Endovascular management of acute ischemic stroke · Cooperative Acute Stroke Study I and II trials, along with the ATLANTIS trial, all used intravenous rt-PA within 4–6 hours of

Neurosurg. Focus / Volume 26 / March 2009

Neurosurg Focus 26 (3):E2, 2009

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Stroke is the third cause of death in the US after heart disease and cancer and results in an astound-ing 700,000 people suffering from a stroke each

year.26 Approximately 87% of these strokes are ischemic in which a reduction in cerebral blood flow leads to brain infarction.26 Unfortunately, stroke is also one of the lead-ing causes of long-term disability in the US. It is estimated that $62.7 billion was spent in the management, both short and long term, of stroke in 2007 alone.26 Stroke outcomes are, however, steadily improving as public awareness increases and treatment strategies improve. Following a stroke, 50–70% of patients regain functional indepen-dence, 15–30% of patients are permanently disabled, and only 20% require institutional care.26 The prompt initia-tion of treatment for acute strokes has been established as the standard of care and includes both well-established medical therapies and exciting new endovascular strate-

gies. Strict time constraints, however, surround the med-ical therapy of ischemic stroke, resulting in treatment of only 3–8.5% of patients with this condition.26 Aggressive treatment modalities and a slightly broader treatment window have allowed the advancement of endovascular intervention for acute ischemic stroke.

Acute Stroke and Endovascular ManagementOver the past 2 decades a variety of intravenous

thrombolytic trials have been performed using strepto-kinase, urokinase, rt-PA, r-proUK, and most recently Re-tavase (retaplase). The differences between these agents include stability, half-life, fibrin selectivity, and mecha-nism of action.28 In the late 1980s and early 1990s, 8 large multicenter trails of intravenous thrombolysis were reported. The first 3 were trials of intravenous streptoki-nase and included the Multicenter Acute Stroke Trial–Europe, the Australian Streptokinase Trial, and the Mul-ticenter Acute Stroke Trial–Italy. These trials failed to show any benefit within 4–6 hours after symptom onset and were stopped early due to a high rate of ICH and death in the treatment arm. The use of streptokinase in stroke was therefore abandoned. The next drug to un-dergo evaluation was intravenous rt-PA. The European Cooperative Acute Stroke Study I and II trials, along with the ATLANTIS trial, all used intravenous rt-PA within 4–6 hours of stroke onset. These trials failed to show any

Endovascular management of acute ischemic stroke

A reviewChirag D. ganDhi, M.D., Lana D. Christiano, M.D., anD CharLes J. PrestigiaCoMo, M.D.Department of Neurological Surgery, University of Medicine and Dentistry of New Jersey, Newark, New Jersey

The management of stroke has progressed significantly over the past 2 decades due to successful treatment protocols including intravenous and intraarterial options. The intravenous administration of tissue plasminogen ac-tivator within an established treatment window has been proven in large, well-designed studies. The evolution of endovascular strategies for acute stroke has been prompted by the limits of the intravenous treatment, as well as by the desire to demonstrate improved recanalization rates and improved long-term outcomes. The intervention-al treatment options available today are the intraarterial administration of tissue plasminogen activator and newer antiplatelet agents, mechanical thrombectomy with the MERCI device and the Penumbra system, and intracranial angioplasty and stent placement. In this review the authors outline the major studies that have defined the cur-rent field of acute stroke management and discuss the basic treatment paradigms that are commonly used today. (DOI: 10.3171.2009.1.FOCUS08275)

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Abbreviations used in this paper: ATLANTIS = Ateplase Thrombolysis for Acute Non-Interventional Therapy in Stroke; ICA = internal carotid artery; ICH = intracranial hemorrhage; IMS = Interventional Management of Stroke; MCA = middle cerebral artery; MERCI = Mechanical Embolus Removal in Cerebral Ischemia; NIHSS = National Institutes of Health Stroke Scale; NINDS = National Institute of Neurological Disorders and Stroke; PROACT = Prolyse in Acute Cerebral Thromboembolism; PTA = percutaneous transluminal angioplasty; r-proUK = recombinant prourokinase; rt-PA = recombinant tissue plasminogen activator; TIMI = Thrombolysis in Myocardial Infarction.

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C. D. Gandhi, L. D. Christiano, and C. J. Prestigiacomo

2 Neurosurg. Focus / Volume 26 / March 2009

benefit at their primary endpoint of neurological improve-ment at 90 days.10

To date, the only intravenous thrombolysis trials that have shown a benefit for acute stroke patients have been the NINDS trials.22 The main difference from previous stroke trials was the early time to treatment of < 3 hours from symptom onset. Intravenous rt-PA was given as 0.9 mg/kg of body weight with a maximum dose of 90 mg. Compared with the placebo study arm, patients in the treatment arm were 30% more likely to have minimal or no disability at 90 days. The symptomatic ICH rate with-in 24–36 hours was higher in those receiving treatment compared with the controls (6.4 and 0.6%, respectively). However, despite this elevated rate of hemorrhage, the mortality rate at 90 days was similar between the treat-ment and control groups. Based on this two-part clini-cal trial that established a 3-hour therapeutic window, the FDA approved the use of intravenous rt-PA in 1996.

Since the approval of intravenous rt-PA, multiple studies have attempted to stratify subgroups of patients who would benefit from intravenous thrombolysis alone and those who might require further endovascular treat-ment. In a recent review of 54 patients with proximal MCA occlusion receiving intravenous rt-PA within 3 hours, Labiche et al.17 found that 75% of patients who had early recanalization and a significant clinical recovery within 2 hours of drug administration had sustained clini-cal benefit at 3 months. This particular analysis was not performed as primary endpoints during the NINDS tri-als, but post hoc analysis of the NINDS data parallels this conclusion.8 In another study, Felberg et al.5 demonstrated that the restoration of flow at the end of intravenous rt-PA infusion was a significant factor in differentiating pa-tients who would make a dramatic recovery from those who would not. Normal restoration of flow was seen in 58% of patients who experienced a dramatic recovery and in 14% of those who did not experience a dramatic recovery. One of the potential treatment applications of this concept could be that patients with persistent proxi-mal occlusion without signs of early recovery may be candidates for further interventional management. In the subset of patients who do not improve after intravenous thrombolysis, prompt MR imaging, with particular atten-tion to large mismatches between diffusion and perfusion sequences, has become routine at many institutions.29 If there is a salvageable ischemic penumbra, without ICH, endovascular therapy should be considered the next step in treatment and has been described by some as a “res-cue” procedure.16

Intraarterial ThrombolysisOne of the main limitations to intravenous rt-PA has

been the strict 3-hour time window for initiating thera-py. This window, combined with a limited public health awareness of stroke, has limited the use of intravenous thrombolysis to < 5% of eligible candidates.3 Intraarterial thrombolysis was first studied as an alternative to intrave-nous thrombolysis to address this time limit. The idea be-hind intraarterial thrombolysis is rapid local delivery of drug with a greater concentration of thrombolytic agent at the site of occlusion and lower concentrations systemical-

ly. Theoretically this should lead to improved recanaliza-tion and reduced hemorrhagic complications, but because of the differences in stroke severity, time to treatment, and increased rates of MCA recanalization with intraar-terial treatment, direct comparisons have been difficult and currently no controlled studies exist.

The pretreatment evaluation for intraarterial treat-ment is similar to that for intravenous treatment: Once an acute stroke is diagnosed, baseline CT scanning or, more recently, MR imaging is commonly performed to exclude ICH, identify a point of occlusion, and define the region of salvageable brain parenchyma. A catheter ce-rebral angiogram is then performed to confirm the point of occlusion and assess the degree of collateral circula-tion. A microcatheter is advanced either to the base of the clot, into the clot, or distal to the clot, and a thrombolytic agent is injected. A variety of agents exist for intraarte-rial thrombolysis, and at our institution retaplase is most commonly used. The thrombolytic agent is infused over 60–120 minutes while intermittent angiographic studies are obtained. Additionally, mechanical disruption of the clot with a guidewire or balloon may be used to effec-tively evacuate clot. The efficacy and safety of intraar-terial r-proUK–based thrombolysis was established in the PROACT I and II studies,6 which were randomized, multicenter, controlled trials. Intraarterial thrombolysis in patients with MCA occlusion was at least as equally effective as intravenous thrombolysis in improving out-come and more effective in reopening the occluded ar-tery (in approximately two-thirds of the cases). This was true even with a longer 6-hour window from symptom onset to treatment. Recanalization rates for intraarterial thrombolysis have been shown to be superior to those for intravenous thrombolysis for major cerebrovascular oc-clusions (70% vs 34%).23 The differences in recanaliza-tion are most apparent with large-vessel occlusion such as proximal MCA, ICA, and intracranial carotid artery “T” occlusion.33

Figure 1 provides a cerebral angiogram of a patient in whom intravenous rt-PA was contraindicated. There is a thromboembolic clot at the left ICA terminus (“T” oc-clusion) resulting in significant occlusion of the left ICA, and no perfusion of the distal vessels. A microcatheter was embedded in the ICA clot, and intraarterial rt-PA (retaplase) was injected into the clot. As clot lysis was vi-sualized on serial angiograms the microcatheter was ad-vanced into the clot, which extended into the M1 segment of the MCA. Figure 2 demonstrates complete recanaliza-tion of the left ICA and MCA after injection of 3 mg of intraarterial rt-PA.

Combined Intravenous and Intraarterial rt-PA Thrombolysis

Although intraarterial thrombolysis has been shown to be effective, the time delay required for cerebral an-giography and microcatheter positioning is a shortcoming. Because of this shortcoming, more recent investigations have combined both intravenous and intraarterial throm-bolysis, allowing for the immediate initiation of intrave-nous thrombolysis within the 3-hour window followed by an intraarterial thrombolysis treatment within the 6-hour




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window, if the patient qualifies for further intervention. A variety of clinical trials have been performed to evaluate both radiographic efficacy of dual treatment and potential improvement in clinical outcomes.

The first of these trials was the Emergency Manage-ment of Stroke Bridging trial in 1999 in which 35 patients with acute stroke were randomized to first receive intra-venous rt-PA or placebo followed by intraarterial rt-PA if the vessel remained occluded.20 Even though 70% of patients who received intravenous rt-PA still had angio-graphically confirmed residual thrombus requiring in-traarterial therapy, those who received the combination of intravenous/intraarterial rt-PA had significantly more complete MCA recanalization than the placebo group (55 vs 10%). In addition, the risk of hemorrhagic complica-tions was similar. Despite the higher rates of recanaliza-tion the clinical outcomes were found to be no different between the 2 groups.

Another trial that studied intravenous and intraar-terial thrombolysis randomized 45 patients with acute stroke to receive early intraarterial thrombolysis followed by an intravenous thrombolysis arm or a control arm.15 Twelve patients received intraarterial thrombolysis with intravenous rt-PA administered afterward in the intensive care unit. Intracranial hemorrhage occurred in 17% of the treatment arm and 6% of the control group, but there was no difference in symptomatic ICH or the mortality rate between the 2 groups. A good outcome, defined as a modified Rankin Scale score of 0–3, at 1 month was seen in 67% of patients in the treatment arm and in 21% of the control group. At 12 months, good outcomes were seen in 83 and 33% of each group, respectively. This study again demonstrates the efficacy of thrombolytic therapy but is unclear on whether the differences in outcome are be-cause of the early intraarterial therapy or the intravenous therapy that followed within 6 hours.

The largest prospective trial to date to study com-bined therapy was the recent IMS trial that was released in 2004.11 Eighty patients with a medial baseline NIHSS score of 18 received intravenous rt-PA within 3 hours of

onset followed by a 2-hour infusion of intraarterial rt-PA. The primary comparisons were with a similar subset of placebo- and intravenous rt-PA–treated patients from the NINDS rt-PA Stroke trial. The 3-month mortality rate of 16% was not statistically different from that in the pla-cebo (24%) and rt-PA treatment (21%) groups from the NINDS trial. The rate of symptomatic ICH (6.3%) was also similar to the rt-PA–treated group (6.6%) but higher than that in the placebo group (1%). The individuals in the IMS trial had significantly better outcomes at 3 months (56%) than the NINDS placebo group for all outcome measures.

A follow-up study by the IMS investigators further compared symptomatic and asymptomatic ICH rates in IMS with other large clinical trials including NINDS, ATLANTIS, European Cooperative Acute Stroke Study, Emergency Management of Stroke Bridging trial, and PROACT.12 Symptomatic ICH occurred in 6% and as-ymptomatic ICH in 43% of patients. The rate of symp-tomatic hemorrhage was similar to that in the intravenous rt-PA–only arm of the NINDS study. The rate of asymp-tomatic hemorrhages was higher than in the NINDS trial but similar to other more recent combined intraarterial-intravenous rt-PA trials. The only 2 factors that were in-dependent risks for any hemorrhage were location (ICA) and atrial fibrillation.

Currently, the results from the IMS II study, a larger follow-up trial for efficacy, are still pending. Enrollment is now underway for the IMS III study to compare intra-venous rt-PA with intraarterial intervention, including the adjuvant use of mechanical thrombolysis. The patients will be randomized into intravenous rt-PA–alone or intra-venous/intraarterial treatment groups. The patients in the intravenous/intraarterial treatment arm will receive intra-venous rt-PA and then undergo immediate angiography. If a clot is still visualized, 1 of 3 intraarterial treatment modalities will be used: the Merci retrieval device, EKOS microinfusion catheter, or intraarterial rt-PA injected at the site of the clot.

Abciximab TrialsThere has been a recent interest in the use of abcix-

imab for acute stroke. Abciximab is a monoclonal anti-body that inhibits platelet aggregation by binding to the platelet fibrinogen receptor glycoprotein IIb/IIIa. Plate-let aggregation is one of the first events to occur in the arterial thrombosis occlusion cascade, and if that initial accumulation of platelets could be inhibited, perhaps re-canalization rates could be improved. Additionally, rt-PA itself promotes thrombus formation by stimulating plas-min production, thereby activating platelets. Blocking platelet activity may therefore also reduce reocclusion rates after intravenous rt-PA administration. Lee et al.18 have studied 16 patients who were given intraarterial UK alone and 20 patients who were given intravenous abcix-imab (0.25-mg/kg bolus) followed by a maintenance dose (0.125 ug/kg/min). These patients also received UK until complete or near-complete vessel patency was restored or until 1,000,000 U of UK had been administered. All patients underwent CT scanning immediately after treat-ment. In the combined urokinase/abciximab group 90%

Fig. 1. Anteroposterior left ICA angiogram demonstrating the top of the ICA occlusion.




exhibited recanalization compared with 44% in the UK group alone. A lower dose of UK was required for re-canalization when used with abciximab. There was no significant difference in the rate of hemorrhage, but there was a trend toward better outcomes in the combination group (80 vs 50%).

The findings of the study by Lee et al.18 support the possibility that the addition of abciximab improved the outcomes of a subgroup of intravenous rt-PA–treated pa-tients who initially responded but experienced early fail-ures due to vessel reocclusion. A recent study looked at 142 consecutive stroke patients with documented MCA occlusion that was treated with intravenous rt-PA.27 Ini-tial recanalization occurred in 61% of patients, but 12% had documented reocclusion on transcranial Doppler ul-trasonography at a mean time of 65 ± 55 minutes after recanalization. One of the independent predictors of reoc-clusion was severe ipsilateral carotid artery disease. The authors suggested that platelet-rich emboli most com-monly found at the carotid artery bifurcation may create a thrombus that could be more resistant to lysis by rt-PA and more prone to reocclusion. The presence of a severe stenosis or occlusion in the carotid artery may also rep-resent a marker of diffuse atherosclerotic disease. In this case the presence of simultaneous thrombus formation at the site of an underlying MCA plaque may lead to incom-plete recanalization and early reocclusion. These types of cases may be ideal for the use of a combination of rt-PA and abciximab, but this premise still requires further study.

Although the use of abciximab has not been well established in the management of acute stroke, there ex-ists a growing body of literature suggesting that it may be of significant benefit in the treatment of intraprocedural thromboembolic complications.2,32 A majority of these are small case reports, but the authors of the largest series reviewed 29 patients in whom cerebral arterial throm-boembolic occlusions developed intraoperatively and in whom abciximab was administered within 60 minutes.32 Angiographic improvement was seen in 81% of the cases. There were 3 ICHs that occurred when abciximab was ad-ministered with mechanical clot disruption. Two of these

hemorrhages also received rt-PA. At follow-up, 83% of the patients were independent, 10% were dependent, and 7% had died. In the hyperacute period of a thromboem-bolic event, platelet aggregation is known to play a large role in the formation of the initial thrombus plug. Abcix-imab is believed to disrupt this initial process and is ideal in intraprocedural complications because treatment can be administered while in the hyperacute state. Because of the increased rate of ICH with mechanical clot dis-ruption, some interventionalists do not recommend using these devices with abciximab.

Recent publications have raised the concern that ab-ciximab causes ICH.24 One of the reasons cited has been the relatively long half-life of the drug that can cause low-

Fig. 2. Anteroposterior left ICA angiogram obtained after a 3-mg in-jection of intraarterial retaplase, demonstrating recanalization of the ICA with flow through the ICA, MCA, and anterior cerebral artery (ACA).

Fig. 3. Images of the Merci retrieval device. A: The device is de-ployed distal to the clot. B: The clot is embedded within the coils of the retriever device. C: The balloon guide proximal to the clot is in-flated to control blood flow. D. While aspirating, the retriever and clot are retracted into the microcatheter. Image used with the permission of Concentric Medical, Inc.

Fig. 4. Anteroposterior left ICA angiogram demonstrating significant clot in the cavernous ICA extending into the MCA




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level blockade of platelet receptors up to 15 days after ad-ministration. Numerous prospective studies have detailed the safety and efficacy of abciximab. A randomized, double-blinded, placebo-controlled dose-escalationstudy conducted by the Abciximab in Stroke Investigators1 showed no difference in the risk of asymptomatic ICH (7%) detected on 3-month poststudy CT scans compared with controls (5%) and illustrated a trend toward better outcomes in the abciximab treatment arm. Another study showed that abciximab was safe and posed no increased risk of ICH during carotid artery stent placement in 151 consecutive patients when used in combination with hep-arin or aspirin.13 The newer glycoprotein IIb/IIIa receptor agonists eptifibatide and tirofiban have shorter half-lives (2.5 and 2 hours, respectively) and are thought to be po-tentially safer.

Mechanical Embolectomy: the Merci DeviceGiven the risk of ICH and limited time constraints

associated with thrombolytic agents, alternate means of removing a clot are in the forefront of stroke research. The MERCI Stroke trial was designed to test an intraar-terial mechanical thromboembolic retrieval device that was developed to address some of the shortcomings of intravenous rt-PA therapy.31 The Merci device (Concen-tric Medical), approved by the FDA in 2004, consists of a flexible tapered nitinol wire with 5 helical loops that can be embedded within the thrombus for retrieval. Fig-ure 3 demonstrates the Merci retrieval device. The FDA-approved Phase I and II trials were performed at 25 par-ticipating hospitals in the US. The primary endpoint was successful revascularization in all treatable vessels and major device-related complications. Revascularization criteria were based on the TIMI Scale score and defined as either TIMI 2 or 3. The inclusion criteria were patients with an acute stroke whose NIHSS score was > 8, who

were treated within 8 hours of symptom onset, were in-eligible for intravenous rt-PA, and who had an angiogram documenting the point of occlusion. Patients with an in-ternational normalized ratio < 3.0 were included in Part II of the study, which broadens the potential treatment group compared with previous studies.

Of the 1809 patients screened, 151 were enrolled, and of these, 141 patients had the Merci device used. In the overall group, 48% of occluded vessels were recanalized with a 7.1% rate of clinically significant procedural com-plications, a 7.8% rate of symptomatic ICH, and a 44% mortality rate. The baseline control arm was the spon-taneous recanalization rate of 18% from the PROACT II study. Device complication included vascular perforation, intramural arterial dissection, or embolization of a previ-ously unaffected territory. In addition, patients in whom recanalization was successful were more likely to experi-ence a good neurological outcome (modified Rankin Scale score of 0–2) at 90 days (46 vs 10%, respectively) and the mortality rate was lower (32 vs 54%, respectively).

Figure 4 shows an anterior cerebral angiogram ob-tained in a patient who presented outside of the 3-hour window for intravenous rt-PA. She was taken to the an-giography suite where a thromboembolic clot was noted in the cavernous ICA (Fig. 4). A microcatheter was passed distal to the clot, which indicated that the clot extended well into the MCA M2 segment. The Merci device was deployed within the clot and retracted; the corkscrew-like appearance of the deployed device is demonstrated in Fig. 5. A large clot was noted within the aspirate when the ICA clot was engaged with the L5 Merci device, and a smaller MCA clot was noted to be embedded within this device (Fig. 6). The subsequent cerebral angiogram (Fig. 7) demonstrated recanalization of the left ICA with per-fusion of the distal intracranial vessels.

Most recently, the Multi-MERCI Stroke trial results were published. This multicenter, prospective, single-arm trial is similar to the previous MERCI trials; however, this study included patients receiving intravenous rt-PA

Fig. 5. Anteroposterior view of the Merci device (arrow) embedded in the left MCA clot.

Fig. 6. The clot was evacuated with the use of the Merci device. The arrow indicates the ICA clot that was removed with the L6 device. The arrowhead points to the MCA clot embedded in the L5 device.

Fig. 7. Anteroposterior left ICA angiogram acquired after mechani-cal embolectomy with the Merci device. Recanalization was established through the left ICA, ACA, and MCA.




with persistent arterial occlusion. The primary endpoints evaluated were recanalization rates of intracranial oc-cluded vessels and procedural complications.30

Of the 1088 patients screened for the Multi MERCI Stroke trial, 177 patients were enrolled, and in 164 pa-tients the Merci retractor device was used. In the overall group, 68% of the occluded vessels were recanalized with a 5.5% rate of clinically significant procedural complica-tions, a 9.8% symptomatic ICH, and a 34% mortality rate at 90 days. Additionally, despite the inclusion of patients receiving intravenous rt-PA, there was no statistical dif-ference in the ICH rate or procedure-related complica-tions compared with earlier MERCI trials, indicating that preprocedural intravenous rt-PA is safe. Much like earlier MERCI trials, Multi MERCI demonstrated that patients with successful recanalization were more likely to have a good neurological outcome (modified Rankin Scale score of 0–2) at 90 days (49 vs 10%, respectively) and the mor-tality was lower (25 vs 52%, respectively).

The Merci device has been shown to be useful, es-pecially in large-vessel occlusions, and the safety profile of the device is comparable to previous acute stroke in-terventions. Additionally, this device has proven that re-canalization is significantly associated with better neu-rological outcomes and lower mortality rates. It has not yet, however, been proven to be effective in a prospective randomized controlled trial for improving clinical out-comes.

There are 2 ongoing trials using the device, the MR and Recanalization of Stroke Clots Using Embolectomy and the IMS III trial. The former investigation is an NIH-sponsored trial to determine if diffusion-perfusion MR imaging prior to stroke intervention can identify patients who might benefit from mechanical embolectomy with the MERCI device. Finally, the IMS III trial will study in-travenous rt-PA versus intraarterial multimodality treat-ments. The patients will be randomized into intravenous rt-PA alone or intravenous/intraarterial treatment groups. The patients in the intravenous/intraarterial treatment arm will receive intravenous rt-PA and then undergo im-mediate angiography. If a clot is still observed, 1 of 3 in-traarterial treatment modalities will be used: the Merci retrieval device, EKOS microinfusion catheter, or intraar-terial rt-PA injection at the site of the clot.

Mechanical Embolectomy: The Penumbra SystemThe Penumbra system (Penumbra, Inc. (Fig. 8]) is a

device by which a thromboembolic clot can be removed from large intracranial vessels. The device removes thrombus via aspiration, mechanical disruption, and ex-traction. Once the catheter is positioned just proximal to the clot, the aspiration pump is connected to the cath-eter. The aspiration pump generates a vacuum of −20 in of Hg, which reduces the clot burden.4 The separator is then advanced through the catheter into the distal clot, aiding in the aspirating-debulking process. If thrombus persists, direct mechanical removal of thrombus may be performed with the aid of the thrombus removal ring. The thrombus removal ring works by engaging the clot proxi-mally and extracting underflow arrest with the assistance of a proximal balloon guide catheter.7

Phase I findings of the Penumbra system were re-cently published and demonstrate exciting results. A multicenter, prospective, single-arm trial was designed to evaluate the safety and efficacy of the Penumbra system. The primary endpoint was revascularization of the target vessel defined by a TIMI score of 2 or 3. The secondary endpoints were improving the NIHSS score by 4 points or achieving a modified Rankin Scale score of ≤ 2, and evaluating all-cause death. Twenty-three patients were enrolled in the study and 21 vessels were treated with the Penumbra system. Three patients were not treated due to vessel tortuosity and failure of access, resulting in an ac-cess rate of 87%.4 Recanalization to a TIMI score of 2 or 3 was achieved in all 21 vessels in which the device was deployed. The secondary endpoint of modified Rankin Scale score of ≤ 2 or improvement of NIHSS score by ≥ 4 points was achieved in 45% of the patients.4

The adverse events were within the limits of previ-ous acute stroke studies. Nine (45%) of the enrolled 20 patients died within the 30-day follow-up period. Given the severity of the stroke cases treated, a mean NIHSS score of 20, and the 9 (43%) basilar artery occlusions, the mortality rate was lower than expected; none of the deaths were related to the study device.4 There were 2 procedural complications: a groin hematoma and a suba-rachnoid hemorrhage that resolved spontaneously and did not result in neurological deterioration. In 8 cases an ICH was reported, 2 of which were classified as symptomatic. In 7 of the 8 patients with ICH, intraarterial rt-PA was used after the Penumbra system to treat vessel occlusion distal to the recanalized target vessel.4

Based on the Phase I trial results, the Penumbra sys-tem has been shown to have significant potential for me-chanical embolectomy in the treatment of acute stroke in large intracranial vessels. In 100% of the cases in which the device was deployed, recanalization of the target ves-sel was achieved. Adjunctive therapy with intraarterial rt-PA, however, was associated with a higher incidence of ICH.7 The Penumbra device has recently received FDA approval.

No other mechanical embolectomy device is cur-rently approved by the FDA for use in acute stroke. Two unapproved devices are the Neuronet Endovascular Snare (Guidant Corp.) and the Amplatz Goose Neck Snare (Mi-crovena Corp.). These have only been successfully used

Fig. 8. The Penumbra system: the catheter is positioned just proxi-mal to the clot, the aspiration pump is connected to the catheter, and the separator is advanced through the catheter into the distal clot, aiding in the aspirating-debulking process. Image used with the per-mission of Penumbra, Inc.




7

in a limited number of patients without any larger-scale demonstration of efficacy or safety.14

Angioplasty and Stent PlacementConcerns remain about the limited treatment win-

dow and associated hemorrhage risk of intravenous and intraarterial thrombolytics and the disappointing rates of recanalization reported with mechanical embolectomy. This concern has prompted the application of other tech-niques including intracranial angioplasty and stenting, used so successfully in the cardiac literature; the direct application of techniques described in the cardiac litera-ture, however, must be considered conservatively given that the vasculature and circulation of the cardiac system differ significantly from the cerebrovascular system.

The largest study of angioplasty for acute stroke was conducted by Nakano et al.21 Thirty-six patients present-ing with acute strokes underwent thrombolytic therapy alone, and 34 other patients were treated first with PTA and subsequent thrombolytic therapy was added if needed for distal embolization. The rate of partial or complete re-canalization based on TIMI scores was 91.2% with PTA and 63.9% with thrombolytic therapy only. The incidence of ICH was 2.9 and 19.4%, respectively. This risk differ-ence highlights one of the potential benefits of PTA. In-dependent outcome was also better in the PTA group than the thrombolytic-only group (73.5 vs 50%, respectively).

Other smaller studies have also reported improve-ment in NIHSS score for patients who underwent angio-plasty in addition to intravenous rt-PA.25,34 One of the im-portant conclusions of these studies was the development of a protocol to ensure that angioplasty is not significantly delayed while evaluating the efficacy of already initiated thrombolytic therapy. In the most recent study, the authors conducted a retrospective review of 9 patients with acute strokes and MCA or intracranial ICA occlusion who un-derwent PTA.20 All patients underwent head CT scanning to assess the location of the occlusion and CT perfusion scanning to assess tissue salvageability. Patients available within the intravenous rt-PA window received the medi-cation and all patients were promptly taken for angiogra-phy, intraarterial rt-PA, and PTA. The mean time from CT scanning to vessel canalization was 2.1 hours, with an 89% recanalization rate, and 56% of patients experi-enced good outcomes. This study demonstrated that PTA potentially shortens recanalization times in well-selected patients. However, the findings did not prove that rapid recanalization with PTA leads to more tissue saved when compared with conventional thrombolysis alone.

Although limited data exist regarding the rate of acute restenosis after intracranial PTA for stroke, con-cerns based on the cardiac literature persist and the ad-ditional treatment of occlusive and atherosclerotic lesions with intracranial stent therapy is becoming more popular. In a multicenter randomized trial comparing stent place-ment with angioplasty for acute myocardial infarction, the mean minimal luminal diameter was larger with stent therapy than with angioplasty alone.7 In addition, the need for target-vessel revascularization because of ischemia, as well as death and reinfarction, were lower with stenting. The trial concluded that in patients with acute myocardial

infarction, implantation of a stent has clinical benefits be-yond those of angioplasty alone.

Reports on the intracranial application of stent tech-nology are limited in the current stroke literature. The largest and most current study retrospectively analyzed 19 patients with acute stroke who underwent intracranial stent placement after failure of pharmacological and/or mechanical thrombolysis.19 All patients had an NIHSS score > 16 with 8 occlusions in the ICA terminus, 7 in the MCA, and 4 in the basilar artery. The overall recanaliza-tion rate was 79% with only 1 asymptomatic ICH. Le-sions at the ICA bifurcation and older age were associated with poor outcomes. These results suggest that intracra-nial stent insertion may be a viable option for recalcitrant arterial occlusions. This study also highlights some of the limitations of intracranial stents, which include the risk of vessel rupture or dissection and the long-term risks of restenosis. In addition, until recently, stents that were ap-propriately sized and trackable to intracranial vessels did not exist. Small coronary stents are now available that can be placed in the intracranial vasculature, but with the variety of stents now available it may be difficult to standardize the stents used in clinical studies, as was the problem in the report by Levy et al.19 In 2005 the first FDA-approved intracranial stent (WingSpan; Boston Scientific) was released. To date its applications are for intracranial atherosclerotic disease and not acute stroke, but as experience with the device grows, so perhaps will the applications.

ConclusionsThe prompt and aggressive management of acute

stroke has been shown to directly affect clinical out-comes. The 3-hour window remains a critical time pe-riod in which intravenous rt-PA needs to be administered to be of benefit. However, additional stroke studies have demonstrated that most patients do not receive intrave-nous thrombolysis and many others simply do not qualify. Newer endovascular technologies have greatly expanded the treatment armamentarium of stroke clinicians with catheter-based thrombolytic and antiplatelet adminis-tration, mechanical embolectomy, and angioplasty with stent placement. Many of these approaches have yet to prove their benefits in controlled clinical trials, but they offer new hope for a very large population of patients.

Disclosure

Dr. Prestigiacomo reports being a consultant for Boston Scientific, Thermopeutix, Micrus Endovascular, and Aesculap as well as a stockholder in Thermopeutics.

References

1. The Abciximab in Ischemic Stroke Investigators: Abciximab in acute ischemic stroke: a randomized, double-blind, placebo-controlled, dose-escalation study. Stroke 31:601–609, 2000

2. Alexander MJ, Duckwiler GR, Gobin YP, Vinuela F: Man-agement of intraprocedural arterial thrombus in cerebral an-eurysm embolization with abciximab: technical case report. Neurosurgery 50:899–902, 2002

3. Barber PA, Zhang J, Demchuk AM, Hill MD, Buchan AM:




Why are stroke patients excluded from TPA therapy? An anal-ysis of patient eligibility. Neurology 56:1015–1020, 2001

4. Bose A, Henkes H, Alfke K, Mayer TE, Berlis A, Branca V, Po Sit S: The Penumbra System: a mechanical device for the treatment of acute stroke due to thromboembolism. AJNR Am J Neuroradiol 29:1409–1413, 2008

5. Felberg RA, Okon NJ, El-Mitwalli A, Burgin WS, Grotta JC, Alexandrov AV: Early dramatic recovery during intrave-nous tissue plasminogen activator infusion: clinical pattern and outcome in acute middle cerebral artery stroke. Stroke 33:1301–1307, 2002

6. Furlan A, Higashida R, Wechsler L, Gent M, Rowley H, Kase C, et al: Intra-arterial prourokinase for acute ischemic stroke. The PROACT II study: a randomized controlled trial. Prol-yse in Acute Cerebral Thromboembolism. JAMA 282:2003–2011, 1999

7. Grines CL, Cox DA, Stone GW, Garcia E, Mattos LA, Gi-ambartolomei A, et al: Coronary angioplasty with or without stent implantation for acute myocardial infarction. Stent Pri-mary Angioplasty in Myocardial Infarction Study Group. N Engl J Med 341:1949–1956, 1999

8. Haley EC Jr, Lewandowski C, Tilley BC: Myths regarding the NINDS rt-PA Stroke Trial: setting the record straight. Ann Emerg Med 30:676–682, 1997

9. Henkes H, Miloslavski E, Lowens S, Reinartz J, Liebig T, Kuhne D: Treatment of intracranial atherosclerotic stenoses with balloon dilatation and self-expanding stent deployment (WingSpan). Neuroradiology 47:222–228, 2005

10. Higashida RT, Furlan AJ, Roberts H, Tomsick T, Connors B, Barr J, et al: Trial design and reporting standards for intra-ar-terial cerebral thrombolysis for acute ischemic stroke. Stroke 34:e109–e137, 2003

11. The Interventional Management of Stroke Study Investiga-tors: Combined intravenous and intra-arterial recanalization for acute ischemic stroke. Stroke 35:904–911, 2004

12. The Interventional Management of Stroke Study Investiga-tors: Hemorrhage in the Interventional Management of Stroke study: Stroke 37:847–851, 2006

13. Kapadia SR, Bajzer CT, Ziada KM, Bhatt DL, Wazni OM, Sil-ver MJ, et al: Initial experience of platelet glycoprotein IIb/IIIa inhibition with abciximab during carotid stenting: a safe and effective adjunctive therapy. Stroke 32:2328–2332, 2001

14. Katz JM, Gobin YP: Merci Retriever in acute stroke treatment. Expert Rev Med Devices 3:273–280, 2006

15. Keris V, Rudnicka S, Vorona V, Enina G, Tilgale B, Fricbergs J: Combined intraarterial/intravenous thrombolysis for acute ischemic stroke. AJNR Am J Neuroradiol 22:352–358, 2001

16. Kim DJ, Kim DI, Kim SH, Lee KY, Heo JH, Han SW: Res-cue localized intra-arterial thrombolysis for hyperacute MCA ischemic stroke patients after early non-responsive intrave-nous tissue plasminogen activator therapy. Neuroradiology 47:616–621, 2005

17. Labiche LA, Al-Senani F, Wojner AW, Grotta JC, Malkoff M, Alexandrov AV: Is the benefit of early recanalization sustained at 3 months? A prospective cohort study. Stroke 34:695–698, 2003

18. Lee DH, Jo KD, Kim HG, Choi SJ, Jung SM, Ryu DS, et al: Local intraarterial urokinase thrombolysis of acute ischemic stroke with or without intravenous abciximab: a pilot study. J Vasc Interv Radiol 13:769–774, 2002

19. Levy EI, Ecker RD, Horowitz MB, Gupta R, Hanel RA, Sau-vageau E, et al: Stent-assisted intracranial recanalization for acute stroke: early results. Neurosurgery 58:458–463, 2006

20. Lum C, Stys PK, Hogan MJ, Nguyen TB, Srinivasan A, Goyal M: Acute anterior circulation stroke: recanalization using clot angioplasty. Can J Neurol Sci 33:217–222, 2006

21. Nakano S, Iseda T, Yoneyama T, Kawano H, Wakisaka S: Di-rect percutaneous transluminal angioplasty for acute middle cerebral artery trunk occlusion: an alternative option to intra-arterial thrombolysis. Stroke 33:2872–2876, 2002

22. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group: Tissue plasminogen activator for acute ischemic stroke. N Engl J Med 333:1581–1587, 1995

23. Pessin MS, del Soppo GJ, Furlan AJ: Thrombolytic treat-ment in acute stroke: review and update of selective topics, in Moskowitz M, Calplan LR (eds): Cerebrovascular Diseases: Nineteenth Princeton Review Stroke Conference. Boston, MA: Butterworth-Heinemann, 1995, pp 409–418

24. Qureshi AI, Saad M, Zaidat OO, Suarez JI, Alexander MJ, Fareed M, et al: Intracerebral hemorrhages associated with neurointerventional procedures using a combination of anti-thrombotic agents including abciximab. Stroke 33:1916–1919, 2002

25. Ringer AJ, Qureshi AI, Fessler RD, Guterman LR, Hopkins LN: Angioplasty of intracranial occlusion resistant to throm-bolysis in acute ischemic stroke. Neurosurgery 48:1282–1290, 2001

26. Rosamond W, Flegal K, Friday G, Furie K, Go A, Greenlund K, et al: Heart disease and stroke statistics–2007 update: a report from the American Heart Association Statistics Com-mittee and Stroke Statistics Subcommittee. Circulation 115:e172, 2007

27. Rubiera M, Alvarez-Sabin J, Ribo M, Montaner J, Santama-rina E, Arenillas JF, et al: Predictors of early arterial reocclu-sion after tissue plasminogen activator-induced recanalization in acute ischemic stroke. Stroke 36:1452–1456, 2005

28. Schellinger PD, Fiebach JB, Mohr A, Ringleb PA, Jansen O, Hacke W: Thrombolytic therapy for ischemic stroke–a review. Part I–Intravenous thrombolysis. Crit Care Med 29:1812–1818, 2001

29. Selco SL, Liebeskind DS: Hyperacute imaging of ischemic stroke: role in therapeutic management. Curr Cardiol Rep 7:10–15, 2005

30. Smith WS, Sung G, Saver J, Budzik R, Duckwiler G, Liebes-kind DS, et al: Mechanical thrombectomy for acute isch-emic stroke: final results of the Multi MERCI trial. Stroke 39:1205–1212, 2008

31. Smith WS, Sung G, Starkman S, Saver JL, Kidwell CS, Gobin YP, et al: Safety and efficacy of mechanical embolectomy in acute ischemic stroke: results of the MERCI trial. Stroke 36:1432–1438, 2005

32. Velat GJ, Burry MV, Eskioglu E, Dettorre RR, Firment CS, Mericle RA: The use of abciximab in the treatment of acute cerebral thromboembolic events during neuroendovascular procedures. Surg Neurol 65:352–359, 2006

33. von Kummer R, Holle R, Rosin L, Forsting M, Hacke W: Does arterial recanalization improve outcome in carotid territory stroke? Stroke 26:581–587, 1995

34. Yoneyama T, Nakano S, Kawano H, Iseda T, Ikeda T, Goya T, et al: Combined direct percutaneous transluminal angioplasty and low-dose native tissue plasminogen activator therapy for acute embolic middle cerebral artery trunk occlusion. AJNR Am J Neuroradiol 23:277–281, 2002

Manuscript submitted November 15, 2008.Accepted January 8, 2009.Address correspondence to: Lana D. Christiano, M.D., Department

of Neurological Surgery, University of Medicine and Dentistry of New Jersey, 90 Bergen Street, Suite 8100, Newark, New Jersey 07103. email: [email protected].


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Endovascular management of acute ischemic stroke · Cooperative Acute Stroke Study I and II trials, along with the ATLANTIS trial, all used intravenous rt-PA within 4–6 hours of