Review
State-of-the-art reperfusion strategies for acute ischemic stroke

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Abstract

Timely recanalization of the occluded artery is the only effective treatment for acute ischemic stroke. Intravenous tissue plasminogen activator (IV tPA), administered within 3 hours of symptom onset, is the only United States Food and Drug Administration-approved treatment. This short window often precludes effective intervention, and IV tPA often fails to recanalize major and mid-sized arteries. Intra-arterial thrombolysis has been used for decades, but its safety and effectiveness in cerebrovascular occlusions is also limited. Recently, new mechanical neuroendovascular devices have shown high recanalization rates with acceptable safety in early studies. Multi-modal reperfusion therapy (MMRT) – including intra-arterial infusion of thrombolytics and/or antiplatelet agents, mechanical clot disruption and retrieval, and balloon angioplasty with stent placement – is the prevailing concept for the management of major acute stroke. Recent results suggest that MMRT results in higher chances for both recanalization of the occluded artery and reperfusion of the ischemic tissue.

Introduction

With an annual incidence of 795,000 and mortality of about 140,000, stroke is the third leading cause of death and the leading cause of adult disability in the USA.1 A recent report on the lifetime risk of stroke from the Framingham Study found that one in five middle-aged women and one in six men are expected to suffer a stroke in their lifetimes.2 Worldwide, there were an estimated 5.54 million deaths from stroke in 1999, making it the second most common cause of death.3

Most patients presenting with acute ischemic stroke (AIS) have arterial thrombi that occlude extracranial and/or intracranial arteries. Fast dissolution of the thrombi and arterial recanalization in AIS often lead to dramatic clinical recovery.4 Intravenously administered tissue plasminogen activator (IV tPA) is intended to induce thrombolysis. IV tPA, administered within 3 hours of symptom onset, remains the only United States Food and Drug Administration (FDA)-approved thrombolytic agent for AIS.5

While IV tPA improved outcomes in ischemic stroke, most patients with stroke present more than 3 hours after stroke onset, and thus efforts are constantly made to identify subpopulations in which the IV tPA window for therapy can be extended.6 The last decade has been a period of rapid advance in physiopathology and neuroimaging of cerebral ischemia. These advances I have directly improved the management of patients with AIS. Treatment in the acute phase is largely aimed at partially or completely restoring blood flow in the affected artery. Since “time is brain,” timely recanalization of the occluded cerebral artery may restore cerebral perfusion, thereby salvaging threatened ischemic tissue and improving clinical outcome.7 Therefore, the true success of recanalization therapy depends on timing as well as the degree of reperfusion. However, as with myocardial infarction, recanalization and reperfusion of ischemic tissue may occasionally exacerbate tissue damage by reperfusion injury, cerebral edema, and hemorrhagic transformation.7 Additional pharmaceutical agents, as well as an increasing variety of devices tailored to neuroendovascular applications, used alone and in combination, have been used to achieve recanalization and reperfusion in AIS. We aimed to review these approaches and the current understanding of recanalization in stroke patients.

Section snippets

Intravenous thrombolysis

IV tPA, the only FDA-approved treatment for stroke, is of demonstrated and substantial benefit for select patients with acute cerebral ischemia when administered in the first 3 hours after stroke onset. Treatment with IV tPA is supported by two phase 3 National Institute of Neurological Disorders and Stroke (NINDS) trials.5 The NINDS Trials 1 and 2 together randomized 624 participants to receive 0.9 mg/kg of IV tPA or placebo within 3 hours of stroke onset. The proportion of patients with

Intra-arterial thrombolysis

Intra-arterial (IA) administration of thrombolytics can reduce the overall quantity of drug used and increase the efficiency of drug delivery into the clot, thus increasing the chances for recanalization. PROACT II is the only randomized study to date that has examined the safety and efficacy of IA thrombolysis in patients with AIS.26 Outcomes in 121 patients treated with IA prourokinase + heparin in 3-to-6 hours from stroke onset were compared with those in 59 patients treated with heparin

Mechanical clot retrieval

Several devices aiming to aspirate or retrieve the occluding clot in patients who are ineligible for IA thrombolysis have been devised, with the snare and basket Mechanical Embolus Removal in Cerebral Ischemia (MERCI) devices (Concentric Medical, Mountain View, CA, USA) gaining most attention.[35], [36] The MERCI approach entails deploying a corkscrew-like retrieval device into the clot. The balloon of the guiding catheter is inflated proximally to the clot, to achieve flow arrest and prevent

Initial low-dose IV tPA with late IA tPA and IA ultrasound

The Interventional Management of Stroke (IMS) I and II studies examined the effects of initial low dose IV tPA treatment (0.6 mg/kg) combined with late IA tPA in patients whose vessel failed to recanalize after the IV bolus in 80 and 81 patients respectively.44 Some patients also received IA ultrasound administered with a specialized device, the EKOS EkoSonic Endovascular System (EKOS Corporation, Bothell, WA, USA) after evidence showed that ultrasound energy hastens clot breakdown.[45], [46]

Endovascular angioplasty and stenting

Balloon angioplasty with or without stent placement represents a different approach to the recanalization of arterial occlusion. This strategy, which is similar to the approach commonly taken in patients with acute myocardial infarction, was hampered for a long time by the absence of dedicated catheters for the cerebral vasculature. The cerebral blood vessels are suspended in cerebrospinal fluid, without the firm muscular support of the myocardium, thus they are more prone to dissections and

Stent-based thrombectomy

The Solitaire AB stent (ev3, Irvine, CA, USA) is a self-expanding microstent especially designed for neurointerventional use that offers the unique capability of being able to be fully deployed and then completely retrieved, if it has not been detached. It was originally designed for the treatment of cerebral aneurysms. Castaño et al. tested whether the Solitaire AB stent could be used as a novel mechanical embolectomy device for large artery occlusions of the anterior circulation in patients

Multimodal reperfusion therapy

Because the results of the previously discussed interventions are similar and because reperfusion significantly improves outcome, attempts were made to use more than one endovascular modality to achieve quick reperfusion. This approach, termed multimodal reperfusion therapy (MMRT), is the mainstay of endovascular therapy of stroke in our Center, in both the posterior55 and anterior circulation.56

The MMRT approach is particularly promising for patients with anterior circulation infarcts. MMRT,

Discussion

Reperfusion is associated with better outcome after stroke, and vessel recanalization is crucial to increasing the possibility of meaningful tissue reperfusion. These attempts should be carried out as early if possible, since it is plausible that earlier recanalization will result in increased tissue salvage and a better functional outcome. Therefore, in patients who fail to reperfuse the ischemic tissue after IV thrombolysis, and in those who are ineligible or inadequate candidates for such

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