Second, by bringing a new optimism to physicians and scientists, this discovery has attracted numerous clinical scientists to the field of stroke.Third, the use of intravenous tPA led to the creation of primary stroke centers in the US.2 This center designation allows a community to triage pre-hospital patients directly to centers that treat stroke with tPA and away from hospitals that lack these resources. The era of intravenous tPA alone, however, is in transition as newer interventional therapies are becoming conventional.With the US Food and Drug Administration (FDA) clearance in 2004 of the first medical device to mechanically open large intracranial arteries by endovascular means (the Concentric Retriever), there has been increased enthusiasm for treating stroke by direct mechanical intervention, and most recently there has been a call for the designation of comprehensive stroke centers to treat the most severe forms of stroke.3
The call by thought-leaders in stroke for creation of comprehensive stroke centers signifies a solid endorsement that more aggressive endovascular techniques have an important role in stroke therapy. This endorsement stems from two main lines of evidence: large vessel occlusions (basilar, carotid terminus, middle cerebral artery) portend a poor prognosis with a mortality of 53–92%;4–7 and only 20% of untreated patients achieve a good neurological outcome at three months.1 Although tPA can improve this outcome, it is clear that intravenous (IV) tPA restores perfusion of large vessels at most one in five times, and less than half of patients have a good neurological outcome.1 This is likely due to the relatively larger clot burden of large vessel occlusions, the difficulty of delivering a high concentration of tPA directly to the clot when it is administered intravenously, and the relatively low concentration of plasminogen within the clot itself. At least one of these challenges can be mitigated—by instilling a plasminogen activator directly into the clot via catheter, recanalization rates are higher. The Prolyse in Acute Cerebral Thromboembolism (PROACT)-II study found that, for middle cerebral artery occlusions, recanalization rates of 66% can be seen and neurological outcomes statistically improve.8 However, attempts to thrombolyse clots within other arteries (carotid terminus and basilar artery) have proven more difficult. Also, many patients have contraindications for plasminogen activators like recent surgery, trauma, or bleeding disorders, limiting their broad application.
Endovascular thrombectomy is an innovative strategy to open intracranial vessels with a mechanical device introduced via catheter from the groin. The technique carries the intuitive appeal that opening a cerebral vessel quickly by mechanical means could be used in any patient with a large vessel occlusion, including those with tPA contraindications, and in any large vessel regardless of clot burden. The efficacy and safety of this technique was reported in the Mechanical Embolus Removal in Cerebral Ischemia (MERCI) trial, whereby the Concentric Retriever was tested in patients within eight hours of stroke symptom onset.9 The Retriever is a soft, helically shaped, tapered nitinol wire that is delivered into the arterial clot via catheter, then removed from the body with the clot to restore blood flow.The device was found to restore vascular patency in 48% of patients, all of whom were ineligible for tPA. This trial provided data to the FDA to clear the device for clinical use in 2004, and it became the first ever device cleared for use in acute ischemic stroke. Both the PROACT-II8 and MERCI9 studies considered together provide evidence that restoring perfusion improves patient outcome and endovascular techniques have a place in the management of stroke. Further device innovation will likely improve upon the recanalization rate found in the MERCI trial; already, newer generation devices are being tested in the Multi MERCI trial with a favorable trend.10 Any mechanical device will likely be limited to large proximal intracranial vessels, so a combination of thrombolytic therapy with device will often be necessary to completely clear out the clot during stroke. It is still unclear how one should combine thrombolytic agents and mechanical thrombectomy to safely and effectively restore vascular patency, or how best to combine IV and intra-arterial (IA) lytic therapy.A combination of drug and device is undergoing study in the Multi MERCI trial where IV tPA pre-treatment is allowed for tPA-eligible patients and thrombectomy is performed for vessels that fail to recanalize. This strategy will work well in practice where the primary stroke center can administer intravenous tPA and rapidly refer the patient to a comprehensive stroke center that has endovascular intervention available. Interim analysis of this combination approach suggests the method is safe.10A controlled trial, Magnetic Resonance and Recanalization of Stroke Clots Using Embolectomy (MR RESCUE), of thrombectomy compared with medical therapy alone is on-going to test whether thrombectomy definitively improves clinical outcome in a randomized, prospective clinical trial. One can also combine IV and IA tPA in the same patient as studied in the Interventional Management of Stroke (IMS)-I and II trials,11,12 achieving high rates of recanalization with acceptable safety. IMS-III will investigate the safety and efficacy of IV tPA alone compared with IV tPA combined with endovascular treatment where further IA lytics can be given or mechanical means using the Concentric Retreiver or an ultrasonic catheter can be used. This study will provide important safety and efficacy data to physicians and patients so that clinical decisions can be better informed.
Mechanical reperfusion of the brain carries risk. Introduction of mechanical devices into the arteries of the brain must be done with skill. However, even in the best hands, there is still a risk that reperfusion of the brain can have serious consequences in the form of reperfusion hemorrhage. In PROACT-II, the risk of developing a symptomatic (i.e. associated with neurological decline) intracranial hemorrhage (ICH) in patients who received IA thrombolysis was 10%.8 If tPA is given IV, this risk is around 6%.1 In MERCI, the rate of symptomatic ICH was 7.8%, in between the risks of IA and IV thrombolytics. Some of these hemorrhages were related to vascular perforation with the device, but the others were related to reperfusion of a blood vessel injured by the stroke itself. Thus, reperfusion hemorrhage is not simply related to the use of thrombolytic agents, it is also a function of ischemic injury to the vascular wall and how this artery responds to restoration of blood flow. A novel neuroprotective drug (NXY-059) appears to cut the symptomatic intracranial hemorrhage risk by more than half, likely by protecting the endothelium from the oxidative stress of reperfusion.13 It is likely a similar vascular protective effect will be seen with mechanical revascularization, making both plasminogen activators and mechanical thrombectomy safer.
In summary, mechanical intervention to open occluded intracranial vessels during acute ischemic stroke is both feasible and effective to restore blood flow during acute ischemic stroke. The growing number of physicians trained to perform thrombectomy and IA administration of plasminogen activators is growing rapidly.This network of primary and comprehensive stroke centers will provide rapid, innovative treatment to a larger proportion of stroke patients, with those in the most critical need getting the most aggressive forms of therapy.
