Mechanical thrombectomy for acute ischemic stroke: The road thus far
Early restoration of flow to perfuse the salvageable brain tissue in acute ischemic stroke significantly reduces mortality and morbidity. Recanalization of large vessel occlusions has not been more than 10-20% with intravenous thrombolysis. Use of mechanical devices in acute ischemic stroke has shown promise in greater recanalization rates and hopefully will yield more optimal stroke outcomes. The results of the recent trials appear promising as the devices continue to evolve, become more operator friendly, and patient outcomes improve.
Keywords: Acute ischemic stroke, large vessel occlusion, mechanical thrombectomy, MERCI, penumbra, stentrievers, thrombolysis
The range of treatment modalities available for acute ischemic stroke (AIS) has expanded considerably in recent years. Dynamic advances in neuroimaging techniques, improving understanding of the pathophysiology of stroke mechanism has changed the nihilistic approach of the past to one of hope, resolve, and commitment. In general, the timing of various therapeutic interventions is limited to the evolution of the ischemic process. There is a great deal of emerging evidence that may suggest that the duration of the ischemic penumbra varies considerably. This may depend upon factors such as the underlying mechanisms of ischemia and the rate of recanalization. There is evidence that the ischemic penumbra may persist for up to 48 hours after onset, but in others, it may be 3 hours or even less.  A meta-analysis of 53 studies suggests that spontaneous or therapeutic recanalization and reperfusion in acute ischemic stroke are associated with improved functional outcomes and reduced mortality.  The survival of bulk of ischemic tissue is dependent upon early energy failure and ionic imbalances, and smaller volumes are dependent upon neurotoxic, inflammatory processes, and on apoptosis.
More than 5 million strokes occur per year worldwide, making stoke as the second most common cause of death, and the leading cause of disability.  However, unlike the rapid advancements in cardiac interventions, the progress as regards endovascular revascularization interventions in AIS has not been optimal. This may partly be due to small subset of the total number of strokes being amenable to endovascular intervention. The number of acute strokes potentially requiring emergent intervention may only be 7-15% of total, because many of these acute strokes may be hemorrhages, or due to small vessel disease, transient, or mini strokes, major end-of-life strokes or very minor strokes that may not warrant the risk of an interventional procedure.  Besides, most health care centers do not receive stroke patients within the window period of intervention (<1-7%).  Even in developed countries with well organized and equipped aggressive stroke centers, less than 10% of stroke patients receive some form of acute reperfusion therapy. 
Mechanical thrombectomy devices specifically for AIS intervention were developed in the 1990s concomitant to the advances in bioengineering devices which produced microcatheters and guide-wires amenable and safe to navigate the extremely complex and tortuous cerebral vasculature. Theoretically, mechanical devices provide several advantages over pharmacological thrombolysis, including revascularizations of large artery occlusions, more complete recanalization under observation, lesser amount of lytics to be used, reduced risk of hemorrhage, and a longer time interval for intervention.  Six broad groupings classify neurothrombectomy devices: clot retrievers, aspiration or suction devices, snare-like devices, ultrasonograpjhy technologies, or lasers, and now stent retrievers.  Potential harms associated with navigating mechanical devices into the intracranial circulation may include direct trauma to the neurovasculature (including vasospasm, vessel dissection, perforation or rupture) and fragmenting thrombi into previously unaffected vessels and cerebral territories.
A total of seven retrieval devices were evaluated for stroke applications. Of which two devices have received FDA approval for use. The success of an application in these devices is gauged by percentage of recanalization of the occluded artery.
A venture capital-funded endeavor, Concentric Medical, was the first to seek a stroke indication for its foreign-body retriever. By crossing the site of occlusion, this corkscrew-shaped device pulls the occlusive thromboembolus into an extracranial guide catheter under active suction. Successive generations of the MERCI device have been reported in three prospective, single-arm, nonrandomized, multicenter feasibility, and safety studies. [6,7] Enrolled patients were treated within 8 hours of stroke onset. Primary outcome measures included: partial or complete recanalization of the occlusion (Thrombolysis in Myocardial Infarction (TIMI) grade 2 or 3) and safety.  Secondary outcomes included clinical outcome, (stroke, myocardial infarction (MI), death) at 30 or 90 days. Apparent limitations included operator learning curve, need to traverse the occluded artery to deploy the device distal to the occlusion, duration required to perform multiple passes with the device, clot fragmentation, and embolization.
First-generation MERCI devices achieved recanalization rates of 48% and when coupled with intra-arterial thrombolytic drugs, recanalization rates of 60% have been reported. Multi-MERCI was an international, multicenter, prospective, single-arm trial of thrombectomy in patients with large vessel stroke treated within 8 hours of symptom onset.  Patients with large-vessel occlusion after IV tissue plasminogen activator (tPA) treatment were included. Once the newer generation (L5 Retriever) device became available, investigators were instructed to use the L5 Retriever to open vessels and could substantially use older generation devices and/or intra-arterial tPA. Primary outcome was recanalization of the target vessel. Of 164 patients who received thrombectomy and 131 initially treated with L5 Retriever, successful recanalization was achieved in 57.3% with L5 Retriever alone and in 69.5% with additional adjunctive therapy. Favorable outcome (modified Rankin Scale (mRS) 0-2) was observed in 34% and mortality in 36%. Symptomatic intracranial hemorrhage was observed 9.8% (2.4% had parenchymal hematoma grade II). 
The Penumbra system is an increasingly popular device (especially in India) and uses two types of devices to remove occlusive thromboembolus in AIS. The Penumbra device acts on the proximal face of the occlusion without traversing the occluded artery. An aspiration device is used to debulk and extract the clot. A second retriever device resembling a stent attached to a guidewire is used to remove resistant clot. Like the MERCI device, the time window for intervention remains at 8 hours post stroke onset in patients ineligible for or failed intravenous thrombolysis. The Penumbra Pivotal Stroke Trial was a prospective, single-arm, multicenter study that showed a high rate of TIMI grade 2 or 3 recanalization in 81.6% of treated vessels. Yet, good clinical outcomes at 90 days occurred in only 25% of patients.  Although recanalization correlated with improvements in patients outcome (>4 points on the National Institute of Stroke Scale (NIHSS) in 57.8%; mRS: 0 to 2 in 25%), the relationship is not linear, and was less than expected. The reasons for this disparity remain nebulous although some explanations had been offered including extensive distal embolization of the vascular tree. Some investigators use the modified Thrombolysis in Cerebral Infarction (TICI) score [Table 1] instead of TIMI. 
The other devices which have FDA clearance for retrieval of intravascular foreign bodies to infusion of fluids into the peripheral vasculature include: (1) The In-Time (Boston Specific, Natick, Massachusetts); (2) Alligator (Chestnut Medical Technologies, Menlo Park, California), (3) Amplatz Gooseneck (ev3 Endovascular, Plymouth, Minnesota); and (4) EnSnare (Merit Medical Systems, Gainesville, Florida). The EKOS (EKOS, Bothell, Washington) and OmniWave (OmniSonics, Wilmington, Massachusetts) systems have been cleared for infusion of fluids into the peripheral vasculature. The LaTIS laser (Spectranetics, Colorado Springs, Colorado) and Oasis Thrombectomy System ( Boston Specific) have been cleared for removal of thrombi from vascular and hemodialysis access grafts.  The AmplatzThrombectomy device has been cleared for dissolution of thrombi within dialysis fistulae. These devices have been used in case studies of AIS with variable results. Data on experience with these devices in stroke are limited. 
Stenting in the treatment of acute ischemic stroke
Self-expandable stents (SES) were approved for vessel remodeling in the treatment of cerebral aneurysms and intracranial atherosclerotic disease. The Enterprise stent (Cordis Neurovascular, Miami Lakes, FL, USA), the Neuroform system (Stryker, Natick, MA, USA), and the Leo stent (Balt Extrusion, Montmorency, France) are devices introduced for stent-assisted coiling of wide-neck aneurysms. The Wingspan system (Stryker, Natick, USA) was approved for treatment of intracranial atherosclerosis.  These devices have been used as off-label devices in the treatment of acute ischemic stroke.
The first case of cerebral revascularization with deployment of SES was reported in the year 2006.  A Neuroform stent was deployed in an occluded left middle cerebral artery after the intra-arterial (IA) infusion of glycoprotein (GP) IIb/IIIa inhibitor failed to recanalize the vessel. Levy et al. reported subsequently a 100% successful deployment of SES (16 Neuroform and 3 Wingspan stents) in the target occlusion, achieving a TICI/TIMI grade 2/3 recanalization in 79% of lesions. Four patients (22%) had a mRS of <3 at 3 months and 2 patients (11%) suffered symptomatic intracranial hemorrhage.  However, most studies published have been retrospective single-center reports with sample sizes ranging between 9 and 20 patients. [14,15] Although these cohorts are small, recanalization rates of 92% and 100% have been reported in cases where other thrombectomy devices have failed. The stent-assisted recanalization in AIS (SARIS) study is a prospective trial that recently reported preliminary data in the treatment of 20 patients with AIS, TIMI grade 2/3 was achieved in 100% of cases with a 5% rate of symptomatic intracranial hemorrhage. A 6-month follow-up of the SARIS trial reported mRS<2 in 55% of patients and a mortality rate of 35%. None of the patients had in stent restenosis and all had TIMI grade 3 in angiographic follow-up. 
SES like the Enterprise, Neuroform, and Wingsan systems appear to have better navigability, trigger less vasospasm, and side-branch occlusions than balloon inflation in vessels with an unknown diameter. However, SES can only be used in >2 mm vessels and chemical thrombolysis may be needed to achieve complete distal recanalization, increasing the risk of symptomatic intracerebral hemorrhage (sICH). A large multicenter retrospective study that included 1122 patients with AIS determined that patients treated with multimodal therapy had significantly higher TIMI grade 2/3 recanalization rates (74%) compared with pharmacological therapy only (61%) or mechanical treatment alone (63%). 
Limitations of SES in AIS
To eliminate the potential limitations of SES, the "stentrievers" have been developed. The stentriever can acts as a stent and recanalize the occluded lumen. It can be retrieved, so that it does not become a permanent implant and while being retrieved it can function as a thrombectomy device as well.
The earliest of such devices was named Neuronet (Guidant, Menlo Park, CA, USA), but the device was not widely commercialized. The most popular of these devices is the Solitaire revascularization device which is a stent-based thrombectomy system with a closed cell design specifically designed to operate as a "retrieval" stent. The device has a dual purpose: Temporal intracranial bypass with flow restoration through the occluded arterial segment; and clot retrieval after trapping the thrombus into its cells.
Initial reports on this device were by Castano et al.,  who deployed the Solitaire AB stent in 20 patients with AIS and large vessel occlusion in the anterior circulation. TICI grade 2b/3 was achieved in 90% of treated vessels and no procedural complications noted. sICH occurred in 10% of patients and 45% achieved a mRS <2 in 3 months. The Solitaire stent was designed initially as an aneurysm neck bridging stent. The device was deployed for 1 or 2 minutes before retrieving it to perform embolectomy. The successful off-label use of this stent prompted the creation of the Solitaire FR device with minimal modifications from the AB version, and specifically designed for treatment of AIS. Subsequent studies reported a TICI grade 2b/3 in 89% and 91% and mRS of <2 in 46% and 50% at discharge and at 90 days. Vasospasm during retrieval of the fully deployed stent was a common phenomenon. Investigators of the rescue, combined and stand-alone thrombectomy (RECOST) study achieved TICI 3 grade in 84% of patients with AIS treated with the Solitaire FR/AB device. At 3 months, 54% of patients achieved a mRS of < 2 and 2% had subarachnoid hemorrhage (SAH). The device was deployed for 2-7 minutes in the target occlusion before thrombectomy. 
The Trevo System is a non-deployable stent-like device currently being used in Europe and Canada. The soft body of the device allows easy navigation through tortuous vessels and its distal closed-end is intended to prevent vessel perforation. The device can be used in vessels ranging from 1.5 to 3.5 mm in diameter.  The orientation of the stent struts has the broader portion of the struts facing the vessel lumen in order to optimize thrombus incorporation. A single center experience with 10 patients treated with Solitaire-assisted thrombectomy has been published in this edition. Successful recanalization was achieved in 20% and a good functional outcome in 40%.
Two studies are underway to test retrievable stents in the treatment of AIS. The trial and Cost Effectiveness Evaluation of IA Thrombectomy in AIS (THRACE) study will compare IV thrombolysis with thrombectomy procedures using the Merci retriever, Penumbra system, Catch device (Balt Extrusion, Montmorency, France), and the Solitaire FB stent in 480 patients. The Thrombectomy Revascularization of Large Vessel Occlusions (TREVO 2) study was recently started in the USA and will compare the Trevo system versus the Merci retriever in the treatment of AIS. Approximately 178 patients would be enrolled in the study. The Solitaire FR with the Intention for Thrombectomy (SWIFT) study compared Solitaire FR with MERCI retriever in 200 patients. The Solitaire group had a higher recanalization rate and achieved better outcomes of mRS 0-2 than did the Merci group. 
Advantages of the stentrievers
Deployment of the stent at the occlusion site with immediate flow restoration to the area at risk will increase the tissue salvage.
Stentrievers gradually expand as they are pulled proximally into the guide catheter. The inherent radial force of the stentriever theoretically traps the clot against the vessel wall during thrombectomy. This may prevent the retrieved thrombi from dislodging from the stentriever and embolizing distally.
Limitations of the stentrievers
Once the stent expands through the occlusion, thrombus material may be pushed into the perforating arteries. This phenomenon has been described as "snow-plowing," and may account for strokes in the perforator territories once the main artery has been recanalized and may be one of the drawbacks of this technique.
The deployment time may be prolonged and cut into the narrow therapeutic time window for intervention. It is advisable to unsheathe the device for at least 2 minutes to allow full expansion of the nitinol struts through the thrombus, and this facilitates clot entrapment and later ion thrombectomy. Deployment times have varied from 1 to 7 minutes among different studies.
Withdrawing the unfolded stent to perform thrombectomy increases the risk of intimal injury to the vessel wall and also the incidence of vasospasm.
Predictors of outcome after IA/mechanical thrombectomy
A scoring system that can help identify patients at high risk for futile recanalization must be developed to avoid unnecessary expenditure and efforts besides a possible injury to the patients. The University of Houston group developed a simple scoring system called the Houston Intra-arterial Therapy (HIAT) score that was based on a retrospective analysis of 190 patients who underwent intra-arterial therapy at their center from 1998 to 2007.  The HIAT score was then retrospectively applied to a different group of 175 patients treated with intra-arterial techniques between 1992 and 2007 at the University of California Los Angeles Medical Center. The HIAT score performed equally well in both cohorts. The maximal HIAT score showed an increased risk of intracranial hemorrhage and a poor outcome. Of the predictors identified for poor outcome after stroke (age, NIHSS score, admission glucose, history of coronary artery disease, history of diabetes mellitus, and previous stroke), only age, NIHSS score, and admission glucose remained as significant predictors of poor outcome. Using these parameters, age, NIHSS score, and admission glucose were taken for determining the HIAT score. One point was given for each variable (age >75 yrs; NIHSS score >18; and admission glucose >150 mg/dL). The sum of points resulted in a score that was named as HIAT score. HIAT score ranges from 0 to 3. Other such scores include the Totaled Health Risks in Vascular Events (THRIVE).  Non score related predictors include duration of the intra-arterial therapy and no mismatch on diffusion-perfusion imaging. HIAT and other similar scoring systems become important in the triage of acute ischemic stroke patients in decision making (whether to proceed with aggressive and expensive interventional treatment measures).
The management of acute ischemic stroke is rapidly developing. Acute ischemic stroke remains a major cause of death and disability worldwide but the number of patients requiring emergency endovascular interventions is largely unknown and may be contained to a small percentage. Public health initiatives to enhance public awareness, response to stroke, prompt transportation facilities, rapid and accessible radiology centers and widely available and accessible certified stroke centers will help triage more patients in the accepted time intervals for appropriate interventions. The analysis of the available literature concludes that there is paucity of high-quality research, many unanswered questions, and a need for further research to determine the optimal device(s), their efficacy and their safety. But the results of the recent trials appear promising as the devices continue to evolve, become more operator friendly, and patient outcomes improve. Till as such time we have safer, more effective and more broadly applicable intervention devices, we continue to try and triage stroke victims more promptly to salvage the critically perfused cerebral tissue.