Mechanical Thrombolytic Treatment Techniques
While intravenous (IV) tissue-type plasminogen activator (tPA) had been the only medical therapy approved for treatment of acute stroke in the United States, four trials have now shown the efficacy of endovascular therapy, the most recent of which, SWIFT-PRIME, was presented at a plenary session of the International Stroke Conference in Nashville on February 11, 2015. [1, 2, 3] Almost 50% of patients treated with tPA alone in the National Institutes of Neurologic Disorders and Stroke (NINDS) trial had achieved essentially full recovery.  However, subgroup analyses of the NINDS data showed that patients with severe strokes had only an 8% likelihood of achieving clinically significant improvement with tPA.  The poor outcome in these patients has inspired the search for acute-stroke treatments that are more effective than tPA.
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. [6, 7] The most recently developed devices, known as retrievable stents or stentrievers, have shown higher recanalization rates and better outcomes than those seen with the older Merci Retriever.
Trials now also show better outcomes with mechanical embolectomy than with IV tPA alone but 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. [8, 9, 10] 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).  Finally, the small (n=118) MechanicalRetrieva land 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. 
Newer trials, including MR CLEAN, EXTEND-IA, ESCAPE, and SWIFT PRIME, required imaging that confirmed large vessel occlusion. [1, 2, 3] In addition, the trials incorporated the use of newer technologies using the retrievable stents.
MR CLEAN was the first of the positive endovascular treatment trials to be reported.  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 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.  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 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 was the last of the four trials to be completed and the results were reported at the International Stroke Conference in Nashville, TN on February 11, 2015. 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 thecontrol group (35.5%).
Stryker Neurovascular Trevo Stent Retriever
The Trevo stent retriever received US Food and Drug Administration (FDA) clearance in 2012 after a randomized, multicenter trial showed superior revascularization and patient outcomes with this device compared with the Merci Retriever. 
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. 
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). [15, 16]
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 has received approval from the US Food and Drug Administration (FDA) for use in patients with persistent vessel occlusion after IV tPA. 
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). 
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. [19, 20]
Initial results for one study, reported at the International Stroke Conference in New Orleans in February 2008, found that the recanalization rate for patients treated with the Penumbra system, measured for the target vessel, was 81.6%. Symptomatic intracranial hemorrhages occurred in 11.2% of patients. A modified Rankin score of 2 or less at 90 days was seen in 25% of patients. 
In anecdotal reports, interventionists 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. 
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 yet received FDA approval for use against acute stroke. It is currently being studied to determine its efficacy in such treatments.
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 stentriever devices, and 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 will 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.