonance Angiography; CTA - Computed Tomography Angiography; MR-DWI - Magnetic Resonance-Diffusion Weighted Imaging; CTP - Computed Tomography Perfusion
Other Indications for Endovascular Treatment
Vertebrobasilar Circulation Stroke
Approximately 20% of all ischemic strokes occur in the vertebrobasilar circulation, which includes acute basilar artery occlusion (BAO), and upto 80–90% of patients with acute basilar artery occlusion have a fatal and poor outcome.27 Unlike anterior circulation ischemic stroke, data on use of endovascular therapy and its efficacy in achieving successful revascularization in large vessel occlusion within vertebrobasilar circulation is sparse. However, small single-centre studies have shown good functional outcomes following basilar thrombectomy ranging from 30% to 48% and lower mortality (approximately 30 percent) than expected when compared with outcomes among patients who did not receive endovascular therapy.28–30 Due to lack of randomized controlled trials on endovascular treatment in patients with basilar artery occlusion, management of such patients should be guided by the severity of the symptoms, time of onset of symptoms, age, clinical status of the patient and presence of collaterals after careful evaluation of non-invasive vessel imaging.
Tandem Occlusions
Tandem occlusions, defined as simultaneous occurrence of an intracranial large vessel occlusion and a high-grade stenosis or occlusion of the ipsilateral proximal internal carotid artery (at the level of the cervical internal carotid artery), accounts for 10–20% of large vessel strokes.31,32 Previous studies have shown that patients with tandem occlusion (cervical ICA-MCA) have a lower likelihood of recanalization and poor outcomes as compared to isolated MCA occlusion after treatment with intravenous thrombolysis.32,33 Consequently, endovascular treatment has evolved as a more effective treatment option with or without prior intravenous rt-PA. However, there is uncertainty regarding the best approach (anterograde vs. retrograde) for treating tandem occlusions in acute ischemic stroke due to lack of randomized multicenter trials evaluating the different approaches and its effect on clinical outcomes. In a systematic review by Mbabuike et al.34 patients with acute ischemic stroke with tandem occlusions, a distal to proximal revascularization approach appeared to be more practical and effective with an advantage of decreased time to reperfusion and hence better functional outcome. The optimum approach for management of tandem occlusions and choice of therapy for management of proximal occlusion should be ascertained on an individual case to case basis after careful evaluation of the clinical severity, age, presence or absence of collaterals and bleeding risks.
Cerebral Angiography
Endovascular access is obtained through the common femoral artery in most cases. However, in patients with severe ilio-femoral arterial occlusions, unfavorable aortic arch anatomy, extremely tortuous vessels; alternate routes like trans-radial or trans-brachial can be used. After achieving access, a standard diagnostic catheter can then be used to engage the carotid arteries at which time digital subtraction angiography (DSA) is performed to visualize the cerebral vessels focusing on the specific artery of interest, its distal branches, site of occlusion and presence or absence of collaterals (Figure 2 and Figure 3). Other supplementary catheters like micro-catheter to pass the site of occlusion and large bore catheters for aspiration can then be utilized depending on the vessel caliber and site of occlusion.
Endovascular Recanalization Techniques
Endovascular therapy for management of acute ischemic stroke from a large vessel occlusion, has evolved rapidly over the years due to availability of newer generation thrombectomy devices and advancements in the catheter technology. Historically, intra-arterial fibrinolytic therapy with use of recombinant pro-urokinase in the vessel of interest, to achieve clot lysis, was used to achieve recanalization.35,36
Neurointerventionalists than began attempting mechanical thrombus disruption by repeated probing of the thrombus by a micro guidewire, microcatheter or snares. This when combined with use of intra-arterial fibrinolytic therapy leads to an increase in the surface area on which fibrinolytic agents can act, thus increasing efficacy of thrombolytic therapy [Figure 4 (a) and (b)]. 37–39 However, there is a risk of clot fragmentation and distal embolization with this approach leading to suboptimal rates of reperfusion. Intracranial stenting within the occluded segment using the Enterprise vascular reconstructive device (Codman, Raynham, Massachusetts, USA) was also tested as a potential tool to achieve mechanical clot disruption and partial restoration of blood flow in acute ischemic stroke.40,41 However, its use has been limited due to concomitant use of dual antiplatelets during the procedure and risks of bleeding.
Mechanical Thrombectomy Devices
The Merci retriever (Concentric Medical, Mountain View, California, USA), was the first stroke device to be approved by the FDA for mechanical thrombectomy in acute ischemic stroke patients. The Merci device (Mechanical Embolus Removal in Cerebral Ischemia) works primarily by advancing through the occlusion/thrombus using a micro-catheter and deploying distal to the thrombus [Figure 4 (c)]. This is followed by withdrawal of the Merci retriever with the thrombus captured by its helical loops, alongside the micro-catheter, using manual aspiration with a large syringe to reverse the flow and further aspirate any clot debris. However, thrombectomy with Merci device was associated with lower rates of recanalization ranging between 46%–55%.42,43
The next generation of mechanical thrombectomy devices, stent retriever, brought a paradigm shift in the endovascular management of acute ischemic stroke. Solitaire (ev3 Endovascular, Plymouth, Minnesota, USA) and Trevo Pro (Stryker Neurovascular, Kalamazoo Michigan, USA) are the most common stent retrievers used in the recent thrombectomy trials that showed a higher recanalization rates and a shorter time to treatment in ischemic stroke from large vessel occlusions.17–21,25,26 Stent retrievers are re-sheathable, re-constrainable, self-expanding stents mounted on a wire and are deployed within the thrombus through a microcatheter. The radial force of the stent compresses the thrombus against the vessel wall allowing restoration of the blood flow immediately. Leaving the device in place, for up to 5 mins, promotes engagement of the device with thrombus. The micro-catheter and stent are then withdrawn gently under continuous aspiration using a large syringe through the guiding-catheter to prevent the development of an embolism [Figure 4 (e)]. The use of stent retrievers is indicated in preference to the coil retrievers such as Merci device for mechanical thrombectomy 23
More recently, large caliber aspiration catheters have been made available [ACE 68, 5MAX, 5MAX ACE (Penumbra Inc., Alameda, CA, USA), AXS Catalyst 6 (Stryker), Sofia 6F (MicroVention, Aliso Viejo, CA, USA)] that can be advanced easily in the cerebral vasculature and can be placed at the level of thrombus over a microcatheter and is used to aspirate the thrombus directly using a syringe or Penumbra aspiration pump that is part of the Penumbra thrombectomy/aspiration system [Figure 4 (d)].44
Figure 5 summaries the different endovascular revascularization strategies available currently. In general, the technical goal of the thrombectomy procedure should be reperfusion to a modified Thrombolysis in Cerebral Infarction (mTICI) grade 2b/3 angiographic result [2b= antegrade reperfusion of more than half of the previously occluded target artery ischemic territory, 3= complete antegrade reperfusion of the previously occluded target artery ischemic territory with absence of visualized occlusion in all distal branches],45 to maximize the probability of a good functional clinical outcome [Figure 3 (a) and (b)]. The use of adjunctive salvage techniques, including IA fibrinolysis, may be reasonable to achieve mTICI 2b/3 angiographic results if completed within 6h of symptom onset.23
Choice of Anesthesia
Both general anesthesia and conscious sedation can be used during endovascular therapy in acute ischemic stroke patients. However, the choice between general anesthesia and conscious sedation should be individualized based on clinical characteristics, tolerance of procedure and patient risk factors. A recent meta-analysis showed that use of general anesthesia may be associated with poorer outcomes as compared to conscious sedation in the setting of endovascular therapy.46 However, general anesthesia may be preferable in patients with depressed level of consciousness, respiratory compromise, and uncooperative or agitated patients for airway protection.
Post Procedure Care
All patients who undergo endovascular therapy for acute ischemic stroke should be admitted to neurological critical care units for closer monitoring. Low threshold should be kept for obtaining a non-contrast CT head to detect hemorrhagic transformation, particularly in patients who develop neurological decline post procedure. There is no consensus regarding the appropriate timing of obtaining follow up CT head and can range from immediately post procedure to 24 hours.
There is very limited data available to guide BP management during and after the procedure in patients who undergo mechanical thrombectomy. The ESCAPE protocol states that SBP ≥150 mm Hg is probably useful in promoting and keeping collateral flow adequate while the artery remains occluded.18 The DAWN protocol recommends maintaining SBP <140 mm Hg in the first 24 hours in subjects who are reperfused after mechanical thrombectomy.27 According to current AHA guidelines, it might be reasonable to maintain BP at a level < 180/105 mm Hg in patients who undergo mechanical thrombectomy with successful reperfusion.23
Vascular groin complications can arise from use of multiple or large bore catheters and should be monitored regularly. A standardized protocol should be followed diligently by the nursing staff and physicians for assessment of vascular complications and maintenance of hemostasis at the puncture site either with use of manual compression or vascular closure devices. Other post-procedural complications can include cardiac arrhythmias, temperature dysregulation, respiratory failure, hemorrhagic transformation, malignant cerebral edema, stroke evolution, and vessel re-thrombosis.
Conclusion
Endovascular therapy for management of acute ischemic stroke has evolved tremendously over the recent years and is currently considered standard of care in selected patients with large vessel occlusion within the anterior circulation. Figure 6 depicts a flowchart summarizing the imaging and patient selection criteria for endovascular therapy in patients with acute ischemic stroke. Diagnostic advancements in imaging with availability of multi model imaging protocols including CT perfusion, MR-DWI and MR-perfusion has made it possible to extend the time window for endovascular therapy up to 24 hours in select patient population, leading to improved functional outcomes. Recognition of large vessel related stroke and timely transfer of patients to specialized stroke centers with endovascular intervention capabilities, can help improve patient outcomes and improve stroke related morbidity.
Footnotes
Kunal Bhatia, MD, (above), MSMA member since 2020, Sachin Bhagavan, MD, Navpreet Bains, DO, Brandi French, MD, Farhan Siddiq, MD, Camilo R. Gomez, MD, and Adnan I. Qureshi, MD are all with University of Missouri - Columbia School of Medicine/MU Health Care in Columbia, Missouri.
Disclosure
None reported.
References
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