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Past, Present, and Future Perspectives on the Endovascular Treatment of Acute Ischemic Stroke
Past, Present, and Future Perspectives on the Endovascular Treatment of Acute Ischemic Stroke Omar M. Arnaout, MD,* Rudy J. Rahme, MD,* Tarek Y. El Ahmadieh, MD,* Salah G. Aoun, MD,* H. Hunt Batjer, MD, FACS, FAANS,* and Bernard R. Bendok, MD, FACS, FAANS*,† Interventional neuroradiology plays a continuously expanding and exciting role in the treatment of acute stroke, as evidenced by the development of several important advances, including the advent of multiple new devices and therapies. Furthermore, guidelines regarding endovascular interventions in the setting of acute stroke have been developed and used. In addition to technological advances, the field of pharmacology in the setting of acute stroke is constantly evolving. In a rapidly expanding field, we aim to review significant recent advances related to the endovascular treatment of stroke as well as provide perspective for future directions. Tech Vasc Interventional Rad 15:87-92 © 2012 Elsevier Inc. All rights reserved. KEYWORDS stroke, thrombectomy, mechanical thrombolysis, pharmacological thrombolysis
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troke continues to be the third leading cause of death in the United States, with an approximate incidence of 800,000 people annually. Eighty-five percent of strokes are ischemic in nature, with an associated mortality between 53% and 92%.1-4 During the past 2 decades, several studies have shown that the effectiveness of interventional therapy for stroke is time-dependent.5 Furthermore, successful recanalization of a previously occluded vessel correlates with improvement in clinical outcome.2,6,7 Subsequently, the focus of treatment for acute stroke starts with prompt and accurate diagnosis of ischemic brain tissue at risk, followed by time sensitive delivery of therapy that effectively and safely restores flow to that vascular territory. Studies assessing the time frame available to salvage brain tissue have suggested that tissue may continue to be at risk up to 24 hours after stroke onset; however, the clinical significance of this extended window is unclear.8,9 Although intravenous tissue plasminogen activator (IV tPA) administration has shown benefit up to 3 hours from stroke onset, extension of the window to 6 hours has failed to show benefit.10,11 In contrast, recent combined analysis of several studies has suggested that the benefit of *Department of Neurological Surgery, Northwestern University, Feinberg School of Medicine, McGaw Medical Center, Chicago, IL. †Department of Radiology, Northwestern University, Feinberg School of Medicine, McGaw Medical Center, Chicago, IL. Address reprint requests to Bernard R. Bendok, MD, FACS, FAANS, Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, 676 N St Clair St, Suite 2210, Chicago, IL 60611. E-mail: [email protected] 1089-2516/12/$-see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1053/j.tvir.2011.12.001
IV tPA may extend to 4.5 hours after stroke onset.5 Additionally, recent trials have investigated the use of intra-arterial (IA) infusion of thrombolytics at the location of the thrombus within 6 hours of stroke onset.12-15 In addition to pharmacological thrombolysis, several devices for mechanical thrombolysis and/or thrombectomy have now been approved. Despite our understanding of time sensitivity of the disease, it is estimated that ⬍5% of patients receive Food and Drug Administration-approved thrombolytic therapy.16 This is likely because of several factors including the narrow time window for treatment and the presence of precluding comorbidities,17 in addition to other factors including the fact that many acute ischemic strokes are due to small-vessel occlusions or are too mild to warrant the risk of endovascular treatment.18 Therefore, it becomes evident that the logistics of care delivery as well as treatment options must be improved so that more patients are properly and promptly transferred to, and evaluated at, appropriate treatment centers. This review summarizes recent landmark studies related to the treatment of acute ischemic stroke as well as ongoing promising trials leading future directions.
Landmark Studies Prolyse in Acute Cerebral Thromboembolism I (1998, N ⴝ 46) The prolyse in acute cerebral thromboembolism (PROACT) trial was a multicenter, prospective, randomized controlled 87
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88 trial that compared the efficacy of direct IA infusion of prourokinase (pro-UK) versus placebo for the treatment of symptomatic middle cerebral artery (MCA) occlusion within 6 hours of stroke onset.14 Pro-UK is a proenzyme that is locally converted to urokinase by fibrin-associated plasmin at the thrombus surface, and whose effects are augmented by the presence of heparin. It is noteworthy that the investigators chose to include only MCA strokes (M1 and M2 branches) to increase the homogeneity of the patient population. The recanalization of an occluded vessel, evidenced by achieving a Thrombolysis in Myocardial Infarction score of 2 or 3, was significantly more likely in the pro-UK group versus the placebo group (57.7% vs 14.3%, respectively). There was also a 9.4% improvement in clinical outcome (assessed by a modified Rankin score [mRS] of 0 or 1) and a 16% reduction in mortality at 90 days, although neither change was statistically significant. The overall risk of intracranial hemorrhage (ICH) was higher in the pro-UK group to 42.3% compared to 7.1% in the placebo group, although only 15.4% of hemorrhages were symptomatic (defined as a decline in neurological status). Notably, the rate of developing ICH postprocedurally decreased to 20% from 72.7% after the investigators reduced the dose of heparin being used. Concurrently, there was a reduction in the rate of recanalization from 81.8% to 40%.
PROACT II (1999, N ⴝ 180) The PROACT II study, which was enrolling at the time the results of PROACT were published, was a multicenter, prospective, randomized controlled trial that primarily aimed at assessing neurological outcome of the use of IA pro-UK in the treatment of MCA strokes.15 Unlike the original PROACT trial, the investigators used a control group, where no IA infusion was performed in place of a placebo infusion. Although the investigators used the lower heparin dose from the latter part of the original trial, they increased the dose of IA pro-UK to 9 mg/h from 6 mg/h. The recanalization rate in the pro-UK group was 66%, representing a statistically significant 15% absolute increase over the control group, which was attributed to the higher pro-UK dose. Although the rate of ICH was 35% (compared with 13% in the control group), the rate of symptomatic hemorrhage was 10% (compared with 2% in the control group). Although mortality at 90 days was not significantly improved (25% vs 27% in the control group), good neurological outcomes (mRS ⱕ2) were significantly better in the pro-UK group (40% vs 25% in the control group).
Interventional Management of Stroke (2006, N ⴝ 80) The Interventional Management of Stroke (IMS) study, a multicenter, prospective, single-arm study, aimed to assess the feasibility and safety of combined IV and IA tPA administered within 3 hours of stroke onset.12 The investigators used historical controls from the National Institute of Neurological Disorders and Stroke (NINDS) trial of IV tPA
alone10 and built on earlier data from the Emergency Management of Stroke study.19 The investigators found that good neurological outcome at 90 days (43%) and mortality at 90 days (16%) were significantly improved compared with the placebo arm of the NINDS trial (28% and 24%, respectively). There was no difference in the rate of symptomatic hemorrhage comparable with the IV tPA arm of the NINDS study (6.3% vs 6.6%, respectively). Although there was no significant improvement in neurological outcome or mortality rates compared with the IV tPA arm of NINDS, the IMS study included patients with a higher median NIHSS score (18% vs 14%, respectively) and more patients with atrial fibrillation (increasing their risk for larger emboli), and as such, the results were considered promising for potential benefit over IV tPA alone and warranting further investigation. Notably, there was a trend toward significance for improvement in neurological outcome at 90 days in the subgroup of patients treated within the first 3 to 4 hours of onset compared with those treated more than 4 hours later, affirming the association between earlier revascularization and outcome.
IMS II (2007, N ⴝ 81) The second IMS trial used an identical protocol to IMS I, with the addition of an investigational EKOS microinfusion catheter (EKOS, Bothell, WA, USA).13 The catheter combines a traditional targeted drug infusion mechanism with a lowenergy ultrasonography to facilitate penetration of tissue plasminogen activator (tPA) into the thrombus and theoretically enhance thrombolysis. Of the 81 enrolled patients, ultrasonography was activated for use in 33 patients (40.7%). The investigators also aimed to further demonstrate the results of IMS I while plans for a phase III trial were ongoing. Although there was an increase in the incidence of ICH in IMS II compared with IMS I (9.9% vs 6.3%, respectively), the results were not significantly different for hemorrhage, neurological outcome, revascularization rate, or mortality. However, a significant improvement over the placebo arm of the NINDS trial was again demonstrated, comparing a combined IA/IV approach and IV alone.
Mechanical Embolus Removal in Cerebral Ischemia (2005, N ⴝ 151, 2008, N ⴝ 164) The mechanical embolus removal in cerebral ischemia (MERCI) trial evaluated the efficacy and safety of a mechanical endovascular device (which consists of a Nitinol core wire with shaped loops at the distal end designed to engage the thrombus) in the revascularization of an occluded large cerebral vessel within 8 hours of stroke onset (Fig. 1).20,21 The original study was subsequently updated with the MultiMERCI trial incorporating a newer generation of the device.21 The population of patients included in both studies were those ineligible to receive IV tPA (either arriving too late or having a contraindication for its use). The MERCI trial was a multicenter, prospective, single-arm trial that referred to the control arm of the PROACT II trial as historical control. Although the therapeutic window was 8 hours, the median
Endovascular treatment of acute ischemic stroke
89 and an improvement in the mortality or neurological outcome at 90 days, although statistically insignificant.
Penumbra (2009, N ⴝ 125) The Penumbra device was introduced in the United States in 2008 after results from a European safety trial were published (Fig. 2).22 The system consists of a thrombus debulking and aspiration component as well as a direct thrombus extraction component. The safety and efficacy of the device were reported in a multicenter, prospective, single-arm trial with the goal of establishing substantial equivalence to its predicate device—the Merci clot retrieval system. Although the revascularization rate using the Penumbra device was the highest of the prospective trials at 81.6% (compared with 55% in the Multi-MERCI trial and 66% in the PROACT II trial), the neurological outcome was comparable or lower (25% with mRS ⱕ2, vs 36% in the MultiMERCI trial and 40% in the PROACT II trial). The investigators attribute this disparity to the lack of sufficient power and higher baseline NIHSS score.
Stent-Assisted Recanalization in Acute Ischemic Stroke (2009, N ⴝ 20)
Figure 1 Merci Retriever device which is a corkscrew-shaped product designed to remove blood clots from large vessels in patients experiencing acute ischemic stroke.
time from onset to treatment was 4.3 hours in both studies. The recanalization rate was significantly higher than that in the control arm of PROACT II (48% vs 18%, respectively), but lower than that in the IA tPA group (66%). The proportion of patients achieving mRS ⱕ2 at 90 days was comparable to that in the control arm of PROACT II (22.6% vs 25%, respectively). In contrast, the mortality rate of 43.5% was significantly higher than that reported in most prospective studies of the treatment of acute stroke. The investigators attributed this elevated mortality to a higher baseline NIHSS score (median 18) and higher proportion of basilar artery and internal carotid artery terminus occlusions. The introduction of a new generation of the device in the Multi-MERCI trial resulted in a significantly higher recanalization rate (55%)
The use of endovascular stents has been recently advocated in the setting of acute stroke.23 Based on retrospective data regarding the use of intracranial stents as a salvage technique in acute stroke, the SARIS trial (stent-assisted recanalization in acute ischemic stroke) aimed to evaluate the safety of stent deployment as a primary therapeutic intervention for acute stroke using a prospective, single-arm study design. The investigators used the Wingspan (Boston Scientific, Natick, MA) and the Enterprise (Cordis, Bridgewater, NJ) intracranial self-expanding stents. All 20 cases included in the trial were successfully revascularized, although 60% of patients required the use of an adjuvant intraprocedural pharmacological infusion (eptifibatide or tPA) or angioplasty. The risk of subsequent asymptomatic and symptomatic hemorrhage was 10% and 5%, respectively, and no procedure-related complications were reported. With regard to neurological outcomes, 45% of patients achieved an mRS score of 1 or less at 1 month follow-up. The results of the SARIS trial are difficult to directly compare with the large randomized prospective trials because it included a small number of patients with a relatively low median NIHSS score (13% vs 19% in IMS II and 17% in PROACT II), was nonrandomized, and included only short follow-up; nonetheless, the results represent an encouraging foundation for further investigation into the role of stenting for stroke treatment.
Ongoing Trials To avoid the need for antiplatelet agents following stent deployment, hybrid devices are now being introduced that combine removable intracranial stenting and thrombectomy: the “Solitaire FR With the Intention for Thrombectomy”24 (Fig. 3) and the “Thrombectomy Revascularization of Large Vessel Occlusion in Acute Ischemic Stroke” (TREVO),25 and the trials are underway on similar devices.
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Figure 2 Penumbra Device.
Future Directions Logistics of Care
Figure 3 Stent deployed around blood clot allowing the retrieval of the occluding clot and the reperfusion of the blocked artery.
Improved stroke care begins at the pre-hospital stage; The California Acute Stroke Prototype Registry investigators estimate ⬎10-fold increase in the number of patients receiving appropriate treatment if the hospital arrival time is within 1 hour of symptom onset,26 highlighting the importance of public education and emergency medical services response time. Future first responders to the scene of a suspected stroke may be able to perform real-time neuroimaging rapidly with subsequent transmission of images to the receiving medical center such that the time to diagnosis, triage, and catheterization (if deemed necessary) is optimized. Real-time neuroimaging using transcranial ultrasonography, especially with the concurrent use of ultrasonography contrast agents, may prove beneficial in providing such rapid assessment of occluded cerebral vessels in the field.27 Color-coded duplex ultrasonography has been shown to correctly differentiate hemorrhagic stroke from ischemic stroke in 95% of cases when compared with computed tomography scanning.28 Furthermore, the use of cerebroprotective agents, again possibly administered in the field or early in the provision of stroke care, may further contribute to improved outcomes. With our current knowledge, patients arriving at a stroke treatment center outside of the defined windows for thrombolysis have few options outside of future stroke prevention and rehabilitation; therefore, extension of the therapeutic window is critical for allowing more patients to benefit from acute stroke treatment. The replacement of the traditional
Endovascular treatment of acute ischemic stroke “stopwatch” approach to stroke with a more dynamic and functional time window is likely to take place, with growing evidence in clinical trials with the usefulness of magnetic resonance imaging-based patient selection for thrombolysis (desmoteplase in acute ischemic stroke (DIAS), diffusion and perfusion imaging evaluation for understanding stroke evolution (DEFUSE), and dose escalation of desmoteplase in acute stroke (DEDAS) trials).29 The ongoing Third International Stroke Trial and Mechanical Retrieval and Recanalization of Stroke Clots Using Embolectomy (MR RESCUE) trial will also likely impact whether future patients are offered thrombolysis outside the conventional window.
Technological Advances The incorporation of interventional approaches as an adjunct or alternative to intravenous thrombolysis in the setting of acute stroke is a rapidly growing field with a recent explosion in the number of devices available to the interventionalist. The PROACT trial was one of the first large multicenter trials to investigate the use of intravenous thrombolytic agents for the treatment of acute stroke; the study was followed by several other randomized trials, including the IMS study, which described the use of IV tPA as a bridge toward catheter-directed arterial infusion of the thrombolytic. IMS II introduced data regarding the use of low-energy sonography in addition to local thrombolysis. Subsequent studies have evaluated mechanical clot retrieval devices, including the MERCI and Penumbra trials.29 Investigations and breakthroughs are likely to continue in both pharmacological and mechanical thrombolysis, with the future generation of devices likely to include a combination of the 2 modalities to achieve increased recanalization rates.30,31 Future devices are also likely to address the issue of distal emboli during clot manipulation.32 In addition to clot removal and microinfusion devices, the use of retrievable stents for the acute revascularization of thromboembolic stroke is a topic of great interest that is currently being evaluated.33,34 Stenting may prove useful as an adjunct to thrombolysis for immediate reperfusion with subsequent retrieval, or alternatively left in place for permanent deployment.
Pharmacological Advances Promising pharmacological options for the treatment of acute ischemic stroke can be organized in 1 of 3 categories: 1. Novel thromboembolic agents and adjuvants (including antiplatelet and anticoagulation agents). Microplasmin, a recombinant form of human plasmin, may have a reduced propensity to cause bleeding compared with tPA and has been shown to be tolerable in human volunteers and efficacious in animal models of stroke. Microplasmin is currently under investigation to determine the clinical efficacy in human acute ischemic stroke patients.35 2. Neuroprotective agents that have been an attractive but so far elusive target. At the time of this writing, more than 160 trials for ischemic stroke neuroprotective
91 agents have been initiated.36 Unfortunately, few have produced positive results. However, notable recent exceptions include high-dose human albumin therapy, which showed promising results in the original Albumin in Acute Stroke trial.37 A larger randomized multicenter placebo-controlled efficacy trial is now underway.29 Additionally, magnesium, which has been shown so far to be a rather weak neuroprotectant,38 continues to be under investigation because it is a safe and relatively inexpensive agent that may be administered in the hyperacute pre-hospital setting or during interventional procedures.29 3. Agents that contribute to the recovery of lost or dormant neuronal function. Although currently at its infancy stages, future interventional approaches may include local administration of neurorestorative agents, such as stem cells of both exogenous and endogenous origins, or neurotrophic molecules that promote and direct endogenous neurogenesis.39,40
Conclusions Neurointerventional surgery for the treatment of ischemic stroke is a rapidly expanding field with constantly improving tools and ever evolving indications. Recanalization rates appear to be on the rise in more recent studies compared to early studies. As data continues to accumulate regarding new treatment modalities and technologies, neurosurgeons, radiologists and neurologists should come together to design new treatment paradigms. Much work remains to streamline the care of stroke patients so that appropriate patients can be treated in a timely manner.
References 1. Brückmann H, Ferbert A, Del Zoppo G, et al: Acute vertebral-basilar thrombosis. Angiologic-clinical comparison and therapeutic implications. Acta Radio Suppl 369:38-42, 1986 2. Brandt T, von Kummer R, Müller-Küppers M, et al: Thrombolytic therapy of acute basilar artery occlusion. Variables affecting recanalization and outcome. Stroke 27:875-881, 1996 3. Hacke W, Schwab S, Horn M, et al: ‘Malignant’ middle cerebral artery territory infarction: Clinical course and prognostic signs. Arch Neurol 53:309-315, 1996 4. Jansen O, Von Kummer R, Forsting M, et al: Thrombolytic therapy in acute occlusion of the intracranial internal carotid artery bifurcation. Am J Neuroradiol 16:1977-1986, 1995 5. Hacke W, Donnan G, Fieschi C, et al: Association of outcome with early stroke treatment: Pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials. Lancet 363:768-774, 2004 6. Hacke W, Zeumer H, Ferbert A, et al: Intra-arterial thrombolytic therapy improves outcome in patients with acute vertebrobasilar occlusive disease. Stroke 19:1216-1222, 1988 7. Suarez J, Sunshine J, Tarr R, et al: Predictors of clinical improvement, angiographic recanalization, and intracranial hemorrhage after intraarterial thrombolysis for acute ischemic stroke. Stroke 30:2094-2100, 1999 8. Fisher M, Prichard JW, Warach S: New magnetic resonance techniques for acute ischemic stroke. JAMA 274:908-911, 1995 9. Staroselskaya I, Baird A, Linfante I: Correlations between MR diffusion perfusion studies and MRA in acute stroke. Neurology 52:455, 1999 10. Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-pa stroke study group. N Engl J Med 333:1581-1587, 1995
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92 11. Yamaguchi T, Hayakawa T, Kiuchi H: Intravenous tissue plasminogen activator ameliorates the outcome of hyperacute embolic stroke. Cerebrovasc Dis 3:269-272, 1993 12. IMS Study Investigators: Combined intravenous and intra-arterial recanalization for acute ischemic stroke: The interventional management of stroke study. Stroke 35:904-911, 2004 13. IMS II Trial Investigators: The interventional management of stroke (IMS) II study. Stroke 38:2127-2135, 2007 14. del Zoppo GJ, Higashida RT, Furlan AJ, et al: PROACT: A phase II randomized trial of recombinant pro-urokinase by direct arterial delivery in acute middle cerebral artery stroke. PROACT investigators. Prolyse in acute cerebral thromboembolism. Stroke 29:4-11, 1998 15. Furlan A, Higashida R, Wechsler L, et al: Intra-arterial prourokinase for acute ischemic stroke. The PROACT II study: A randomized controlled trial. Prolyse in acute cerebral thromboembolism. JAMA 282:20032011, 1999 16. Katzan IL, Hammer MD, Furlan AJ, et al: Quality improvement and tissue-type plasminogen activator for acute ischemic stroke: A cleveland update. Stroke 34:799-800, 2003 17. Adult stroke: part 9. Circulation 112:IV111-IV120, 2005 18. Cloft HJ, Rabinstein A, Lanzino G, et al: Intra-arterial stroke therapy: An assessment of demand and available work force. Am J Neuroradiol 30:453, 2009 19. Lewandowski C, Frankel M, Tomsick T, et al: Combined intravenous and intra-arterial r-TPA versus intra-arterial therapy of acute ischemic stroke emergency management of stroke (EMS) bridging trial. Stroke 30:2598-2605, 1999 20. Smith W, Sung G, Starkman S, et al: Safety and efficacy of mechanical embolectomy in acute ischemic stroke results of the MERCI trial. Stroke 36:1432-1438, 2005 21. Smith WS, Sung G, Saver J, et al: Mechanical thrombectomy for acute ischemic stroke: Final results of the multi merci trial. Stroke 39:1205, 2008 22. Penumbra Pivotal Stroke Trial Investigators: The penumbra pivotal stroke trial: Safety and effectiveness of a new generation of mechanical devices for clot removal in intracranial large vessel occlusive disease. Stroke 40:2761-2768, 2009 23. Levy E, Siddiqui A, Crumlish A, et al: First food and drug administration-approved prospective trial of primary intracranial stenting for acute stroke. Saris (stent-assisted recanalization in acute ischemic stroke). Stroke 40:3552-3556, 2009 24. ClinicalTrials.Gov: Solitaire™ Fr with the Intention for Thrombectomy (SWIFT) Study. ClinicalTrials.Gov, 2009. Available at: http://clinicaltrial. gov/ct2/show/NCT01054560?term⫽solitaire&rank⫽1 25. ClinicalTrials.Gov: Randomized Trial Evaluating Performance of the trevo Retriever Versus the Merci Retriever in Acute Ischemic Stroke
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(Trevo2). ClinicalTrials.Gov, 2011. Available at: http://clinicaltrial.gov/ ct2/show/NCT01270867?term⫽Trevo2&rank⫽1 California Acute Stroke Pilot Registry (CASPR) Investigators: Prioritizing interventions to improve rates of thrombolysis for ischemic stroke. Neurology 64:654-659, 2005 Seidel G, Meairs S: Ultrasound contrast agents in ischemic stroke. Cerebrovasc Dis 27:25-39, 2009 (suppl 2) Mäurer M, Shambal S, Berg D, et al: Differentiation between intracerebral hemorrhage and ischemic stroke by transcranial color-coded duplex-sonography. Stroke 29:2563, 1998 Goldberg M: Stroke Trials Registry, 2010. Available at: http://clinicaltrial. gov/ct2/show/NCT00638781?term⫽DIAS&rank⫽4:; http://clinicaltrial.gov/ ct2/show/NCT01349946?term⫽DEFUSE&rank⫽1; http://clinicaltrial.gov/ ct2/show/NCT00638248?term⫽DEDAS&rank⫽1. Accessed January 2012 Hopkins L, Ecker R: Cerebral endovascular neurosurgery. Neurosurgery 62:1483-1501, 2008 Sugrue PA, Hage ZA, Surdell DL, et al: Basilar artery occlusion following c1 lateral mass fracture managed by mechanical and pharmacological thrombolysis. Neurocrit Care 11:255-260, 2009 Liebig T, Reinartz J, Hannes R, et al: Comparative in vitro study of five mechanical embolectomy systems: Effectiveness of clot removal and risk of distal embolization. Neuroradiology 50:43-52, 2008 Wakhloo A, Gounis M: Retrievable closed cell intracranial stent for foreign body and clot removal. Neurosurgery 62:ONS390-ONS393, 2008 (5 suppl 2) Zaidat OO, Wolfe T, Hussain SI, et al: Interventional acute ischemic stroke therapy with intracranial self-expanding stent. Stroke 39:2392, 2008 Thijs V, Peeters A, Vosko M, et al: Randomized, placebo-controlled, dose-ranging clinical trial of intravenous microplasmin in patients with acute ischemic stroke. Stroke 40:3789-3795, 2009 Internet Stroke Center WU: Stroke Trials Registry, 2010. Available at: http://www.strokecenter.org/trials/clinicalstudies/list Palesch YY, Hill MD, Ryckborst KJ, et al: The alias pilot trial: A doseescalation and safety study of albumin therapy for acute ischemic stroke—II: Neurologic outcome and efficacy analysis. Stroke 37:21072114, 2006 Muir KW, Lees KR, Ford I, et al: Magnesium for acute stroke (intravenous magnesium efficacy in stroke trial): Randomised controlled trial. Lancet 363:439, 2004 Burns TC, Verfaillie CM, Low WC: Stem cells for ischemic brain injury: A critical review. J Comp Neurol 515:125-144, 2009 Chen J, Sanberg PR, Li Y, et al: Intravenous administration of human umbilical cord blood reduces behavioral deficits after stroke in rats. Stroke 32:2682, 2001
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troke continues to be the third leading cause of death in the United States, with an approximate incidence of 800,000 people annually. Eighty-five percent of strokes are ischemic in nature, with an associated mortality between 53% and 92%.1-4 During the past 2 decades, several studies have shown that the effectiveness of interventional therapy for stroke is time-dependent.5 Furthermore, successful recanalization of a previously occluded vessel correlates with improvement in clinical outcome.2,6,7 Subsequently, the focus of treatment for acute stroke starts with prompt and accurate diagnosis of ischemic brain tissue at risk, followed by time sensitive delivery of therapy that effectively and safely restores flow to that vascular territory. Studies assessing the time frame available to salvage brain tissue have suggested that tissue may continue to be at risk up to 24 hours after stroke onset; however, the clinical significance of this extended window is unclear.8,9 Although intravenous tissue plasminogen activator (IV tPA) administration has shown benefit up to 3 hours from stroke onset, extension of the window to 6 hours has failed to show benefit.10,11 In contrast, recent combined analysis of several studies has suggested that the benefit of *Department of Neurological Surgery, Northwestern University, Feinberg School of Medicine, McGaw Medical Center, Chicago, IL. †Department of Radiology, Northwestern University, Feinberg School of Medicine, McGaw Medical Center, Chicago, IL. Address reprint requests to Bernard R. Bendok, MD, FACS, FAANS, Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, 676 N St Clair St, Suite 2210, Chicago, IL 60611. E-mail: [email protected] 1089-2516/12/$-see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1053/j.tvir.2011.12.001
IV tPA may extend to 4.5 hours after stroke onset.5 Additionally, recent trials have investigated the use of intra-arterial (IA) infusion of thrombolytics at the location of the thrombus within 6 hours of stroke onset.12-15 In addition to pharmacological thrombolysis, several devices for mechanical thrombolysis and/or thrombectomy have now been approved. Despite our understanding of time sensitivity of the disease, it is estimated that ⬍5% of patients receive Food and Drug Administration-approved thrombolytic therapy.16 This is likely because of several factors including the narrow time window for treatment and the presence of precluding comorbidities,17 in addition to other factors including the fact that many acute ischemic strokes are due to small-vessel occlusions or are too mild to warrant the risk of endovascular treatment.18 Therefore, it becomes evident that the logistics of care delivery as well as treatment options must be improved so that more patients are properly and promptly transferred to, and evaluated at, appropriate treatment centers. This review summarizes recent landmark studies related to the treatment of acute ischemic stroke as well as ongoing promising trials leading future directions.
Landmark Studies Prolyse in Acute Cerebral Thromboembolism I (1998, N ⴝ 46) The prolyse in acute cerebral thromboembolism (PROACT) trial was a multicenter, prospective, randomized controlled 87
O.M. Arnaout et al
88 trial that compared the efficacy of direct IA infusion of prourokinase (pro-UK) versus placebo for the treatment of symptomatic middle cerebral artery (MCA) occlusion within 6 hours of stroke onset.14 Pro-UK is a proenzyme that is locally converted to urokinase by fibrin-associated plasmin at the thrombus surface, and whose effects are augmented by the presence of heparin. It is noteworthy that the investigators chose to include only MCA strokes (M1 and M2 branches) to increase the homogeneity of the patient population. The recanalization of an occluded vessel, evidenced by achieving a Thrombolysis in Myocardial Infarction score of 2 or 3, was significantly more likely in the pro-UK group versus the placebo group (57.7% vs 14.3%, respectively). There was also a 9.4% improvement in clinical outcome (assessed by a modified Rankin score [mRS] of 0 or 1) and a 16% reduction in mortality at 90 days, although neither change was statistically significant. The overall risk of intracranial hemorrhage (ICH) was higher in the pro-UK group to 42.3% compared to 7.1% in the placebo group, although only 15.4% of hemorrhages were symptomatic (defined as a decline in neurological status). Notably, the rate of developing ICH postprocedurally decreased to 20% from 72.7% after the investigators reduced the dose of heparin being used. Concurrently, there was a reduction in the rate of recanalization from 81.8% to 40%.
PROACT II (1999, N ⴝ 180) The PROACT II study, which was enrolling at the time the results of PROACT were published, was a multicenter, prospective, randomized controlled trial that primarily aimed at assessing neurological outcome of the use of IA pro-UK in the treatment of MCA strokes.15 Unlike the original PROACT trial, the investigators used a control group, where no IA infusion was performed in place of a placebo infusion. Although the investigators used the lower heparin dose from the latter part of the original trial, they increased the dose of IA pro-UK to 9 mg/h from 6 mg/h. The recanalization rate in the pro-UK group was 66%, representing a statistically significant 15% absolute increase over the control group, which was attributed to the higher pro-UK dose. Although the rate of ICH was 35% (compared with 13% in the control group), the rate of symptomatic hemorrhage was 10% (compared with 2% in the control group). Although mortality at 90 days was not significantly improved (25% vs 27% in the control group), good neurological outcomes (mRS ⱕ2) were significantly better in the pro-UK group (40% vs 25% in the control group).
Interventional Management of Stroke (2006, N ⴝ 80) The Interventional Management of Stroke (IMS) study, a multicenter, prospective, single-arm study, aimed to assess the feasibility and safety of combined IV and IA tPA administered within 3 hours of stroke onset.12 The investigators used historical controls from the National Institute of Neurological Disorders and Stroke (NINDS) trial of IV tPA
alone10 and built on earlier data from the Emergency Management of Stroke study.19 The investigators found that good neurological outcome at 90 days (43%) and mortality at 90 days (16%) were significantly improved compared with the placebo arm of the NINDS trial (28% and 24%, respectively). There was no difference in the rate of symptomatic hemorrhage comparable with the IV tPA arm of the NINDS study (6.3% vs 6.6%, respectively). Although there was no significant improvement in neurological outcome or mortality rates compared with the IV tPA arm of NINDS, the IMS study included patients with a higher median NIHSS score (18% vs 14%, respectively) and more patients with atrial fibrillation (increasing their risk for larger emboli), and as such, the results were considered promising for potential benefit over IV tPA alone and warranting further investigation. Notably, there was a trend toward significance for improvement in neurological outcome at 90 days in the subgroup of patients treated within the first 3 to 4 hours of onset compared with those treated more than 4 hours later, affirming the association between earlier revascularization and outcome.
IMS II (2007, N ⴝ 81) The second IMS trial used an identical protocol to IMS I, with the addition of an investigational EKOS microinfusion catheter (EKOS, Bothell, WA, USA).13 The catheter combines a traditional targeted drug infusion mechanism with a lowenergy ultrasonography to facilitate penetration of tissue plasminogen activator (tPA) into the thrombus and theoretically enhance thrombolysis. Of the 81 enrolled patients, ultrasonography was activated for use in 33 patients (40.7%). The investigators also aimed to further demonstrate the results of IMS I while plans for a phase III trial were ongoing. Although there was an increase in the incidence of ICH in IMS II compared with IMS I (9.9% vs 6.3%, respectively), the results were not significantly different for hemorrhage, neurological outcome, revascularization rate, or mortality. However, a significant improvement over the placebo arm of the NINDS trial was again demonstrated, comparing a combined IA/IV approach and IV alone.
Mechanical Embolus Removal in Cerebral Ischemia (2005, N ⴝ 151, 2008, N ⴝ 164) The mechanical embolus removal in cerebral ischemia (MERCI) trial evaluated the efficacy and safety of a mechanical endovascular device (which consists of a Nitinol core wire with shaped loops at the distal end designed to engage the thrombus) in the revascularization of an occluded large cerebral vessel within 8 hours of stroke onset (Fig. 1).20,21 The original study was subsequently updated with the MultiMERCI trial incorporating a newer generation of the device.21 The population of patients included in both studies were those ineligible to receive IV tPA (either arriving too late or having a contraindication for its use). The MERCI trial was a multicenter, prospective, single-arm trial that referred to the control arm of the PROACT II trial as historical control. Although the therapeutic window was 8 hours, the median
Endovascular treatment of acute ischemic stroke
89 and an improvement in the mortality or neurological outcome at 90 days, although statistically insignificant.
Penumbra (2009, N ⴝ 125) The Penumbra device was introduced in the United States in 2008 after results from a European safety trial were published (Fig. 2).22 The system consists of a thrombus debulking and aspiration component as well as a direct thrombus extraction component. The safety and efficacy of the device were reported in a multicenter, prospective, single-arm trial with the goal of establishing substantial equivalence to its predicate device—the Merci clot retrieval system. Although the revascularization rate using the Penumbra device was the highest of the prospective trials at 81.6% (compared with 55% in the Multi-MERCI trial and 66% in the PROACT II trial), the neurological outcome was comparable or lower (25% with mRS ⱕ2, vs 36% in the MultiMERCI trial and 40% in the PROACT II trial). The investigators attribute this disparity to the lack of sufficient power and higher baseline NIHSS score.
Stent-Assisted Recanalization in Acute Ischemic Stroke (2009, N ⴝ 20)
Figure 1 Merci Retriever device which is a corkscrew-shaped product designed to remove blood clots from large vessels in patients experiencing acute ischemic stroke.
time from onset to treatment was 4.3 hours in both studies. The recanalization rate was significantly higher than that in the control arm of PROACT II (48% vs 18%, respectively), but lower than that in the IA tPA group (66%). The proportion of patients achieving mRS ⱕ2 at 90 days was comparable to that in the control arm of PROACT II (22.6% vs 25%, respectively). In contrast, the mortality rate of 43.5% was significantly higher than that reported in most prospective studies of the treatment of acute stroke. The investigators attributed this elevated mortality to a higher baseline NIHSS score (median 18) and higher proportion of basilar artery and internal carotid artery terminus occlusions. The introduction of a new generation of the device in the Multi-MERCI trial resulted in a significantly higher recanalization rate (55%)
The use of endovascular stents has been recently advocated in the setting of acute stroke.23 Based on retrospective data regarding the use of intracranial stents as a salvage technique in acute stroke, the SARIS trial (stent-assisted recanalization in acute ischemic stroke) aimed to evaluate the safety of stent deployment as a primary therapeutic intervention for acute stroke using a prospective, single-arm study design. The investigators used the Wingspan (Boston Scientific, Natick, MA) and the Enterprise (Cordis, Bridgewater, NJ) intracranial self-expanding stents. All 20 cases included in the trial were successfully revascularized, although 60% of patients required the use of an adjuvant intraprocedural pharmacological infusion (eptifibatide or tPA) or angioplasty. The risk of subsequent asymptomatic and symptomatic hemorrhage was 10% and 5%, respectively, and no procedure-related complications were reported. With regard to neurological outcomes, 45% of patients achieved an mRS score of 1 or less at 1 month follow-up. The results of the SARIS trial are difficult to directly compare with the large randomized prospective trials because it included a small number of patients with a relatively low median NIHSS score (13% vs 19% in IMS II and 17% in PROACT II), was nonrandomized, and included only short follow-up; nonetheless, the results represent an encouraging foundation for further investigation into the role of stenting for stroke treatment.
Ongoing Trials To avoid the need for antiplatelet agents following stent deployment, hybrid devices are now being introduced that combine removable intracranial stenting and thrombectomy: the “Solitaire FR With the Intention for Thrombectomy”24 (Fig. 3) and the “Thrombectomy Revascularization of Large Vessel Occlusion in Acute Ischemic Stroke” (TREVO),25 and the trials are underway on similar devices.
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Figure 2 Penumbra Device.
Future Directions Logistics of Care
Figure 3 Stent deployed around blood clot allowing the retrieval of the occluding clot and the reperfusion of the blocked artery.
Improved stroke care begins at the pre-hospital stage; The California Acute Stroke Prototype Registry investigators estimate ⬎10-fold increase in the number of patients receiving appropriate treatment if the hospital arrival time is within 1 hour of symptom onset,26 highlighting the importance of public education and emergency medical services response time. Future first responders to the scene of a suspected stroke may be able to perform real-time neuroimaging rapidly with subsequent transmission of images to the receiving medical center such that the time to diagnosis, triage, and catheterization (if deemed necessary) is optimized. Real-time neuroimaging using transcranial ultrasonography, especially with the concurrent use of ultrasonography contrast agents, may prove beneficial in providing such rapid assessment of occluded cerebral vessels in the field.27 Color-coded duplex ultrasonography has been shown to correctly differentiate hemorrhagic stroke from ischemic stroke in 95% of cases when compared with computed tomography scanning.28 Furthermore, the use of cerebroprotective agents, again possibly administered in the field or early in the provision of stroke care, may further contribute to improved outcomes. With our current knowledge, patients arriving at a stroke treatment center outside of the defined windows for thrombolysis have few options outside of future stroke prevention and rehabilitation; therefore, extension of the therapeutic window is critical for allowing more patients to benefit from acute stroke treatment. The replacement of the traditional
Endovascular treatment of acute ischemic stroke “stopwatch” approach to stroke with a more dynamic and functional time window is likely to take place, with growing evidence in clinical trials with the usefulness of magnetic resonance imaging-based patient selection for thrombolysis (desmoteplase in acute ischemic stroke (DIAS), diffusion and perfusion imaging evaluation for understanding stroke evolution (DEFUSE), and dose escalation of desmoteplase in acute stroke (DEDAS) trials).29 The ongoing Third International Stroke Trial and Mechanical Retrieval and Recanalization of Stroke Clots Using Embolectomy (MR RESCUE) trial will also likely impact whether future patients are offered thrombolysis outside the conventional window.
Technological Advances The incorporation of interventional approaches as an adjunct or alternative to intravenous thrombolysis in the setting of acute stroke is a rapidly growing field with a recent explosion in the number of devices available to the interventionalist. The PROACT trial was one of the first large multicenter trials to investigate the use of intravenous thrombolytic agents for the treatment of acute stroke; the study was followed by several other randomized trials, including the IMS study, which described the use of IV tPA as a bridge toward catheter-directed arterial infusion of the thrombolytic. IMS II introduced data regarding the use of low-energy sonography in addition to local thrombolysis. Subsequent studies have evaluated mechanical clot retrieval devices, including the MERCI and Penumbra trials.29 Investigations and breakthroughs are likely to continue in both pharmacological and mechanical thrombolysis, with the future generation of devices likely to include a combination of the 2 modalities to achieve increased recanalization rates.30,31 Future devices are also likely to address the issue of distal emboli during clot manipulation.32 In addition to clot removal and microinfusion devices, the use of retrievable stents for the acute revascularization of thromboembolic stroke is a topic of great interest that is currently being evaluated.33,34 Stenting may prove useful as an adjunct to thrombolysis for immediate reperfusion with subsequent retrieval, or alternatively left in place for permanent deployment.
Pharmacological Advances Promising pharmacological options for the treatment of acute ischemic stroke can be organized in 1 of 3 categories: 1. Novel thromboembolic agents and adjuvants (including antiplatelet and anticoagulation agents). Microplasmin, a recombinant form of human plasmin, may have a reduced propensity to cause bleeding compared with tPA and has been shown to be tolerable in human volunteers and efficacious in animal models of stroke. Microplasmin is currently under investigation to determine the clinical efficacy in human acute ischemic stroke patients.35 2. Neuroprotective agents that have been an attractive but so far elusive target. At the time of this writing, more than 160 trials for ischemic stroke neuroprotective
91 agents have been initiated.36 Unfortunately, few have produced positive results. However, notable recent exceptions include high-dose human albumin therapy, which showed promising results in the original Albumin in Acute Stroke trial.37 A larger randomized multicenter placebo-controlled efficacy trial is now underway.29 Additionally, magnesium, which has been shown so far to be a rather weak neuroprotectant,38 continues to be under investigation because it is a safe and relatively inexpensive agent that may be administered in the hyperacute pre-hospital setting or during interventional procedures.29 3. Agents that contribute to the recovery of lost or dormant neuronal function. Although currently at its infancy stages, future interventional approaches may include local administration of neurorestorative agents, such as stem cells of both exogenous and endogenous origins, or neurotrophic molecules that promote and direct endogenous neurogenesis.39,40
Conclusions Neurointerventional surgery for the treatment of ischemic stroke is a rapidly expanding field with constantly improving tools and ever evolving indications. Recanalization rates appear to be on the rise in more recent studies compared to early studies. As data continues to accumulate regarding new treatment modalities and technologies, neurosurgeons, radiologists and neurologists should come together to design new treatment paradigms. Much work remains to streamline the care of stroke patients so that appropriate patients can be treated in a timely manner.
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