12 Mechanical Thrombectomy in Acute Ischemic Stroke
Abstract
Acute ischemic strokes are a devastating condition and represent 85% of all cerebrovascular accidents.1 For every minute of delay in the treatment of ischemic stroke, 1.9 million cells die in the brain and 13.8 million synapses and 12 kilometers of axonal fibers are lost.2
Rapid advances in devices have propelled the evolution of mechanical thrombectomy over the past decade from rudimentary mechanical disruption and intra-arterial thrombolytic infusions to increasingly effective thrombectomy devices.
The initial thrombectomy trials3,4,5,6 failed to demonstrate a benefit of mechanical thrombectomy over intravenous tissue plasminogen activator (tPA). More recently, multiple, large, mul-ticenter trials validated the efficacy of mechanical thrombectomy with newer generations of thrombectomy devices.7,8,9,10,11 These trials changed the paradigm of ischemic stroke treatment, clearly demonstrating the efficacy of endovascular treatment for stroke patients with large vessel occlusions.
Keywords: stroke, mechanical thrombectomy, landmark papers, evidence, large vessel occlusion
12.1 Goals
1. Review the literature that forms the basis of mechanical thrombectomy in acute ischemic stroke for large-vessel occlusion (LVO).
2. Critically analyze the steps to follow on stroke protocol and the decision for endovascular treatment.
3. Critically analyze the importance of imaging studies and its role in patient selection.
12.2 Case Example
12.2.1History of Present Illness
A 63-year-old woman with a history of hypertension and hyper-lipidemia presented with left-sided facial palsy, right gaze deviation, left-sided weakness, and a National Institutes of Health Stroke Scale (NIHSS) score of 12. The patient had a noncontrast computed tomography (NCCT), a CT angiogram (CTA), and CT perfusion of the brain. The NCCT demonstrated an Alberta Stroke Program Early CT score (ASPECTS) of 10. The CTA demonstrated a right Ml occlusion with poor collaterals (▶ Fig. 12.1) and the CT perfusion demonstrated a large area of ischemic penumbra with no infarct (▶ Fig. 12.2). Time from symptom onset was 90 minutes. The patient received intravenous (IV) recombinant tissue plasminogen activator (rTPA) and was transported to the angiography suite for mechanical thrombectomy.
12.2.2 Treatment Plan
Under conscious sedation, the right common femoral artery was accessed and a 9 F sheath was introduced. A right carotid arteriogram showed complete occlusion of the right Ml (▶ Fig. 12.3).
The thrombus was removed using a direct aspiration first pass technique (ADAPT). Control angiography demonstrated thrombolysis in cerebral infarction (TICI) 3, complete recanali-zation of the branch with normal anterograde flow (▶ Fig. 12.4).
12.2.3 Follow-up
The patient was transferred to the intensive care unit following the procedure. She made a complete recovery within 6 hours of the procedure and was subsequently discharged home following a short stay in the hospital.
12.3 Case Summary
1. Which were the main objectives of NCCT?
The noncontrast CT Head is obtained to exclude other possible etiologies for the patient’s symptoms. In addition, these initial scans may identify an LVO (hyperdense artery sign) and/or early signs of completed infarctions (loss of gray-white differentiation, gyrus effacement, etc.). Numerous studies have shown that the baseline central infarct size is a powerful predictor of ischemic stroke treatment outcomes. Although diffusion-weighted magnetic resonance imaging (MRI) is the most accurate method of determining cerebral infarction, CT is still the most commonly used imaging modality due to its rapidity and availability.
Fig. 12.1 Computed tomography angiogram (CTA) demonstrating right M1 occlusion.
Fig. 12.3 Anteroposterior (AP) projections of the right internal carotid angiogram with occlusion of the right proximal Ml segment.
Fig. 12.4 Anteroposterior (AP) projections of right internal carotid angiogram demonstrating complete recanalization (thrombolysis in cerebral infarction [TIG] 3) with normal antegrade flow.
ASPECTS is a favorable predictor of perfusion and is used for selection of candidates for thrombolytic and endovascular treatment.12 This 10-point radiographic score is a semiquantitative classification system that improves the detection of ischemic changes. Elevated ASPECTS are significantly associated with improved functional outcomes, reduced mortality, and lower rates of symptomatic intracranial hemorrhage following thrombectomy, as well as a positive predictor of functional independence at 90 days.13 The ASPECTS score is increasingly used due to its rapidity, simplicity, and reproducibility.14
ASPECTS segments the vascular territories of the middle cerebral artery and deducts one point for each affected territory.
• Caudate nucleus.
• Putamen.
• Internal capsule.
• Insular rim.
• Ml: “anterior cortex of the middle cerebral artery (MCA)” corresponding to the frontal operculum.
• M2: “lateral cortex of MCA to the insular rim” corresponding to the anterior temporal lobe.
• M3: “posterior cortex of MCA” corresponding to posterior temporal lobe.
• M4: “territory of MCA immediately superior to Ml.”
• M5: “lateral territory immediately above M2.”
• M6: “posterior territory immediately above M3.”
Ml to M3 are measured at the level of the basal ganglia, while the M4 to M6 territories are measured at the level of the lateral ventricles.15
2. What are the main objectives ofCTA?
The CTA Head is obtained to determine the presence of an LVO and identify potential patients for mechanical thrombectomy.16 In addition, it assesses the extent of the patient’s collateral circulation, which plays an important role in maintaining the viability of tissues in the early hours of an ischemic stroke. CTA, rather than MRA, appears to be the most useful for the evaluation of cortical collaterals.17 The prognostic impact of collaterals has been demonstrated on clinical outcome, initial NIHSS score, and infarct size.18 In addition, cerebral blood volume (CBV), ASPECTS score, mean transit time (MTT), and time to max have all been found to correlate with the extent of collateral circulation.19,20 Patient selection remains a critical area of further investigation for mechanical thrombectomy.21
3. What is the role of CTperfusion in patient selection?
The decrease in cerebral blood flow (CBF) is initially offset by the increase in collaterals manifested in local CBV. This maintains the viability of the tissue at risk (penumbra). This decrease in CBF is also demonstrated by an increase in the MTT. However, when both the CBF and CBV fall, the tissue is considered to be nonviable. Thus, the addition of perfusion techniques differentiates the hypoperfused territory (penumbra) from the infarcted territory (core).
4. What other factors influence stroke outcome?
In addition to the level of occlusion and NIHSS at presentation, several other factors (successful recanalization, established infarct core, ASPECTS, age, baseline functional status, and collateral status) also influence the outcome following stroke.22
5. Is there a relation between NIHSS score and LVO?
An NIHSS score of 8 was used to select candidates for intervention due to its high sensitivity and specificity in detecting LVOs.17 However, patients with LVOs can also present with mild neurological deficits.20 In addition, there is significant variability in outcomes of patients with LVOs and low-admission NIHSS.23
The presence of an underlying LVO in a patient with a low NIHSS can be a strong predictor of neurological deterioration.24 These patients who underwent MT demonstrated a shift toward improved outcomes compared with the best medical management.25
6. Should patients who do not meet the inclusion criteria of the published studies be considered for MT?
While exceptions for use of MT in cases not meeting strict criteria are allowable, it remains unknown whether patients will be excluded from treatment.26 Bhole et al21 demonstrated that 33% of the cases in their series treated outside standard recommendations still attained a modified Rankin score (mRS) of<2 by 3 months. In addition, nearly half of their MT cases would have been denied MT if top-tier criteria were used to select patients.
In addition, basilar artery occlusions, which were not included in the initial or subsequent studies, are a particularly devastating event with uniformly poor outcomes if recanalization is not achieved early.27
7. What would have happened if the patient experienced a wake-up stroke?
Wake-up strokes represent up to 25% of acute ischemic strokes and largely fall outside of the traditional 6-hour window for MT.28 However, studies suggest that the majority of these strokes occur closer to the time of awakening.29,30,31,32,33,34 Additional imaging studies, such as CT and MR perfusion studies, can be employed to select these patients for treatment.35,36,37
12.4 Level of Evidence
An emergency NCCT is recommended prior to initiating any specific treatment for acute stroke (Class I, Level of Evidence A).
Noninvasive intracranial vascular study is strongly recommended during the initial imaging evaluation of the acute stroke patient but should not delay intravenous rTPA if indicated (Class I, Level of Evidence A).
Administration of intravenous rTPA is recommended for eligible patients who can be treated within 3 to 4.5 hours after stroke onset (Class I, Level of Evidence B).
Patients eligible for intravenous rTPA should receive intravenous rTPA even if endovascular treatments are being considered (Class I, Level of Evidence A).
Observing patients after intravenous rTPA to assess for clinical response before pursuing endovascular therapy is not recommended (Class III, Level of Evidence B-R).
Patients should receive MT if they meet the appropriate criteria (Class I, Level of Evidence A).
TICI 2b/3 recanalization following MT maximizes the probability of a good functional clinical outcome (Class I, Level of Evidence A).
Endovascular therapy should be carried out in an experienced stroke center with rapid access to qualified neurointer-ventionalists (Class I, Level of Evidence E).
12.5 Landmark Papers
Langhorne P, Williams BO, Gilchrist W, Howie K. Do stroke units save lives? Lancet. 1993 Aug 14;342(8868):395-398.3S
This seminal paper initiated the fertile ground for stroke research and treatment. Using the newly introduced meta-analysis technique, the authors found that dedicated stroke units improved patient outcomes.
They 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 10 trials, 8 of which used a strict randomization procedure. A total of 1,586 stroke patients were included: 766 were 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 3 months) after a 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. They concluded that management of stroke patients in a dedicated 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): 25S2-25S7.39
In 1995, the first study with a positive impact for treatment of stroke patients was published demonstrating a statistically significant improvement in outcomes with administration of IV rTPA within 3 hours of symptom onset. Patients receiving the medication had at least a 30% better outcome in terms of disability at 3 months. Patients with IV rTPA also had a reduction in 3-month mortality of 17% versus 21% (p = 0.30). However, there was an increase in the percentage of hemorrhagic conversion of 6.4% versus only 0.6% in control (p < 0.001). The findings were statistically significant with a clear benefit of IV rTPA treatment with a required number needed to treat (NNT) of 8 to obtain favorable results.
Hacke W, Kaste M, Bluhmki E, et al; ECASS Investigators. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med 2008;359(13):1317-1329.40
In 2008, the second statistically significant study was published that supported treatment with IV rTPA: ECASS III. This work increased the therapeutic window from 3 to 4.5 hours following symptom onset. There was no difference in mortality, but it demonstrated improved morbidity with an NNT of 14 for “favorable results.” Based upon these two studies, for patients meeting national and international eligibility guidelines, IV rTPA improves functional outcomes at 3 and 6 months when given within the first 4.5 hours.
Endovascular treatment
Broderick JP, Palesch YY, Demchuk AM, et al; Interventional Management of Stroke (IMS) III Investigators. Endovascular therapy after intravenous t-PA versus t-PA alone for stroke. N Engl J Med 2013;368( 10):893-903.5
Kidwell CSJahan R, GornbeinJ, et al; MR RESCUE Investigators. A trial of imaging selection and endovascular treatment for ischemic stroke. N Engl J Med 2013;368(W):914-923.3
Ciccone A, Valvassori L, Nichelatti M, et al; SYNTHESIS Expansion Investigators. Endovascular treatment for acute ischemic stroke. N Engl J Med 2013;368(W):904-913.4
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 scores 10 or score of 8 to 9 with CT angiographic evidence of an occlusion of the first segment of the middle cerebral artery [Ml ], internal carotid artery, or basilar artery). Participants randomly assigned to the endovascular therapy group underwent angiography as soon as possible. Participants who had no angiographic evidence of a treatable occlusion received no additional treatment, while 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 Ml, 44% for a single M2 occlusion, and 23% for multiple M2 occlusions. The trial was terminated early due to futility as defined by the prespecified rules. There was no significant difference between the endovascular therapy and intravenous tPA groups in the overall proportion of participants with an mRS 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 embolec-tomy and studied clinical outcomes in subgroups with and without a “penumbral pattern” on MRI or CT of each treatment arm. There was no improvement in revascularization, tissue reperfusion, or clinical outcomes in the embolectomy group compared to the standard care group.
SYNTHESIS compared endovascular therapy versus IV tPA during the first 4.5 hours from symptom onset. The study included 362 patients (181 in each group). There were no significant differences with respect to prognosis (30.4% endovascular vs. 34.8% intravenous), hemorrhagic complications, or mortality.
Numerous concerns regarding various aspects of these trials were raised. First, only MR RESCUE routinely identified LVO with either CTA or MRA. In IMS III, CTA was performed in only 47% of patients and 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 an LVO.
Moreover, modern thrombectomy devices, such as retrievable stents and aspiration catheters were used in only a minority of patients. The use of older, less effective endovascular technology resulted in significantly lower rates of successful recanalization. The rates of TICI 2b or 3 recanalization were 40% in IMS III and 27% in MR RESCUE. Recanalization rates were not reported in SYNTHESIS expansion. The use of first-generation thrombectomy devices and techniques could explain the low rates of recanalization seen in these studies.
Furthermore, patients with minor ischemic deficits were included. These patients may not have the same benefit as those with LVOs. SYNTHESIS expansion also compared thrombectomy versus IV tPA, rather than concomitant use. Despite the negative results, these studies pointed the way for new trials on mechanical thrombectomy in LVOs.
Bekhemer O, Beumer F, Berg V, Lingsma H, Schonewile Y, Ne-derkoom V. The randomized trial of intra-arterial treatment for acute ischemic stroke (Mr. CLEAN). NEnglJ Med2015;372.7
MR CLEAN was the first positive trial to be published in January 2015. Five hundred patients (233 intervention and 267 control group) were randomized to medical management versus mechanical thrombectomy. Inclusion criteria consisted of age > 18 years, NIHSS > 2, intervention < 6 hours since the onset of symptoms, proximal vascular occlusion by CTA, and an ASPECTS > 7. IV rTPA was administered to 90% of the patients (87% intervention vs. 91% control). No significant changes were observed in terms of mortality; however, there was a statistically significant decrease in morbidity in the intervention arm with an mRS of 0-2 of 33% with endovascular treatment versus 19% in the control group. TICI 2b-3 reperfusion was achieved in 59% of the cases.
Goyal M, Demchuk A, Menon B, et al. Randomized assay of rapid endovascular treatment of ischemic stroke (ESCAPE). N Engl }Med2015.8
The ESCAPE trial included a total of 315 patients (165 intervention vs. 150 control), with an NIHSS more than 12, ASPECTS more than 5, treatment within 12 hours, diagnosis of proximal occlusion by CTA, and perfusion imaging for evaluation of collateral circulation. IV rTPA was administered in 76% of the patients (72.7% intervention vs. 78.6% control group). This study was terminated 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 0-2) in 53% with intervention versus 29% in the control group (NNT = 4) and a decrease in mortality of 10% versus 19%, respectively.
In the ESCAPE trial, a short imaging-to-reperfusion time significantly improved the chance of achieving a functionally independent outcome.
Campbell B, Mitchell P, Kleinig T, Dewey H, Churilov L, Yassi N. Endovascular therapy for ischemic stroke with perfusion-imaging selection (EXTEND-IA). N EnglJ Med 2015;372(11):1009-1018.9
EXTEND-IA was the smallest trial with n = 70 (35 intervention vs. 35 control). The selection criteria were based on perfusion images of patients with LVO within 4.5 hours from onset of symptoms. There were no age limits or NIHSS limits. IV rTPA was administered in all patients. TICI 2b-3 reperfusion rate was 86% with a favorable outcome (mRS 0-2) in 71% with intervention versus 40% control group. Mortality was 9% in the thrombectomy arm and 20% in the control.
They concluded that early endovascular thrombectomy with stentrievers after IV rTPA resulted in greater reperfusion and early neurologic recovery than rTPA alone in a population with LVO and salvageable tissue on CT perfusion imaging.
In conclusion, the magnitude of the observed benefit in these trials, along with the SWIFT-PRIME10 and REVASCAT11 studies, was dramatic. The findings suggested a superior outcome following treatment with IV thrombolysis and thrombectomy using modern thrombectomy devices compared with best medical treatment alone. The successes from these trials compared with the earlier ones have been mostly attributed to improved thrombectomy devices with faster and higher rates of recanali-zation and improved study protocols.
Nogueira RG, Jadhav AP, Haussen DC, et al. Thrombectomy 6 to 24 hours after stroke with a mismatch between deficit and infarct. N EnglJ Med. 2017 Nov 11.41
The DAWN trial was a multicenter, prospective, randomized, open-label trial with a Bayesian adaptive-enrichment design and with blinded assessment of end points. This study supported the use of a stent retriever beyond the 8-hour indicated time limit in late presenting ischemic stroke subjects.
The investigators selected patients arriving after 6 hours from symptom onset for inclusion in the trial by using perfusion imaging and clinical scores to identify those with “target mismatch”—a small core infarct volume with a large area of brain at risk for ischemia. 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.
Patients with an LVO presenting between 6 and 24 hours (average 13 hours) underwent computed tomographic (CT) perfusion or magnetic resonance diffusion-weighted imaging. Patients were selected for randomization if they had a small infarct core in relation to their NIHSS score.
Results showed a two-point difference in the 90-day weighted mRS 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 0-2), with an NNTof 2.8.
Albers GW, Marks MP, Kemp S, Christensen S, Tsai JP, Ortega-Gutierrez S, et al. Thrombectomy for stroke at6tol6 hours with selection by perfusion imaging. The New England Journal of Medicine, 2018.42
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.
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.
The results of DAWN trial and the subsequent DEFUSE III trial expanded the population of patients who could benefit from mechanical thrombectomy for stroke, to significantly reduce functional impairment in the most severely affected patients.
The period, location, number of patients, and centers of the trials that demonstrated the benefit of endovascular stroke treatment are summarized in ▶ Table 12.1.
12.6 Recommendations
Prehospital 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.43
