Current trends in the management of acute ischemic stroke
Stroke is the leading cause of disability and most of the cases are those of ischemic stroke. Management strategies especially for large vessel occlusive stroke have undergone a significant change in the recent years that include widespread use of thrombolytic medications followed by endovascular clot removal. For successful treatment by endovascular thrombectomy, the important factors are patient selection based on clinical criterion including age, time of onset, premorbid clinical condition, co-morbidities, National Institute of Health Stroke Scale, and imaging criterion including computed tomography (CT) head, CT angiogram and CT perfusion. Patients presenting within 4.5 hours of onset are considered for intravenous (IV) recombinant tissue plasminogen activator treatment. Mechanical clot retrieval devices have evolved over the past decade. The Mechanical Embolus Removal in Cerebral Ischemia device was approved first followed by the penumbra revascularization system. They have proven in various studies to improve recanalization with acceptable rates of symptomatic intra-cerebral hemorrhage. Introduction of stent retrievers has led to a new era in the interventional management of acute ischemic stroke (AIS). Recent trials namely MRCLEAN, ESCAPE, SWIFT PRIMEs, and EXTEND-IA have used the stent retriever predominantly and have shown unequivocal benefit in the outcome at 90 days for AIS patients with large vessel occlusion. More recently, a new catheter namely 5 MAX ACE was introduced along with improvement in the suction device. This has led to a direct aspiration first pass technique resulting in faster recanalization. Advancements in the endovascular management of AIS with large vessel occlusion have resulted in a paradigm shift in the way this disease is managed. Improvements in patient selection using clinical and imaging criterion along with technical and technological advancements in mechanical thrombectomy have made possible a significantly improved outcome in stroke patients.
Keywords: Acute stroke; mechanical thrombectomy; thrombolysis
Stroke is the leading cause of disability and the third-leading cause of death. It occurs in 795,000 individuals in the United States every year. The prevalence of stroke ranges from 84–262/100,000 in the rural setting and from 334–424/100,000 in the urban areas in India. The incidence is about 119–145/100,000 based on recent population-based studies. Among them, 80% are ischemic stroke, and hemorrhagic stroke make up the remainder. Preventive and active treatment strategies are constantly being sought to prevent disability and to reduce the financial burden on the society. A giant leap in such a search is the advent of thrombolytic medications followed by endovascular clot removal. The two techniques are constantly improving. There has also been a significant improvement in the imaging standards in the past two decades.
Among all stroke patients, about 7–15% of them are eligible for endovascular intervention, as most strokes are small vessel strokes. Among the eligible patients, only about two-thirds reach a hospital even in an organized health care system. There are, therefore, significant challenges in the implementation of the process to facilitate stroke treatment. Certification of stroke centers as primary, designated, and comprehensive stroke centers helps in providing standardized care of the stroke patients, including their interventional treatment.
Current strategies in acute ischemic stroke (AIS) treatment include: Patient selection, imaging, intravenous (IV) recombinant tissue plasminogen activator (rt-PA), intra-arterial (IA) rt-PA, and mechanical thrombectomy including stent retrievers or direct aspiration.
Patient selection is based on the clinical and imaging criterion. The clinical criteria include the age of the patient, time of onset of stroke, premorbid clinical condition, co-morbidities, and National Institute of Health Stroke Scale (NIHSS) at presentation. The imaging criterion for selection for acute intervention includes noncontrast computed tomography (CT) scan head showing the absence of hemorrhage, CT angiogram (CTA) confirmation of large vessel occlusion, and CT perfusion scan (CTP) to show the presence of ischemic penumbra.
At presentation, standardized clinical quantification and assessment of the extent of stroke is done by the NIHSS. It is also very effective for the inter-personnel communication on the severity of stroke. The time of onset of stroke is a critical factor. Patients presenting within the first 3–4.5 h are eligible for IV t-PA treatment and within the 6 h window are eligible for endovascular interventions. In general, patients with AIS with a NIHSS of more than 8 and presenting within the first 6 h of onset are considered for endovascular intervention.
Age is a relative criterion; generally most patients over the age of 85 do not do well following any form of interventional treatment possibly because of a poor functional reserve. The risk of intervention-associated complication is higher in these patients. Rather than the age, the most important criterion that helps in the selection of patient is the premorbid functional level. Independently functioning patients with a good functional level before the onset of stroke are considered good candidates for interventional treatment.
"Wake up stroke” is an interesting concept in this group of patients where the last seen normal time is considered as the time of onset. To select a subset of these patients for intervention, one has to rely on imaging studies. Co-morbidities like atrial fibrillation do give a fair idea about the cause of stroke and the overall clinical condition of the patient.
The first imaging modality in a patient with stroke is a noncontrast CT scan done firstly to rule out hemorrhage and also an already established stroke, and secondly to look for the presence of the hyperdense middle cerebral artery (MCA) sign that correlates with the clinical presentation [Figure 1]. Alberta stroke program early CT stroke score can be assessed in the noncontrast CT scan, and a score of more than 7 is associated with lesser symptomatic intra-cerebral hemorrhage (SICH) following intervention. CTA from the aortic arch to the intracranial vessels, although not essential in every patient, still is an useful adjunct that can show the location of clot, clot burden, tandem lesions, carotid dissections, and nature of the aortic arch, and its vessels. This considerably aids in planning the modality of intervention [Figure 1].
CTP guides in assessing the relative proportions of the ischemic penumbra and the infarcted tissue. These findings help to stratify the potential benefit of intervention versus the risk of hemorrhagic transformation. Reperfusion into a large necrotic core is ineffective and likely to increase the risk of hemorrhage. Special attention should be paid to the cerebral blood volume (CBV), time to peak (TTP) values, and cerebral blood flow (CBF). A decrease in CBV and CBF is suggestive of infarct; however, tissues with normal CBF and CBV with increased TTP values suggest an ischemic penumbra. In general, patients with less than one-third of the infarcted core in the vascular territory at risk will benefit from endovascular intervention. In patients with no definite time of onset and the CTP showing a large ischemic penumbra do well following intervention. The presence of a chronic infarct, severe microvascular ischemia, and seizures can alter the CTP reading and may be mistaken for an acute infarct. The presence of vascular narrowing can overestimate the areas of the ischemic penumbra and so CTP should always be performed and interpreted in conjugation with CTA.
Magnetic resonance (MR) imaging may be useful in the acute setting to assess for diffusion changes. It is practically not feasible in the acute setting due to its nonavailability in majority of the emergency rooms. MR perfusion imaging that helps to assess perfusion/diffusion mismatch may also be of help, if available in the acute setting.
In AIS, IV rt-PA remains the only United States Food and Drug Administration (USFDA) approved treatment for treating patients within the first 4.5 h of the onset of stroke. rt-PA was first approved in 1996 based on the National Institute of Neurological Disorder and Stroke (NINDS) rt-PA Study for use within the first 3 h after the onset of stroke. The window of usage was later extended to 4.5 h based on the European Co-operative Acute Stroke Study. Since then, various studies have taken place to select the subset of patients based on imaging criterion. The current interventional clinical trials are designed to compare the results of treatment using IV rt-PA with that of interventional treatment.
Various studies were undertaken to prove the efficacy of the use of intra-arterial thrombolysis using Pro-Urokinase. PROACT (Prolyse in Acute Cerebral Thromboembolism) study that was conducted in patients within 6 h of an MCA occlusion, and the PROACT-II study (a phase III prospective, randomized, placebo-controlled study) showed a favorable outcome despite an increased frequency of early spontaneous intracerebral hemorrhage (SICH). Due to non-availability of Pro-Urokinase, rt-PA is used for IA thrombolysis. However, USFDA has not yet approved rt-PA for IA thrombolysis. Theoretically, the advantages of IA thrombolysis include a higher dose delivery directly to the clot. It may be given to patients in whom systemic contraindications for thrombolysis exist. Another advantage is that it may be given with an extended therapeutic window. The disadvantages include a delay in treatment, the inherent risks of catheter manipulation, and the need for proper endovascular facilities and adequately trained personnel. In the current clinical practice, with the rapid development of mechanical clot removal devices, intra-arterial thrombolysis is used as an adjunct to mechanical clot removal.
The combination of IV and IA infusion of rt-PA for the treatment of AIS was studied with Interventional Management of Stroke (IMS) studies. The initial feasibility and safety study resulted in a better outcome compared to placebo treated subjects but not beyond the benefit conferred to the NINDS rt-PA treated group. The IMS-II study evaluated the use of IV rt-PA followed by IA rt-PA coupled with low energy sonography to increase fluid permeation and thrombolytic infusion within the clot using the EKOS Primo Micro-Infusion Catheter (EKOS Corporation, Bothell, Washington). The patients had a better outcome than the placebo-treated ones and better Barthel Index and Global Outcome test compared to the NINDS rt-PA treated group.
The recanalization achieved with IV t-PA was only 30–50%, with even lower rates achieved for larger vessel occlusions. It has also been associated with a re-occlusion rate as high as 17%., In large vessel occlusion, the need for an additional treatment using mechanical devices to achieve revascularization arose. For a long time, clot disruption was achieved utilizing non-dedicated devices like microwires, snares, and angioplasty balloons. However, they were not evaluated for efficacy and safety by prospective trials.
The first special device for clot removal in acute stroke was Mechanical Embolus Removal in Cerebral Ischemia (MERCI) retriever (Concentric Medical, Mountain View, California), a corkscrew-shaped device having a flexible nitinol wire in helical loops, approved by the USFDA in 2004. The MERCI and multi-MERCI trials evaluated the safety and efficacy in the setting of acute stroke within 8 h of onset. The MERCI trial was a pivotal single arm, prospective, multicenter trial in tPA ineligible patients presenting within 8 h. The recanalization rate was 46% with SICH rate of 8%. Multi MERCI trial was a similar study where IV rt-PA refractory patients were included. The recanalization rate was 57%, and the SICH incidence was 10%. The rate of clinically significant device-related complications was 4.5%. Among patients in whom revascularization was achieved, there was a two-fold survival advantage and a significantly higher proportion of patients lived without significant disability. These studies proved the safety of mechanical thrombectomy in IV rt-PA ineligible patients and also in those who required a thrombectomy following administration of IV rt-PA.
The penumbra revascularization system (Penumbra, Inc., Alameda, California) is a device that works by suction of the clot along with disruption. The phase I trial proved the safety of the device. The pivotal penumbra stroke trial was then conducted (a single arm, multicenter, prospective study) in AIS patients who were either ineligible or refractory to IV rt-PA. The recanalization rate was 82% (Thrombolysis in myocardial infarction (TIMI) score 2 and 3) with the incidence of SICH being 11%. This study showed the device to be safe and effective for revascularization in patients with acute large vessel occlusion. The system has a variably sized reperfusion catheter, specific separators for the respective catheter, and a suction tubing connected to the mechanical external suction. The largest reperfusion catheter negotiable through a vessel should be used to facilitate the greatest amount of aspiration possible. As a guidance, 026 reperfusion catheter is used for M3 segment clots; 032 for M2 segment clots; 041 for M1 and vertebro-basilar clots; and 054 for ICA and vertebro-basilar clots. It works better in straight arterial segments than around curves or at branching of vessels. Since its introduction, there has been a significant improvement in the reperfusion catheter systems. They are also used in combination to get access to the clot in tortuous carotid arteries.
Stent assisted revascularization in AIS became popular as several reports claimed the usefulness of self-expanding intracranial stents (used as aneurysm bridging device) in acute stroke treatment., Later, a multi-centric retrospective review of the prospectively collected data from 20 AIS patients treated with Enterprise stent (Codman Neurovascular, Raynham, Massachusetts) placement that was used as a bail-out procedure after the available embolectomy procedures at that time were exhausted, achieved a significant recanalization in all these patients (100%). However, other types of stents were also used as a backup procedure. Subsequently, various single center trials were conducted to study their usefulness and effectiveness., The permanent stent placement has many disadvantages including the need for aggressive anticoagulation followed by antiplatelet treatment. This may often be associated with severe intracranial hemorrhage in nearly 11% of the patients.,
Introduction of stent retrievers led to a new era in the interventional management of AIS. Use of stents to retrieve the clot without their permanent placement incorporates the advantages of a stent including navigability, fast device delivery, and quick flow restoration, without suffering from the disadvantages of a permanent intracranial implant. The stent retrievers such as Solitaire (Covidien/ev3, Dublin, Ireland) or Trevo (Stryker, Kalamazoo, MI, USA) have unique dual functionality, acting as a temporary bypass that provides an immediate flow restoration through the thrombus and also as a clot retriever, trapping thrombus into its cells, [Figure 2] and [Figure 3].
Failure of multicenter trials for acute stroke including the IMS-III, Mechanical Retrieval and Recanalization of Stroke Clots Using Embolectomy and SYNTHESIS expansions trials raised doubts regarding the clinical effectiveness of endovascular treatment in AIS.
IMS-III trial was a multicenter, phase 3, randomized open-label clinical trial comparing the outcome in patients receiving IV rt-PA to patients receiving IV rt-PA and endovascular treatment. There was no improved functional outcome at 3 months. However, in the subgroup analysis, patients with large vessel occlusion had a better outcome with the combined treatment. Although it was the largest randomized stroke trial at that time, it had many flaws and concerns that predominantly included amongst others, a delay in the institution of endovascular treatment by 2 h. Moreover, the IV arm received full dose of rt-PA while the combined arm did not receive the full dose. During the 6 year course of the trial, most patients received endovascular treatment using the MERCI retriever, while the stent retriever became the standard of care with improved recanalization. Therefore, the results of IMS-III did not reflect the significant advances that were in progress in the endovascular technology over the years.
MR RESCUE was a phase 2b, randomized controlled, open-label multicenter trial in which endovascular treatment was compared to the standard medical treatment. The results showed a lower infarct volume in patients with a favorable penumbral pattern irrespective of the treatment arm but without any difference in the functional outcome at 3 months between patients with or without a favorable penumbral pattern. Overall, this trial had a poor enrollment. For endovascular treatment, MERCI or Penumbra devices were used with only 27% recanalization, making it impossible to derive conclusions from such poor recanalization rates. The SYNTHESIS expansion trial, an Italian Medicines Agency funded trial, too failed to prove the superiority of mechanical thrombectomy when compared to the standard IV rt-PA.
Trials comparing the mechanical thrombectomy devices showed a promising result. SWIFT was a multicenter, randomized, prospective trial with blinded primary endpoint ascertainment. SWIFT was designed to provide definitive information on the efficacy and safety of the Solitaire Flow Restoration device in comparison to the first-generation MERCI retriever. Patients in the Solitaire arm had better recanalization (66% vs. 24%), a better 90-day neurological outcome and decreased mortality. Trevo 2 was a randomized, prospective, multicenteric trial. The trial aimed to compare the efficacy and safety of mechanical thrombectomy using the Trevo retriever with that of the first-generation MERCI retriever in AIS. The recanalization rates were better in the Trevo arm (86% vs. 60%). The 90-day neurological outcome was better in the Trevo arm with similar mortality rates. The SWIFT and Trevo 2 trials established the superiority of the stent retrievers over older devices in acute stroke intervention.
The introduction of 5 MAX ACE has made it possible to advance a 5 French catheter to the M1 segment in most cases. This is accompanied by an improvement in the suction device. A Direct Aspiration First Pass Technique (ADAPT) has become feasible. This is the most cost-effective of all the treatment methods currently available. The aspiration component of the ADAPT technique alone was successful in achieving Thrombolysis in Cerebral Infarction (TICI) 2b or 3 revascularization in 78% of cases. The average time from groin puncture to at least TICI 2b recanalization was 37 min. The ninety-day functional outcomes were achieved in 40% patients (modified Rankin score 0–2) [Figure 4].
To prove the effectiveness of mechanical thrombectomy in the management of AIS, a significant breakthrough was achieved with the Multicenter Randomized Clinical Trial of Endovascular Treatment for AIS in the Netherlands. In the study, the patients were randomly assigned to intra-arterial treatment plus IV rt-PA or IV rt-PA alone. The eligible patients had a proximal arterial occlusion in the anterior cerebral circulation that was confirmed on vessel imaging and that could be treated intra-arterially within 6 h after the symptom onset. Retrievable stents were used in 190 of the 233 patients (81.5%) assigned to the intra-arterial treatment. The adjusted common odds ratio was 1.67 (95% confidence interval [CI], 1.21–2.30). There was an absolute difference of 13.5 percentage points (95% CI, 5.9–21.2) in the rate of functional independence (mRS 0–2) in favor of the intervention (32.6% vs. 19.1%). There were no significant differences in mortality or the occurrence of SICH.
Subsequently, other trials namely the ESCAPE, SWIFT PRIME, and EXTEND-IA studies also proved the effectiveness of mechanical thrombectomy in large vessel occlusion.,, In the ESCAPE trial, the modified Rankin's score of 0–2 at 90 days was achieved in 54% patients. The trial also showed a mortality benefit in patients undergoing acute stroke intervention for large vessel occlusion. In EXTEND-IA trial, where CTP was used to select cases presenting within 4.5 h from the time of onset of stroke, an excellent benefit with mechanical thrombectomy using stent retrievers was obtained. The modified Rankin's score of 0–2 at 90 days was achieved in 72% patients. The SWIFT PRIME trial also showed an overwhelming response with the modified Rankin's score of 0–2 at 90 days being achieved in 60% patients.
Currently, with the available data, there is enough evidence to prove that mechanical thrombectomy using modern clinically used clot retrieval devices is useful and effective for the recanalization of large vessel occlusion in AIS. This unambiguously results in a better outcome with an increased number of patients having a modified Rankin's score 0–2 at 90 days. The strategy has significantly improved over time. Today, whenever possible, direct aspiration using a 5 French catheter placed at the clot site is initially attempted. If this is not successful, a stent retriever is used. When the two methods are used in combination, the TICI 2b/3 revascularization rate improves to 95%.
Patients with suspected AIS undergo an emergent head CT to rule out intracranial hemorrhage or other intracranial pathologies like brain tumor, subdural hematoma, etc., On seeing a negative CT scan, without being moved out of the CT table, the patient undergoes a CTA, and in some centers, a perfusion (CTP) scan based on the institutional protocol. However, this step may be avoided in patients with a definite history of poor renal function or in the presence of deranged renal function tests (if available). Patients presenting within 6 h of the onset with negative findings on head CT, presence of a hyperdense MCA sign, CTA findings of large vessel occlusion, or CTP findings of no or limited infarcts (that occupy less than one-third of the MCA territory), and having a large ischemic penumbra, are considered candidates for urgent revascularization. If the patient is seen within 4.5 h of symptom onset and have no contraindication to systemic thrombolysis, IV rt-PA (0.9 mg/kg) is started in them. In patients who present within 6 h of symptom onset at a comprehensive stroke center, the endovascular team is alerted to prepare for an intra-arterial mechanical thrombectomy. If the patient is located in a primary stroke center, IV rt-PA is started for those within 4.5 h of onset and immediately moved to the nearest designated stroke center or comprehensive stroke center where the emergency stroke and endovascular services are intimated before hand to reduce any delay. On arrival, unless there is a neurological improvement, the patient is transferred quickly to the angiography suite for mechanical thrombectomy.
Tremendous progress in the endovascular management of AIS with large vessel occlusion has resulted in a paradigm shift in the way this disease is being managed in the recent times. An improved patient selection using the clinical and imaging criteria along with technical and technological advancements in mechanical thrombectomy have resulted in a significantly improved outcome in stroke patients.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]