Mechanical Thrombolysis in Acute Stroke 

Updated: Jul 19, 2018
  • Author: Helmi L Lutsep, MD; Chief Editor: Stephen A Berman, MD, PhD, MBA  more...
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Mechanical Thrombolytic Treatment Techniques

While intravenous (IV) tissue-type plasminogen activator (tPA) has been the only medical therapy approved by the Food and Drug Administration (FDA) for treatment of acute stroke in the United States, subgroup analyses of the National Institute of Neurologic Disorders and Stroke (NINDS) IV tPA trial have shown that patients with severe strokes only have an 8% likelihood of achieving clinically significant improvement with tPA alone. [1, 2]  Six trials had initially shown the efficacy of endovascular therapy in acute stroke treatment, most treating up to 6 hours after symptom onset. [3, 4, 5, 6, 7, 8]  More recently, the results of a trial called DAWN were published, showing the benefit of endovascular treatment in patients carefully selected with imaging up to 24 hours after last being seen well. [9]  After the results of DAWN were released, the DEFUSE 3 trial, assessing endovascular therapy between 6 and 16 hours of last seen well, was terminated and also showed the benefit of endovascular treatment within this time window [10] . Acute stroke treatment guidelines had initially recommended that mechanical embolectomy be performed up to 6 hours (groin puncture) after symptom onset. [11]  Updated acute stroke guidelines now also recommend mechanical thrombectomy in selected patients with acute ischemic stroke within 6–16 hours of last known normal who have large vessel occlusion in the anterior circulation and meet other DAWN or DEFUSE 3 eligibility critieria and list mechanical thrombectomy as reasonable in selected patients known to be well 6–24 hours earlier. [12]

Mechanical treatments include the use of catheters to directly deliver (during angiography) a clot-disrupting or retrieval device to a thromboembolus that is occluding a cerebral artery. Most devices are used in cerebral vessels that are 2–5 mm. Mechanical thrombolytic devices can remove a clot in a matter of minutes, whereas pharmaceutical thrombolytics, even those delivered intra-arterially, may take as long as 2 hours to dissolve a thrombus. [13, 14] The most recently developed devices, known as stent retrievers or stentrievers, have shown higher recanalization rates and better outcomes than those seen with the older Merci Retriever. [15, 16]  First-line contact aspiration was also not shown to be superior to first-line stent retriever use in achieving revascularization at the end of the procedure. [17]  However, in a recently presented study, an aspiration first-pass technique was found not to be inferior to stent retrievers for clinical outcomes (International Stroke Conference, January 25, 2018, Los Angeles, CA).

While the most recent trials have shown better outcomes with mechanical embolectomy than with IV tPA alone, they were preceded by trials that had failed to show efficacy for endovascular treatment. The Interventional Management of Stroke III trial, the largest of these trials, had been stopped for futility after 656 patients had undergone randomization. However, patients in this trial were not required to have baseline imaging that showed large vessel occlusion, and the majority received treatment with older devices, not with stentrievers. [18, 19, 20] Another trial performed in Italy that compared endovascular therapy with IV tPA also had not shown benefit for endovascular therapy, but this trial also did not require that large vessel occlusion be present and the median National Institutes of Stroke Scale (NIHSS) score in the trial was a low 13. Patients in the interventional group received treatment an hour later than those in the IV tPA group (P< .001). [21] Finally, the small (n=118) Mechanical Retrieval and Recanalization of Stroke Clots Using Embolectomy (MR RESCUE) study also had failed to show that embolectomy was superior to standard care, nor that a favorable penumbral pattern could identify those patients that might benefit from embolectomy. [22]

More recent trials have required imaging that confirmed large vessel occlusion. [3, 4, 5, 6, 7, 8, 9, 10] In addition, these trials have incorporated the use of newer stent retriever technologies.

Positive Endovascular Treatment Trials Enrolling Within 12 Hours of Symptom Onset

The trials enrolling patients with large vessel occlusions within 12 hours of symptom onset are described below.

MR CLEAN

MR CLEAN was the first of the positive endovascular treatment trials to be reported. [3] Five hundred patients were enrolled at 16 centers in the Netherlands. Eligible patients could be treated intra-arterially within 6 hours of symptom onset and had an occlusion of the distal intracranial carotid artery (ICA), middle cerebral artery (MCA) (M1 or M2), or anterior cerebral artery (A1 or A2) established by CTA, MRA, or angiography. They needed to have an NIHSS score of 2 or more. Patients were randomized to intra-arterial treatment plus usual care or usual care alone. Those in the endovascular group received either mechanical thrombectomy, an intra-arterial thrombolytic agent, or both. In the intervention group, 87% received IV tPA compared to 91% in the control group. The majority of the patients in the intervention group were treated with retrievable stents (81.5%). The primary outcome, a shift analysis of the modified Rankin Scale (mRS), showed an adjusted common odds ratio of 1.67 (95% CI1.21-2.30).Functional independence, mRS 0-2, was seen in 32.6% of the intervention group and in 19.1% of the control group (95% CI 5.9-21.2).

EXTEND-IA

EXTEND-IA had planned to randomize 100 patients at 14 centers in Australia and New Zealand to IV tPA plus treatment with the Solitaire FR stent retriever or to IV tPA alone, but the trial was suspended after the enrollment of 70 patients after the results of MR CLEAN were reported. [4] Patients were included in the trial if they could receive IV tPA within 4.5 hours of onset and intra-arterial therapy within 6 hours (groin puncture) and had occlusion of the ICA or MCA M1 or M2 segment by CTA. In addition, CT perfusion imaging processed using RAPID software (Stanford University) showed salvageable brain tissue. The primary outcome, an 8 point or more reduction in the NIHSS or a score of 0 or 1 at day 3, was seen in 80% of those in the endovascular group compared to 37% in the control group (p=0.002). More patients in the endovascular group achieved functional outcome (mRS 0-2); 71% versus 40% in the control group, p=0.01. More patients had also undergone reperfusion at 24 hours in the endovascular groupcompared to the tPA-only group.

ESCAPE

ESCAPE had planned to randomize 500 participants to standard care or standard care plus endovascular treatment with the use of available endovascular devices in Canada, the United States, South Korea, Ireland, and the United Kingdom. However, the trial was stopped for efficacy after an unplanned interim analysis was conducted after 316 patients were enrolled due to the release of the results of MR CLEAN. Patients were included in the trial up to 12 hours after symptom onset but were also required to have a small infarct core by CT and CTA, defined as an ASPECTS sore of 6 to 10, and a proximal artery occlusion in the anterior circulation involving the MCA trunk and immediate branches, with or without occlusion of the intracranial ICA. Patients also had to have good collateral circulation, defined as the filling of 50% or more of the MCA pial arterial circulation on CTA. In the intervention arm, 73% received IV tPA and in the control arm, 79% received IV tPA. The primary outcome, a shift analysis of themRS, favored intervention (common odds ratio 2.6, 95% CI 1.7-3.8; p< 0.001). Functional independence, mRS 0-2 at 90 days, was seen in 53% of the intervention group and 29.3% of the control group (p< 0.001).

SWIFT-PRIME

SWIFT-PRIME randomized patients to IV tPA within 4.5 hours plus endovascular treatment with the Solitaire FR stent retriever device, or to IV tPA alone within 6 hours of symptom onset at centers in the United States and Europe. Patients were 18-80 years of age and had an NIHSS of 8-29. Large vessel occlusion of the intracranial ICA or M1 was confirmed by CTA or MRA and patients with large areas of unsalvageable brain tissue by perfusion imaging, and later in the trial by CTA, were excluded. The study was placed on hold after 196 patients had been enrolled due to the release of the other positive trial results. The primary outcome, a shift analysis of the mRS, showed better outcomes in the interventional group (p=0002). Functional independence, mRS 0-2 at 90 days, was also more often achieved in the endovascular group (60.2%) compared to the control group (35.5%).

REVASCAT

The 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 Eight Hours of Symptom Onset (REVASCAT) study was performed in Spain. [6]  The study randomized patients aged 18–80 years of age to treatment with the Solitaire FR stent retriever device or to medical therapy alone. Patients were excluded if they had a large ischemic core, including an ASPECTS score of less than 7 on CT, or an ASPECTS of less than 6 on MRI diffusion weighted imaging. After 160 patients were enrolled, the inclusion criteria were modified to include patients aged 80–85 years with an ASPECTS of more than 8. A total of 206 patients were enrolled in the study.  An interim analysis was conducted as planned after 25% of the patients in REVASCAT had completed their 90-day follow up, and enrollment was terminated due to the results of the other trials. The intervention group had a good functional outcome in 43.7% (mRS = 0–2) at 90 days while the control group had a 28.2% good functional outcome rate (adjusted odds ratio 2.1, 95 % CI [1.1 to 4.0]).

THRACE

The last of the more acute thrombectomy trials, the THRombectomie des Ateres CErebrales (THRACE) trial, was performed in France and published in 2016. [8]  It included patients aged 18–80 years of age who were randomized to IV thrombolysis alone or to IV thrombolysis plus mechanical embolectomy.  IV thrombolysis had to be started within 4 hours of symptom onset and thrombectomy within 5 hours. Proximal cerebral artery occlusion had to be confirmed by CT or MR angiography, but other imaging inclusions were not required. The trial included 414 patients, all of whom received IV tPA. In the mechanical embolectomy group, 83% were treated with stentrievers. The primary outcome of the the trial was the proportion of patients achieving functional independence (mRS 0-2) at 3 months, excluding those patients who were lost to follow-up or had missing data. The primary outcome was seen in 53% of those in the mechanical embolectomy group versus 42% of the IV thrombolysis group (p=0.028).

Positive Endovascular Trials Enrolling Within a 6-24-Hour Window After Symptom Onset

The trials enrolling patients with large vessel occlusions within 6-–24 hours of symptom onset are described below.

DAWN

The DWI or CTP Assessment with Clinical Mismatch in the Triage of Wake-Up and Late Presenting Strokes Undergoing Neurointervention with Trevo (DAWN) trial was performed in the United States, Canada, Europe, and Australia and enrolled patients known to be well 6 to 24 hours earlier. [9]  Patients were randomized to thrombectomy, performed using the Trevo stentriever device, plus standard care or to standard care alone. Patients were required to have occlusion of the ICA, first segment of the MCA, or both on CT or MR angiography. Patients also needed to have a mismatch between the severity of the clincial deficit and infarct volume. The mismatch criteria varied for those 80 years of age and older and younger patients. Infarct volume was assessed using either diffusion weighted imaging (DWI) or perfusion CT and was measured using automated software (RAPID, iSchemaView). The coprimary end points were the mean score for disability on the utility-weighted mRS and the rate of functional independence (mRS 0-2) at 90 days. After 206 patients were enrolled in the trial, enrollment was stopped because of the results of a prespecified interim analysis. Nine percent of patients in the trial received IV tPA. The mean score on the utility-weighed mRS at 90 days was 5.5 in the thrombectomy group versus 3.4 in the control group (95% credible interval 1.1-3.0) and the rate of functional independence was 49% versus 13% (95% credible interval 24-44). The rate of symptomatic intracranial hemorrhage (ICH) and 90-day mortality did not differ between groups.

DEFUSE 3

The Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke (DEFUSE 3) trial was performed in the United States and enrolled patients known to be well 6 to 16 hours earlier [10]  Patients were randomized to endovascular therapy using any FDA-approved thrombectomy device plus standard medical therapy or to standard medical therapy alone. Patients needed to have an occlusion of the ICA or proximal MCA on CT or MR angiography. They were also required to have an initial infarct volume of < 70 ml, a ratio of volume of ischemic tissue to initial infarct volume of 1.8 or more, and an absolute volume of potentially reversible ischemia of 15 ml or more as measured using automated software (RAPID, iSchemaView). The primary outcome was the ordinal score on the mRS at day 90. After 182 patients were enrolled in the trial, enrollment in DEFUSE 3 was put on hold due to the DAWN results and an early interim analysis was performed. Ten percent of the patients in the trial received IV tPA. Endovascular therapy compared to standard medical therapy alone was associated with a favorable shift in the distribution of functional outcomes on the mRS at 90 days (odds ratio, 2.77; P< 0.001) and a higher rate of functional independence (mRS 0-2), 45% versus 17% (p< 0.001).  Mortality was also lower in the endovascular group versus standard medical therapy group, 14% versus 26% (p=0.05). The rate of symptomatic intracranial hemorrage did not differ significantly between groups. DAWN and DEFUSE 3 showed larger treatment effects than the 6-hour trials, which may have been due to patient selection criteria and also to the low rate of favorable outcomes in the medical control group, in which few patients received IV tPA as a result of their late time of presentation. [10]

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Stent Retriever Devices

Stent retrievers are self-expanding stents that can be deployed and retrieved. When the device is deployed across a thrombus, it pushes the thrombus against the vessel wall and often creates a perfusion channel that immediately starts to reestablish blood flow. The thrombus becomes ensnared within the struts of the stent. The stent is then used to grasp the clot and the stent is retrieved. Three stent retrievers have received FDA clearance.

Stryker Neurovascular Trevo Stent Retriever

The Trevo stent retriever received FDA clearance in 2012 after a randomized, multicenter trial showed superior revascularization and patient outcomes with this device compared with the Merci Retriever. [15]

Covidien Solitaire Stent Retriever System

The Solitaire stent retriever system also received FDA clearance in 2012 after showing better outcomes, better revascularization, and an absence of symptomatic intracranial hemorrhage with this device compared with the Merci Retriever in a randomized, multicenter trial. [16]

Cerenovus EmboTrap II Stent Retriever

The EmboTrap II stent retriever received FDA clearance in 2018 based on the Analysis of Revascularization in Ischemic Stroke With EmboTrap (ARISE) II trial. ARISE II was a single-arm, prospective, multicenter study that compared the EmboTrap device to a composite performance goal criterion derived from the pivotal trials for the Solitaire and Trevo devices. [23]  The primary efficacy end point, modified Thrombolysis in Cerebral Ischemia (mTICI) reperfusion scores ≥2b within 3 passes was achieved in 80.2% (95% confidence interval, 74%–85% versus 56% performance goal criterion; P value, < 0.0001). Functional independence (mRS 0-2) was seen in 67% of patients at 90 days.

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Other Embolectomy Devices

Concentric Merci Retrieval System

The Concentric Merci Retrieval System is a corkscrewlike apparatus designed to remove clots from vessels in patients experiencing an ischemic stroke (Concentric Medical, Inc, Mountain View, Calif) (see the images below). [24, 25]

Concentric MERCI Retriever embedded in a clot. Cou Concentric MERCI Retriever embedded in a clot. Courtesy of Concentric Medical, Inc, Mountain View, Calif.
Clot retrieved from the basilar artery by using th Clot retrieved from the basilar artery by using the MERCI Retriever. Courtesy of Concentric Medical, Inc, Mountain View, Calif, and Yu et al, 2003.

The corkscrew resides in the catheter tip, which shields it from the wall of the vessel until it is ready to be burrowed into the clot. Once lodged in the clot, the device and clot are withdrawn from the vessel. The retriever received approval from the FDA for use in patients with persistent vessel occlusion after IV tPA. [26]

In a study of patients with ischemic stroke, recanalization occurred in 55% of patients who were treated with a MERCI device alone and in 68% of patients who were treated with a MERCI device plus adjuvant treatment. (These figures were the combined results from different models of the device.)

Symptomatic ICH occurred in 9.8% (16/164) of patients overall and a favorable outcome, a modified Rankin score of 2 or less, was seen in 36% of patients at 90 days.

A favorable outcome was seen in 49.1% of revascularized patients, versus 9.6% of those without revascularization. The mortality rate in patients with revascularization was approximately half that of patients with no revascularization (24.8% versus 51.9%, respectively). [27]

Penumbra system

The FDA approved the Penumbra System (Penumbra, Inc, Alameda, Calif) in 2007 to open vessels in patients with ischemic strokes (as demonstrated in the image below). Patients who have received IV tPA can be treated. The device uses aspiration to remove the clot. [28, 29]

Penumbra aspiration. Courtesy of Penumbra, Inc., A Penumbra aspiration. Courtesy of Penumbra, Inc., Alameda, Calif.

The Penumbra pivotal stroke study found that the recanalization rate for patients treated with the Penumbra system, measured for the target vessel, was 81.6%. Symptomatic ICH occurred in 11.2% of patients. A modified Rankin score of 2 or less at 90 days was seen in 25% of patients. [30, 31]

Snarelike devices

In anecdotal reports, interventionists have used retrieval devices to remove thrombi from cerebral vessels. Snares, such as the Neuronet snare (Guidant Endovascular, Santa Clara, Calif), have been developed specifically for use in the treatment of strokes. These devices, which have not yet been evaluated in acute-stroke trials, are simple in design and do not require the clot to be amenable to emulsification.

EKOS ultrasound device

As its name suggests, an ultrasound thrombolytic infusion catheter (EKOS Corporation, Bothell, Wash), seen in the images below, combines the use of a distal ultrasound transducer with infusion of a thrombolytic agent through the microcatheter. [32]

EKOS Micro Infusion Catheter. The catheter has a c EKOS Micro Infusion Catheter. The catheter has a central lumen, an end-hole infusion port, and a 1.7-MHz ultrasound element. Courtesy of EKOS Corporation, Bothell, Wash.
EKOS catheter tip. Courtesy of EKOS Corporation, B EKOS catheter tip. Courtesy of EKOS Corporation, Bothell, Wash.
Schlieren photograph of EKOS device in operation. Schlieren photograph of EKOS device in operation. Courtesy of EKOS Corporation, Bothell, Wash.

Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot to speed its dissolution.

The EKOS product has not received FDA approval for use against acute stroke.

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Questions and Considerations

After approximately 20 years of investigation, studies have proven the benefit of endovascular treatment in selected patients with large vessel strokes compared to medical therapy alone. The development of new device technologies, specifically the stent retiever devices, systems changes allowing for early treatment and better patient selection likely contributed to this success. Even prior to the results of recent trials, endovascular therapy has provided a treatment opportunity for patients unable to receive IV tPA or IV tPA non-responders: those that do not arrive at the hospital early enough to receive IV tPA, those who are not thrombolytic candidates due to a recent surgical procedure or other exclusion, and those treated with IV tPA with residual vessel occlusion.

Since endovascular treatment has now become the standard of care in stroke therapy, hospitals need to be prepared to offer such therapies or be able to rapidly transfer the patient to a hospital that can provide them. New centers able to provide such treatment will be needed in geographic areas without them. Novel models of stroke care, potentially bypassing centers that cannot provide the full spectrum of care for ischemic stroke patients, will have to be considered.

Whether centers can provide endovascular therapy or not, early identification of large vessel occlusion will be critical. Tertiary care centers are likely to obtain CTAs in all nearly all acute stroke patients, treating with IV tPA in those patients that qualify as soon as the non-contrast CT head images are available. Those centers for whom obtaining a CTA is a greater hardship will need to apply generous criteria to determine who will get one and will either be bypassed or will need to transfer the patient to obtain the study elsewhere.

There is currently too little data available to compare the performance of mechanical thrombolytic devices with intra-arterial lytics in the treatment of acute stroke. Devices are potentially able to retrieve large clots that pharmaceutical agents are not able to lyse successfully, and large hemorrhages may occur less frequently with device use. In the end, clots may best be treated with a combined approach using various devices, lytics, and antithrombotics. It is likely that such trials will now develop as the next step toward further improving outcomes in stroke patients.

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