ACUTE HEMORRHAGIC AND ISCHEMIC STROKE ACUTE HEMORRHAGIC AND ISCHEMIC STROKE
TOPIC
The Role of Endovascular Therapy in the Treatment of Acute Ischemic Stroke Joseph C. Serrone, MD* Lincoln Jimenez, MD‡ Andrew J. Ringer, MD* *Department of Neurosurgery, University of Cincinnati, Cincinnati, Ohio; ‡Department of Neurosurgery, University of Florida-Jacksonville, Jacksonville, Florida Correspondence: Andrew J. Ringer, MD, c/o Editorial Office, University of Cincinnati College of Medicine, Department of Neurosurgery, 260 Stetson St, Suite 2200, PO Box 670515, Cincinnati, OH 45267-0515. E-mail: [email protected]
Of the approximately 795 000 strokes in the United States annually, 87% are ischemic and result in significant morbidity and mortality. Improvements in acute ischemic stroke (AIS) outcomes have been achieved with intravenous thrombolytics (IVT) and intraarterial thrombolytics vs supportive medical therapy. Given its ease of administration, noninvasiveness, and most validated efficacy, IVT is the standard of care in AIS patients without contraindications to systemic fibrinolysis. However, patients with large-vessel occlusions respond poorly to IVT. Recent trials designed to select this population for randomization to IVT vs IVT with adjunctive endovascular therapy have not shown improvement in clinical outcomes with endovascular therapy. This could be due to the lack of utilization of modern thrombectomy devices such as Penumbra aspiration devices, Solitaire stent-trievers, or Trevo stent-trievers, which have shown the best recanalization results. Continued improvement in the techniques with using these devices as well as randomized controlled trials using them is warranted. This article defines the goals of AIS revascularization, presents the evolution of treatment from the initial use of IVT to modern thrombectomy devices, and discusses current treatment and ongoing AIS trials.
Received, August 6, 2013. Accepted, October 11, 2013.
KEY WORDS: Acute ischemic stroke, Intra-arterial thrombolysis, Intravenous thrombolytics, Large-vessel occlusion, Revascularization
Copyright © 2014 by the Congress of Neurological Surgeons
Neurosurgery 74:S133–S141, 2014
DOI: 10.1227/NEU.0000000000000224
O
f the approximately 795 000 strokes in the United States annually, 87% are ischemic. The 30-day mortality in this population is 8% to 12%. For survivors aged over 65 years, the morbidity cannot be understated, with 50% having some degree of hemiparesis, 30% unable to ambulate, 19% aphasic, 35% depressed, and 26% residing in a nursing home.1 Improvements in acute ischemic stroke (AIS) outcomes have been achieved with some acute revascularization strategies.2-4 However, because the time-sensitive nature of treatment in AIS, it is estimated that only 5% to 13% of ABBREVIATIONS: AIS, acute ischemic stroke; FDA, Food and Drug Administration; IA, intra-arterial; IAT, intra-arterial thrombolysis; ICA, internal carotid artery; IVT, intravenous thrombolytics; LVO, largevessel occlusion; MCA, middle cerebral artery; mRS, modified Rankin Scale; NIHSSS, National Institute of Health Stroke Scale Score; RCT, randomized controlled trial; TCD, transcranial Doppler; TICI, Thrombolysis In Cerebral Infarction Scale; TIMI, Thrombolysis In Myocardial Infarction
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patients present in the time window for recanalization.5 This article defines the goals of AIS revascularization and presents the evolution of treatment from the initial use of intravenous thrombolytics (IVT) to modern thrombectomy devices.
AIS PATIENTS REQUIRING ENDOVASCULAR TREATMENT Large-Vessel Occlusions The goal of acute stroke management is to promptly identify patients who have an arterial occlusion and recanalize the occluded artery. Patients presenting with hemispheric stroke signs will have an occlusion of the internal carotid artery (ICA) or middle cerebral artery (MCA) segment in approximately 3/4 cases and therefore have a potential target for recanalization.5,6 The National Institute of Health Stroke Scale Score (NIHSSS) is the initial tool for evaluating stroke patients and is predictive for large-vessel occlusion (LVO) in those patients who may be poor responders to IVT and thus better candidates for
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endovascular treatment. In correlating NIHSSS with magnetic resonance angiography findings, Derex et al7 found that every 1 point increase in NIHSSS had an odds ratio of 1.28 for predicting vessel occlusion. Additionally, several authors have correlated proximal angiographic occlusion (ICA, M1, M2, or basilar artery) with an increasing NIHSSS.8,9 Initial evaluation in AIS also includes a noncontrast head computed tomogram (CT) to rule out hemorrhage before considering therapy for recanalization. These studies can also reveal hyperdense intravascular clots that are predictive for occlusion, poor response to IVT, and poorer prognosis.10 At many centers, acute noninvasive vascular imaging is also performed.11 With the goal of selecting stroke patients with LVO, the recently completed IMS-3 trial selected patients for enrollment with an NIHSSS $10 or NIHSSS 8 to 9 with CT angiogram evidence of LVO.12 The next challenge in management of AIS is determining which clots will fibrinolyze with IVT and which will respond better with adjunctive endovascular management. Wolpert et al13 evaluated 93 patients with angiography acutely before and after IVT. Lesions in the ICA, M1, M2, and M3 branches recanalized at 8.7%, 28.9%, 40%, and 47%, respectively, after IVT. Saqqur et al14 had similar findings using transcranial Doppler (TCD) finding recanalization for ICA terminus, M1, and M2 occlusions at 6%, 30%, and 44%, respectively. Additionally, patients with a hyperdense MCA sign on head CT have much lower rates of recanalization.13,15 There is a direct correlation with LVO (ICA, proximal MCA), poor NIHSSS (typically $10), and poor response to IVT. This population, if any, would benefit the most from endovascular care. This is most evident comparing revascularization in IMS 3 by occlusion location. Endovascular therapy achieved recanalization of the ICA, M1, and M2 vessels at 81%, 88%, and 86% compared with respective rates of 35%, 68%, and 77% in the IVT group.12 Patients with LVO that respond poorly to IVT can be selected most quickly and efficiently with a combination of calculating the NIHSSS, a noncontrast head CT, and potentially acute vascular imaging with CT angiography or TCD.
37%, respectively. In PROACT 2, a randomized controlled trial (RCT) showing better outcomes with intra-arterial (IA) urokinase vs placebo, the median time until IA infusion beginning was 5.3 hours, with most patients (63%) achieving recanalization by at least their 1-hour angiogram (possibly earlier but not assessed).4 An absolute line for when to no longer attempt recanalization does not exist and every stroke case has to be evaluated individually. The only certainty is that the chance for a good outcome after recanalization decreases rapidly over the 6hour time period from ictus, emphasizing the urgency for the most prompt recanalization. The possibility to extend the time window of stroke intervention further with perfusion imaging to subselect patients with salvageable penumbra was not proven efficacious in a recent RCT.21 Several studies lend more support for recanalization predicting better outcome regardless of the method of recanalization (Figure 1).12,19,22,23 The angiographic grading scales used to quantify recanalization in stroke are abstracted from the Thrombolysis In Myocardial Infarction (TIMI) grading scales (Table).24 Even the Thrombolysis In Cerebral Infarction Scale (TICI) has evolved since its original description by Mori et al25 and Higashida and Furlan.26 These scales are not specific for different cerebral circulations, do not account for collaterals, and thus poorly represent perfusion to distal branches which is the ultimate goal of treatment in stroke. Since the broad acceptance of the TICI scale, most authors defined meaningful recanalization as TICI 2a (eg, perfusion into only 1 M2 branch
TIMING AND RECANALIZATION Timing from stroke onset to revascularization is paramount. Analysis of IMS 1 and 2 revealed a 10% decrease in the probability of a functional outcome for only a 30-minute delay.16 Two metaanalyses found that the therapeutic effect of IVT is greatest before 1.5 hours, still substantial before 3 or 4.5 hours, but has little if any benefit after 4.5 hours.17,18 Christou et al,19 evaluating the time until recanalization using TCD, found that no patient recanalizing after 300 minutes had a complete recovery. In a prospective evaluation of IVT and intra-arterial thrombolysis (IAT) followed by mechanical therapy if needed, Mazighi et al20 found that favorable outcomes (modified Rankin Scale [mRS] #2) in patients recanalized at ,210 minutes, between 210 and 260 minutes, and .260 minutes occurred in 93%, 67%, and
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FIGURE 1. Chronological comparison of recanalization rates (reported as TICI 2a or better) to neurological outcomes (mRS #2) of 14 randomized controlled trials evaluating interventional therapy in ischemic stroke. Of note, subsequent data have shown that clinical outcomes correlate better with TICI 2b recanalization. mRS, modified Rankin Scale; TICI, Thrombolysis In Cerebral Infarction Scale.
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3
3
2b ($2/3 distal territory) 2b ($1/2 distal territory) TICI
TICI
Higashida26 (2003)
Broderick12 (2013)
TIMI, Thrombolysis In Myocardial Infarction; TICI, Thrombolysis In Cerebral Infarction Scale.
TICI
1 0 Any cerebral
2a (,2/3 distal territory) 2a (,1/2 distal territory) 1 0
4 2 (,1/2 distal territory) 3 ($1/2 distal territory) 1 0
Anterior cerebral circulation Any cerebral
3 2 (slow transit time) 1 0 Coronary
for an MCA stroke) or better.27 However, recent retrospective application of the TICI scale to clinical data has begun to validate TICI 2b (perfusion into 2 or more M2 branches) or better as meaningful reperfusion, a position echoed by the IMS 3 investigators.12,28 The timing and completeness of recanalization are strong predictors of outcome in the ischemic stroke population receiving interventional therapy. Further emphasis should be given to the fact that these are the 2 main variables that interventionalists can improve. Evaluation of several studies and meta-analyses indicate that the timing for meaningful recanalization likely exists at about 4.5 hours from ictus. Recanalization to at least TICI 2b within the 4.5-hour window defines the technical goal of stroke intervention.
RECANALIZATION STRATEGIES
TIMI Study Group24 (1985) Mori25 (1992)
TIMI
No Recanalization Circulation Scale Name
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Author (year)
TABLE. TIMI and TICI Grading Systems
Recanalization, No Perfusion
Partial Perfusion
Partial Perfusion
Complete Perfusion
ROLE OF ENDOVASCULAR THERAPY IN TREATMENT OF ACUTE ISCHEMIC STROKE
As outlined above, the technical goal of treatment of AIS is reperfusion to TICI 2b-3 in 4.5 hours or less. Assessing the efficacy of different acute stroke therapies for recanalization, Rha and Saver23 evaluated 53 studies in a meta-analysis and found the rates of recanalization were: spontaneous (24%), IVT (46.2%), IAT (63.2%), combined IVT/IAT (67.5%), and mechanical (83%). For more distal emboli, IVT is the mainstay of acute ischemic stroke treatment owing to the ease of administration as well as being the most validated in clinical trials. Although not born out in completed RCTs, endovascular therapy with the use of more efficacious modern thrombectomy devices will likely be necessary to improve outcomes in cases of ICA or proximal MCA clots because of the inability of IVT to recanalize these lesions well.29 Endovascular therapy may also be necessary in cases where contraindications to systemic fibrinolytics exist.30 Albeit statistically significant, the efficacy of IVT is not outstanding, with the absolute risk reduction of poor outcome in NINDS and ECASS 3 of only 13% and 7%, respectively. Additionally, 61% of patients in NINDS and 52.4% of patients in ECASS 3 remained with permanent disability or death.2,3 We will briefly summarize IVT and follow with more detailed discussion of endovascular treatment strategies for AIS.
INTRAVENOUS THROMBOLYSIS The benefits of IVT over endovascular treatment include the ease and speed of administration, noninvasiveness, and low cost. Recanalization with IVT is inversely proportional to the size of the clot and thus this therapy has its greatest efficacy with more distal MCA occlusion and poor efficacy with proximal MCA or ICA occlusions. Patients with distal thrombi are typically those who present clinically with lower NIHSSS.8 Although inferior to endovascular care by means of recanalization of LVO, IVT has been demonstrated to be at least equally efficacious in 3 RCTs that have selected for patients with LVO.12,21,31 IVT is thus the standard of care in patients without contraindications to systemic fibrinolysis until further studies demonstrate the superiority of endovascular therapy.
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In the early years of IVT, initial RCTs may have been unsuccessful at proving the efficacy of IVT owing to the overdosing of thrombolytics, use of thrombolytics associated with more hemorrhage, or delayed treatment.32-36 The US Food and Drug Administration (FDA) approved the use of IVT in 1996 after the NINDS rtPA Stroke Trial demonstrated the efficacy of alteplase at 0.9 mg/kg if given within 3 hours. An outcome of mRS 0 to 1 at 3 months had an odds ratio of 1.9 compared with medical management. These outcomes were superior despite the increased incidence of intracranial hemorrhage in patients receiving IVT (6.4% vs 0.6%).2 This window has been extended to 4.5 hours by the vast majority of stroke centers after ECASS 3 which demonstrated an adjusted relative risk of 7.2% for poor outcome (52.4% vs 45.2%, mRS # 1).3 Further extension of the time window for administration of IVT to 6 hours has little support in clinical trials.37 Guidelines for stroke management by the American Heart Association/American Stroke Association recommend administration of IVT to stroke patients up to 4.5 hours from ictus.38
INTRA-ARTERIAL THROMBOLYSIS ALONE The option of IAT offers a more direct instillation of thrombolytics to the offending clot and allows the use of mechanical devices, if needed, because the catheter is already placed in the occluded artery. The drawbacks to IAT compared with IVT include the invasiveness of the therapy with associated vascular complications, costs, and the time delay in obtaining endovascular access while trying to achieve a time-sensitive goal. Although recanalization rates are superior with IAT, if IVT is not also used, the increased infarction that occurs awaiting endovascular access may be too costly to provide clinical benefit. This concern is negated with combination IVT/IAT as discussed later. Support for IAT alone for anterior circulation strokes is derived from 2 RCTs using IA urokinase with placebo controls.4,39 Both trials treated MCA strokes only and had placebo control (ie, not receiving IVT). PROACT 2 randomly assigned 180 of 12 323 (1.4%) screened patients and found better recanalization rates (TIMI 2-3, 66% vs 18%; TIMI 3, 19% vs 2%) and better outcomes (mRS 0-2, 40% vs 25%, P = .04) with IAT than placebo, especially in patients with NIHSSS 11 to 20 (odds ratio = 2.58).4 Similar in design to PROACT 2, the Middle Cerebral Artery Embolism Local Fibrinolytic Intervention Trial (MELT) found better excellent outcomes (mRS 0-1, 42.1% vs 22.8%, P = .045), but good outcomes (mRS 0-2) did not reach statistical significance (49.1% vs 36.8%, P = .35).39 A meta-analysis of 5 RCTs comparing IAT with placebo, which includes the 2 abovementioned trials, found IAT to achieve TIMI 2a-3 recanalization rates of 64.6% and TIMI 3 rates of only 17.8%.40 Despite moderate clinical success, the marginal complete recanalization rates from these trials lends support to mechanical intervention in patients with LVO. IAT without preceding IVT, as used in the PROACT trials and MELT, likely only has a role in patients with relative contraindications to IVT such as recent surgery.41
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COMBINED IVT/IAT AND THE EVOLUTION OF MECHANICAL METHODS Combined use of IVT followed by IAT is attractive to many, because it may take advantage of the rapid administration of the former and the higher recanalization rates of the latter. Additionally, once a catheter is placed in an artery harboring a thrombus, devices for mechanical disruption of the thrombus can be used. Early in the use of thrombolytics for stroke, the Emergency Management of Stroke (EMS) Bridging Trial compared IVT/IAT with placebo/IAT in AIS presenting before 3 hours. IAT was given only proximal to the thrombus with no mechanical disruption of the clot reported in this study. Recanalization was much better in the IVT/IAT group (TIMI 3 recanalization in 54.5% [6/11] vs 10% [1/10]; P = .05).42 In the first report of intentional mechanical disruption for stroke thrombolysis, Ringer et al43 reported that balloon angioplasty resulted in successful recanalization in cases that did not respond to IVT/IAT. A finding corroborated in the RECANALIZE study where investigators found statistically higher TIMI 2a-3 recanalization of 87% vs 52% when IAT with mechanical disruption was used.42 The first Interventional Management of Stroke (IMS-1) study gave 2/3 dose IVT (alteplase, 0.6 mg/kg) followed by IA distal, into, and proximal to the thrombus. The catheter and microwire created mechanical disruption of the thrombus during placement of the catheter.45 IMS-2 trial had a similar design to IMS-1 with the addition of an ultrasound catheter to facilitate clot fragmentation. The IMS 1 and 2 trials achieved TICI 2a-3 recanalization of 56% and 61%, respectively.12,44 Shaltoni et al46 prospectively evaluated the use of full-dose IVT (alteplase, 0.9 mg/kg) followed by IAT with guidewire and catheter mechanical disruption. Despite a majority of their enrolled population having LVO (72.1% with ICA or M1 occlusion, 98.5% ICA, M1, or M2 occlusion), they were able to achieve recanalization of TICI 2a-3 in 72.5%. This recanalization rate was substantially better than the IMS 1 and 2 trials likely because of the use of full-dose IVT; however, intracerebral hemorrhage rates were not increased. In a retrospective review, Levy et al47 demonstrated TIMI 2/3 recanalization in 79% of patients with AIS using stents achieving mRS #3 in 29% of patient recanalized. Although these methods demonstrate improved recanalization rates with mechanical disruption, they have become historic with the advent of devices specifically designed for thrombectomy that have shown superior recanalization results. Mechanical Thrombectomy Devices Devices for embolectomy have been implemented in trials looking at the efficacy of endovascular management of stroke since the Merci retrieval device in 2004.48 The highest recanalization rate of any method has been seen with the newest aspiration devices (Penumbra) and stent-triever devices (Solitaire, Trevo).49-53 The 3
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ROLE OF ENDOVASCULAR THERAPY IN TREATMENT OF ACUTE ISCHEMIC STROKE
recently published RCTs enrolled patients during years that these devices were being approved for use and thus were on the front wave of this technology. Of the 660 patients randomly assigned to endovascular treatment in IMS 3, Synthesis, and MR Rescue trials, device use for thrombectomy was as follows: Merci 18.0%, Prenumbra 10.9%, Solitaire 3.3%, and Trevo 0.8%.12,21,31 Just including second-generation thrombectomy devices (Penumbra, Solitaire, and Trevo), only 99 of 660 patients (15%) had 1 of these devices used. One could argue that these trials may have shown better outcomes had they been performed after the approval of these devices, which would have allowed their more frequent use and better recanalization results. MERCI The Mechanical Embolus Removal in Cerebral Ischemia (MERCI) retrieval system (Concentric Medical Inc, Mountain View, California) was FDA approved in 2004 for patients who fail or are ineligible for IVT.48 It is a flexible corkscrew-shaped nitinol wire delivered through a 2.4F microcatheter distal to the occluded segment of the vessel. When deployed, it expands to its preshaped form and engages the thrombus. The retriever is then pulled into the balloon guide catheter (8F or 9F) under proximal flow arrest and/or active suction. Multiple generations of MERCI devices have been available. They differ from having a basic nitinol wire with helical tapering coil loops (X5 and X6) to the addition of arcading filaments to a nontapering coil loop (L4, L5, and L6) or by having variable pitch loops with attached filaments (V series, latest generation) (Figure 2).54 The MERCI trials were prospective single-arm trials with historical controls, in which the device was used in LVO within 8 hours of stroke onset. The revascularization rate (TIMI 2/3) before any adjuvant treatment in the initial phase MERCI trial and Multi MERCI studies was 48% and 55%, respectively.55,56 Two recent studies, using the TICI scale as opposed to the TIMI scale, reported higher recanalization rates of 60% and 73%.12,57 The rate of good outcome (mRS 0-2) 90 days after ictus was as follows: initial MERCI trial 27.7%, Multi MERCI trial 36%, and Merci retriever in the TREVO 2 trial 22%. Mortality rates in AIS trials using the MERCI device have decreased over time (MERCI 43.5%, Multi MERCI 34.0%, and TREVO 2 trial 24%).55-57 These results could be related to better device safety, practitioner experience, or patient selection. The rate of intracerebral hemorrhage using the Merci retriever was as follows: MERCI trial 7.8%, Multi-MERC trial 9.8%, and TREVO 2 trial 9%.55-57 One of the drawbacks of using Merci retrievers is the rate of vessel perforation, which is 10 times more common with the Merci retriever (10%) than the newer Trevo stent-triever (1%; P = .018).57 This unwanted event may be the result of the active pushing required to deploy the device out of the microcatheter in addition to the higher outward forces, concentrated on the smaller amount of device loops. We currently do not use the Merci device at our institution, in part, owing to the safety profile.
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FIGURE 2. Merci V-series retriever with 7 loops of platinum filaments. Reproduced with permission.
THROMBOASPIRATING DEVICES Devices using suction are theoretically amenable for fresh nonadhesive thrombus. These devices debulk and extract the clot from proximal to distal with the theoretical advantage of fewer embolic debris and less vasospasm.54,58,59 The main disadvantage is the navigability in intracranial vessels. The better known devices in this category are the Penumbra system (Penumbra Inc, Alameda, California) approved in 2008, and the Angiojet/ Neurojet System (Possis Medical, Minneapolis, Minnesota), which is no longer produced because of the safety concerns with early models. The Penumbra system consists of a reperfusion catheter and a microwire (separator) of various sizes with an oliveshaped tip that is used to disrupt the thrombus during aspiration (Figure 3).60 In addition, balloon occlusion at the proximal guide catheter with aspiration to promote flow reversal also facilitates clot extraction.54 In some cases, a second retriever device resembling a stent attached to a guidewire is used to remove the resistant clot. It has proven promising and efficacious in revascularization in both the anterior and posterior circulation.61,62 A multicenter, single-arm pilot trial evaluated the safety and efficacy of the Penumbra system in AIS. The primary outcome was the rate of revascularization (TIMI 2/3). Of 23 patients enrolled in the study, 20 underwent thrombectomy with 100% revascularization. At
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FIGURE 3. Three sizes of the Penumbra MAX system of aspiration catheters with separator devices. Reproduced with permission.
30 days postprocedure, good outcome (mRS #2 or NIHSSS improved $4) was achieved in 45% and all-cause mortality was 45%.61 The Penumbra Pivotal Stroke Trial was a single-arm trial that included 125 patients who presented within 8 hours of stroke with an NIHSSS $8. Recanalization (TIMI 2/3) was achieved in 81.6% with an intracerebral hemorrhage rate of 11.2%. Good outcome (mRS #2) at 90 days was 25% with a mortality rate of 32.8%.52 The Penumbra POST trial reported postmarket results in 157 patients with AIS presenting within 8 hours with LVO. TIMI 2 to 3 occurred in 87% of patients, mRS #2 at 90 days was 41%, procedural adverse events occurred in 5.7%, and all-cause mortality was 20%.53 A modified technique using the Penumbra system involves wedging the tip of the reperfusion catheter to the proximal part of the clot followed by manual suction using a 20- or 50-mL syringe. The separator mechanism is not used in this technique. Twentytwo consecutive patients with LVO were reviewed with TICI 2b-3 results in 81.9% and good outcome (mRS #2) at 3 months in 45.5% of patients.63 Similarly, the simplified application of the penumbra system termed the ADAPT technique reported by Turk et al64 achieved TICI 2b-3 results in 75% of patients at a mean treatment time of 28.1 minutes. This thromboaspirating device along with the next-mentioned stent-trievers may contribute to future improvements in recanalization rates and hopefully clinical improvements.
STENT-TRIEVERS Stent-trievers are among the newest and most efficacious devices. These devices apply a radial force in the center of the thrombus along its whole length. Animal studies have demonstrated high recanalization rates without the loss of vascular integrity.65 Typically, the technique involves proximal flow arrest by using an 8F or 9F balloon guide catheter. A microcatheter is passed through the thrombus to deliver a nitinol stent. The stent is
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then deployed, resulting in the displacement of the thrombus against the blood vessel and integration into the stent-triever. After 3 to 5 minutes, the stent is retrieved. During retrieval, continuous aspiration with a large syringe or a vacuum apparatus is performed.50,66 The current FDA-approved stent-trievers are the Solitaire and Trevo systems, which differ in the clot integration technique. The Trevo device has vertically oriented struts allowing for efficient clot integration (Figure 4A). The Solitaire has a circumferential overlapping design allowing for multiple contact planes with the thrombus (Figure 4B–C). With regard to diameter, the spectrum of vessel size for Trevo and Solitaire is 1.5 to 4 mm and 1.9 to 5.5 mm, respectively. The Trevo device can be used for up to 3 passes per device and 6 passes per vessel, whereas the Solitaire can be used for 2 passes per device and 3 passes per vessel.66 Various studies have demonstrated adequate safety and superiority in recanalization and reperfusion of stent-trievers in comparison with the Merci device.49,51,67 The Solitaire with Intention for Thrombectomy (SWIFT) trial was a randomized, noninferiority trial that compared the efficacy and safety of Solitaire with the Merci Retrieval System.51 This study was stopped early after enrollment of 126 of 250 planned patients because of a significantly higher mortality rate in the Merci arm (17% vs 38%; P = .02). Solitaire showed better TIMI 2 to 3 flow (61% vs 24%, P = .001) and better 3-month clinical outcomes (58% vs 33%, P = .02). A separate analysis also revealed greater rates of TICI 2b-3 reperfusion in the patients treated with the Solitaire device (76% vs 41.5%) and TICI 3 (52% vs 19%).68 As reported by Mokin et al,69 the Solitaire device has commonly been used in combination with the Penumbra aspiration device for the so-called “Solumbra” technique. The Trevo 2 trial was an open-label RCT of Trevo (n = 88) and Merci (n = 90) treated within 8 hours. This trial is the only device publication offering TICI 2b results, and the authors used a more strict definition of $2/3 MCA territory perfusion. TICI 2b-3 flow was achieved in 68% of patients in the Trevo group vs 44% in the Merci group. Complications did not differ between groups (Trevo 15% vs Merci 23%; P = .185). Trevo-treated patients had better 90-day clinical outcomes (mRS ,2, 40% vs 22%, P = .013).49 A study by Broussalis et al67 of 120 patients treated with either stenttrievers (Solitaire and Trevo devices) or Merci system found that successful recanalization (TICI 2b-3) was achieved in 82% of patients treated with stent-trievers compared with 62% of patients treated with the Merci device (P = .016). The mRS 0 to 2 at 90-day clinical outcomes were also better in the stent-triever arm (mRS ,2, 65% vs 35%, P = .002). Severe hemorrhage in this study occurred less frequently in the patients treated with the stent-trievers (10% vs 28%, P = .01). Results from stent-triever trials appear quite promising as a method for acute intracranial revascularization. Current Therapy and Ongoing Trials In light of the most recently published RCTs, IVT remains the standard treatment for acute ischemic stroke. Endovascular
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ROLE OF ENDOVASCULAR THERAPY IN TREATMENT OF ACUTE ISCHEMIC STROKE
FIGURE 4. A, Trevo ProVue self-expanding stent-triever device. Reproduced with permission. B, Solitaire self-expanding stenttriever device. Reproduced with permission. C, balloon guide catheter with aspiration during thrombectomy with Solitaire stenttriever. Inset, clot integrated into Solitaire stent-triever device. Reproduced with permission.
therapy with stent-retrievers and thrombo-aspirating devices outside of patients enrolled in new trials may not be warranted given the results of RCTs to date. Exceptions to this include patients that present in the 4.5-hour window but have contraindications to systemic thrombolytics (eg, recent trauma, surgery, or gastrointestinal bleeding). Continued enrollment into RCTs is justified by the facts that (1) revascularization is positively associated with outcome, (2) second-generation thrombectomy devices are superior to all other methods of revascularization, and (3) second-generation devices were scarcely used in current trials comparing IVT with adjunctive endovascular therapy with IVT alone. Beginning in 2012, 2 trials started randomly assigning patients to IVT or IVT plus adjunctive mechanical thrombectomy with second-generation devices. Inclusion criteria for both trials were age 18 to 85, NIHSSS $8, and required IVT administration before 4.5 hours. The THERAPY trial is sponsored by Penumbra Inc. This study uses the penumbra clot aspiration system with a Separator 3D device as the adjunctive mechanical therapy. Patients must have
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a proximal anterior circulation clot at least 8 mm in length by noncontrast head CT.70 The SWIFT PRIME trial is sponsored by Covidien. This study uses the Solitaire stent-retriever device for adjunctive therapy. Patients are selected by CT angiogram or magnetic resonance angiography demonstration of TICI 0 to 1 occlusion of the MCA or ICA. Additionally, patients are excluded based on CT or MR perfusion imaging demonstrating large areas of infarction relative to penumbra.71 Both studies are early in enrollment with estimated completion dates in 2016 to 2018.
CONCLUSION The technical goal of any revascularization strategy is to achieve TICI 2b-3 recanalization as soon as possible. Although superior recanalization rates have been demonstrated with second-generation thrombectomy devices, the future of endovascular management of stroke may hinge on proving superior outcomes in patients treated with these new devices. Because of the lack of use of secondgeneration thrombectomy devices in current RCTs, clinical
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equipoise exists for treating AIS by using IVT with or without adjunctive second-generation thrombectomy devices. The authors remain optimistic that clinical outcomes will improve as interventional techniques evolve, and therefore believe patients with LVO should be enrolled into clinical trials to determine whether clinical outcomes can be improved upon what is achieved with IVT alone. Disclosure Dr Ringer has received consulting fees from Stryker, Microvention, and Covidien/eV3, but not for any product discussed in this article. The other authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article.
REFERENCES 1. Lloyd-Jones D, Adams RJ, Brown TM, et al. Heart disease and stroke statistics— 2010 update: a report from the American Heart Association. Circulation. 2010; 121(7):e46-e215. 2. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995;333(24):1581-1587. 3. Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med. 2008;359(13):1317-1329. 4. Furlan A, Higashida R, Wechsler L, et al. Intra-arterial prourokinase for acute ischemic stroke. The PROACT II study: a randomized controlled trial. JAMA. 1999;282(21):2003-2011. 5. Zahuranec DB, Majersik JJ. Percentage of acute stroke patients eligible for endovascular treatment. Neurology. 2012;79(13 suppl 1):S22-S25. 6. Fieschi C, Argentino C, Lenzi GL, Sacchetti L, Toni D, Bozzao L. Clinical and instrumental evaluation of patients with ischemic stroke within the first six hours. J Neurol Sci. 1989;91(3):311-322. 7. Derex L, Nighoghossian N, Hermier M, Adeleine P, Froment JC, Trouillas P. Early detection of cerebral arterial occlusion on magnetic resonance angiography: predictive value of the baseline NIHSS score and impact on neurological outcome. Cerebrovasc Dis. 2002;13(4):225-229. 8. Fischer U, Arnold M, Nedeltchev K, Brekenfeld C, et al. NIHSS score and arteriographic findings in acute ischemic stroke. Stroke. 2005;36(10):2121-2125. 9. Nakajima M, Kimura K, Ogata T, Takada T, Uchino M, Minematsu K. Relationships between angiographic findings and National Institutes of Health Stroke Scale score in cases of hyperacute carotid ischemic stroke. AJNR Am J Neuroradiol. 2004;25(2):238-241. 10. Tomsick T, Brott T, Barsan W, et al. Prognostic value of the hyperdense middle cerebral artery sign and stroke scale score before ultraearly thrombolytic therapy. AJNR Am J Neuroradiol. 1996;17(1):79-85. 11. González RG, Copen WA, Schaefer PW, et al. The Massachusetts General Hospital acute stroke imaging algorithm: an experience and evidence based approach. J Neurointerv Surg. 2013;5(suppl 1):i7-i12. 12. Broderick JP, Palesch YY, Demchuk AM, et al. Endovascular therapy after intravenous t-PA versus t-PA Alone for Stroke. N Engl J Med. 2013;368(10):893-903. 13. Wolpert SM, Bruckman H, Greenlee R, et al. Neuroradiologic evaluation of patients with acute stroke treated with recombinant tissue plasminogen activator. Am J Neuroradiol. 1993;14(1):3-13. 14. Saqqur M, Uchino K, Demchuk A, et al. Site of arterial occlusion identified by transcranial doppler predicts the response to intravenous thrombolysis for stroke. Stroke. 2007;38(3):948-954. 15. Riedel CH, Zimmerman P, Jensen-Kondering U, Stingele R, Deuschl G, Jansen O. The importance of size: successful recanalization by intravenous thrombolysis in acute anterior stroke depends on thrombus length. Stroke. 2011; 42(6):1775-1777. 16. Khatri P, Abruzzo T, Yeatts SD, Nichols C, Broderick JP, Tomsick TA. Good clinical outcome after ischemic stroke with successful revascularization is timedependent. Neurology. 2009;73(13):1066-1072. 17. 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. 2004;363(9411):768-774.
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18. Lees KR, Bluhmki E, von Kummer R, et al. Time to treatment with intravenous alteplase and outcome in stroke: an update pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials. Lancet. 2010;375(9727):1695-1703. 19. Christou I, Alexandrov A, Burgin WS, et al. Timing of recanalization after tissue plasminogen activator therapy determined by transcranial doppler correlates with clinical recovery from ischemic stroke. Stroke. 2000;31(8):1812-1816. 20. Mazighi M, Serfaty JM, Labreuche J, et al. Comparison of intravenous alteplase with a combined intravenous—endovascular approach in patients with stroke and confirmed arterial occlusion (RECANALISE study): a prospective cohort study. Lancet. 2009;8(9):802-809. 21. Kidwell CS, Jahan R, Gornbein J, et al. A trial of imaging selection and endovascular treatment for ischemic stroke. N Engl J Med. 2013;368(10):914-923. 22. Tomsick T, Broderick J, Carrozella J, et al. Revascularization results in the interventional management of stroke II trial. AJNR Am J Neuroradiol. 2008;29(3): 582-587. 23. Rha JH, Saver JL. The impact of recanalization on ischemic stroke outcome: a meta-analysis. Stroke. 2007;38(3):967-973. 24. The TIMI Study group. Thrombolysis in Myocardial infarction (TIMI) trial phase I findings. N Engl J Med. 1985;312(14);932-936. 25. Mori E, Yoneda Y, Tabuchi M, et al. Intravenous recombinant tissue plasminogen activator in acute carotid artery territory stroke. Neurology. 1992;42(5):976-982. 26. Higashida RT, Furlan AJ. Trial design and reporting standards for intra-arterial cerebral thrombolysis for acute ischemic stroke. Stroke. 2003;34(8):e109-e137. 27. Fugate JE, Klunder AM, Kallmes DF. What is Meant by “TICI”? [published online ahead of print] AJNR Am J Neuroradiol. 2013. 28. Jayaraman MV, Grossberg JA, Meisel KM, Shaikhouni A, Silver B. The clinical and radiographic importance of distinguishing partial from near-complete reperfusion following intra-arterial stroke therapy. AJNR Am J Neuroradiol. 2013;34(1):135-139. 29. Mokin M, Kass-Hout T, Kass-Hout O, et al. Intravenous thrombolysis and endovascular therapy for acute ischemic stroke with internal carotid artery occlusion: a Systematic review of clinical outcomes. Stroke. 2012;43(9):2362-2368. 30. Blackham KA, Meyers PM, Abruzzo TA, et al. Endovascular therapy of acute ischemic stroke: report of the Standards of Practice Committee of the Society of NeuroInterventional Surgery. J Neurointerv Surg. 2012;4(2):87-93. 31. Ciccone A, Valvassori L, Nichelatti M, et al. Endovascular treatment for acute ischemic stroke. N Engl J Med. 2013;368(10):904-913. 32. Hommel M, Boissel JP, Cornu C, et al. Termination of trial of streptokinase in severe acute ischaemic stroke. Lancet. 1994;345(8941):57. 33. Randomised controlled trial of streptokinase, aspirin, and combination of both in treatment of acute ischaemic stroke. Multicentre Acute Stroke Trial—Italy (MAST-I) Group. Lancet. 1995;346(8989):1509-1514. 34. Thrombolytic therapy with streptokinase in acute ischemic stroke. The multicenter acute stroke Trial—Europe study group. N Engl J Med. 1996;335 (3):145-150. 35. Hacke W, Kaste M, Fieschi C, et al. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke, the European Cooperative acute stroke study (ECASS). JAMA. 1995;274(13):1017-1025. 36. Hacke W, Kaste M, Fieschi C, et al. Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Lancet. 1998;352(9136):1245-1251. 37. The IST-3 Collaborative Group. The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (the third international stroke trial [IST-3]): a randomised controlled trial. Lancet. 2012;379:2352-2363. 38. Jauch EC, Saver JL, Adams HP, et al. Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American stroke association. Stroke. 2013;44(3): 870-947. 39. Ogawa A, Mori E, Minematsu K, et al. Randomized trial of Intraarterial infusion of urokinase within 6 hours of middle cerebral artery stroke: the middle cerebral artery Embolism Local fibrinolytic intervention trial (MELT) Japan. Stroke. 2007; 38(10):2633-2639. 40. Lee M, Keun-Sik H, Saver J. Efficacy of intra-arterial fibrinolysis for acute ischemic stroke: meta-analysis of randomized controlled trials. Stroke. 2010;41(5):932-937. 41. Moazami N, Smedira NG, McCarthy PM. Safety and efficacy of intra-arterial thrombolysis for perioperative stroke after cardiac operation. Ann Thorac Surg. 2001;72(6):1933-1939.
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ROLE OF ENDOVASCULAR THERAPY IN TREATMENT OF ACUTE ISCHEMIC STROKE
42. Lewandowski CA, Frankel M, Tomsick TA, et al. Combined intravenous and intra-arterial r-TPA verusus intra-arterial therapy of acute ischemic stroke. Stroke. 1999;30(12):2598-2605. 43. Ringer AJ, Qureshi AI, Fessler RD, Guterman LR, Hopkins LN. Angioplasty of intracranial occlusion resistant to thrombolysis in acute ischemic stroke. Neurosurgery. 2001;48(6):1282-1290. 44. IMS II Trial Investigators. Interventional Management of sStroke (IMS) II study. Stroke. 2007;38(7):2127-2135. 45. IMS Study Investigators. Combined intravenous and intra-arterial recanalization for acute ischemic stroke: the Interventional Management of Stroke Study. Stroke. 2004;35(4):904-911. 46. Shaltoni HM, Albirght KC, Gonzales NR, et al. Is intra-arterial thrombolysis safe after full-dose intravenous recombinant tissue plasminogen activator for acute ischemic stroke? Stroke. 2007;38(1):80-84. 47. Levy EI, Mehta R, Gupta R, et al. Self-expanding stents for recanalization of acute cerebrovascular occlusions. AJNR Am J Neuroradiol. 2007;28(5):816-822. 48. Gobin YP, Starkman S, Duckwiler GR, et al. MERCI 1: a phase 1 study of mechanical embolus removal in cerebral ischemia. Stroke. 2004;35(12): 2848-2854. 49. Nogueira RG, Lutsep HL, Gupta R, et al. Trevo versus Merci retrievers for thrombectomy revascularisation of large vessel occlusions in acute ischaemic stroke (TREVO 2): a randomised trial. Lancet. 2012;380(9849):1231-1240. 50. Costalat V, Machi P, Lobotesis K, et al. Rescue, combined, and stand-alone thrombectomy in the management of large vessel occlusion stroke using the solitaire device: a prospective 50-patient single-center study: timing, safety, and efficacy. Stroke. 2011;42(7):1929-1935. 51. Saver JL, Jahan R, Levy EI, et al. Solitaire flow restoration device versus the Merci Retriever in patients with acute ischaemic stroke (SWIFT): a randomised, parallelgroup, non-inferiority trial. Lancet. 2012;380(9849):1241-1249. 52. 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. 2009;40(8):2761-2768. 53. Tarr R, Hsu D, Kulcsar Z, et al. The POST trial: initial post-market experience of the Penumbra system: revascularization of large vessel occlusion in acute ischemic stroke in the United States and Europe. J Neurointerv Surg. 2010;2(4):341-344. 54. Nogueira RG, Schwamm LH, Hirsch JA. Endovascular approaches to acute stroke, part 1: drugs, devices, and data. AJNR Am J Neuroradiol. 2009;30(4):649-661. 55. Smith S, Sung G, Starkman S, et al. Safety and efficacy of mechanical embolectomy in acute ischemic stroke: results of the MERCI trial. Stroke. 2005;36(7):1432-1438. 56. Smith WS, Sung G, Saver J, et al. Mechanical thrombectomy for acute ischemic stroke: final results of the Multi MERCI trial. Stroke. 2008;39(4):1205-1212.
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57. Nogueira RG, Levy EI, Gounis M, Siddiqui AH. The Trevo device: preclinical data of a novel stroke thrombectomy device in two different animal models of arterial thrombo-occlusive disease. J Neurointerv Surg. 2012;4(4):295-300. 58. Meyers PM, Schumacher HC, Connolly ES Jr, Heyer EJ, Gray WA, Higashida RT. Current status of endovascular stroke treatment. Circulation. 2011;123(22):2591-2601. 59. Gralla J, Schroth G, Remonda L, Nedeltchev K, Slotboom J, Brekenfeld C. Mechanical thrombectomy for acute ischemic stroke: thrombus-device interaction, efficiency, and complications in vivo. Stroke. 2006;37(12):3019-3024. 60. Benmira S, Banda ZK, Bhattacharya V. The start of a new era for stroke treatment: mechanical thrombectomy devices. Curr Neurovasc Res. 2011;8(1):75-85. 61. Bose A, Henkes H, Alfke K, et al. The penumbra system: a mechanical device for the treatment of acute stroke due to thromboembolism. AJNR Am J Neuroradiol. 2008;29(7):1409-1413. 62. Roth C, Mielke A, Siekmann R, Ferbert A. First experiences with a new device for mechanical thrombectomy in acute basilar artery occlusion. Cerebrovasc Dis. 2011; 32(1):28-34. 63. Kang DH, Hwang YH, Kim YS, Park J, Kwon O, Jung C. Direct thrombus retrieval using the reperfusion catheter of the penumbra system: forced-suction thrombectomy in acute ischemic stroke. AJNR Am J Neuroradiol. 2011;32(2): 283-287. 64. Turk AS, Spiotta A, Frei D, et al. Initial clinical experience with the ADAPT technique: a direct aspiration first pass technique for stroke thrombectomy [published online ahead of print]. J Neurointerv Surg. 2013. 65. Jahan R. Solitaire flow-restoration device for treatment of acute ischemic stroke: safety and recanalization efficacy study in a swine vessel occlusion model. AJNR Am J Neuroradiol. 2010;31(10):1938-1943. 66. Beadell NC, Lutsep H. New stent retriever devices. Curr Atheroscler Rep. 2013;5 (6):333. 67. Broussalis E, Trinka E, Hitzl W, Wallner A, Chroust V, Killer-Oberpfalzer M. Comparison of stent-retriever devices versus the Merci retriever for endovascular treatment of acute stroke. AJNR Am J Neuroradiol. 2013;34(2):366-372. 68. Jadhav AP, Jovin TG. Intra-arterial reperfusion strategies in acute ischemic stroke. J Neurointerv Surg. 2013;5(suppl 1):i66-i69. 69. Mokin M, Dumont TM, Veznedaroglu E, et al. Solitaire Flow Restoration thrombectomy for acute ischemic stroke: retrospective multicenter analysis of early postmarket experience after FDA approval. Neurosurgery. 2013;73(1):19-25. 70. Mocco J. U.S. National Institutes of Health. ClinicalTrials.gov. Available at: http://clinicaltrials.gov/ct2/show/record/NCT01429350. Accessed September 01, 2013. 71. Saver J. U.S. National Institutes of Health. ClinicalTrials.gov. Available at: http:// clinicaltrials.gov/ct2/show/NCT01657461. Accessed September 01, 2013.
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TOPIC
The Role of Endovascular Therapy in the Treatment of Acute Ischemic Stroke Joseph C. Serrone, MD* Lincoln Jimenez, MD‡ Andrew J. Ringer, MD* *Department of Neurosurgery, University of Cincinnati, Cincinnati, Ohio; ‡Department of Neurosurgery, University of Florida-Jacksonville, Jacksonville, Florida Correspondence: Andrew J. Ringer, MD, c/o Editorial Office, University of Cincinnati College of Medicine, Department of Neurosurgery, 260 Stetson St, Suite 2200, PO Box 670515, Cincinnati, OH 45267-0515. E-mail: [email protected]
Of the approximately 795 000 strokes in the United States annually, 87% are ischemic and result in significant morbidity and mortality. Improvements in acute ischemic stroke (AIS) outcomes have been achieved with intravenous thrombolytics (IVT) and intraarterial thrombolytics vs supportive medical therapy. Given its ease of administration, noninvasiveness, and most validated efficacy, IVT is the standard of care in AIS patients without contraindications to systemic fibrinolysis. However, patients with large-vessel occlusions respond poorly to IVT. Recent trials designed to select this population for randomization to IVT vs IVT with adjunctive endovascular therapy have not shown improvement in clinical outcomes with endovascular therapy. This could be due to the lack of utilization of modern thrombectomy devices such as Penumbra aspiration devices, Solitaire stent-trievers, or Trevo stent-trievers, which have shown the best recanalization results. Continued improvement in the techniques with using these devices as well as randomized controlled trials using them is warranted. This article defines the goals of AIS revascularization, presents the evolution of treatment from the initial use of IVT to modern thrombectomy devices, and discusses current treatment and ongoing AIS trials.
Received, August 6, 2013. Accepted, October 11, 2013.
KEY WORDS: Acute ischemic stroke, Intra-arterial thrombolysis, Intravenous thrombolytics, Large-vessel occlusion, Revascularization
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Neurosurgery 74:S133–S141, 2014
DOI: 10.1227/NEU.0000000000000224
O
f the approximately 795 000 strokes in the United States annually, 87% are ischemic. The 30-day mortality in this population is 8% to 12%. For survivors aged over 65 years, the morbidity cannot be understated, with 50% having some degree of hemiparesis, 30% unable to ambulate, 19% aphasic, 35% depressed, and 26% residing in a nursing home.1 Improvements in acute ischemic stroke (AIS) outcomes have been achieved with some acute revascularization strategies.2-4 However, because the time-sensitive nature of treatment in AIS, it is estimated that only 5% to 13% of ABBREVIATIONS: AIS, acute ischemic stroke; FDA, Food and Drug Administration; IA, intra-arterial; IAT, intra-arterial thrombolysis; ICA, internal carotid artery; IVT, intravenous thrombolytics; LVO, largevessel occlusion; MCA, middle cerebral artery; mRS, modified Rankin Scale; NIHSSS, National Institute of Health Stroke Scale Score; RCT, randomized controlled trial; TCD, transcranial Doppler; TICI, Thrombolysis In Cerebral Infarction Scale; TIMI, Thrombolysis In Myocardial Infarction
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patients present in the time window for recanalization.5 This article defines the goals of AIS revascularization and presents the evolution of treatment from the initial use of intravenous thrombolytics (IVT) to modern thrombectomy devices.
AIS PATIENTS REQUIRING ENDOVASCULAR TREATMENT Large-Vessel Occlusions The goal of acute stroke management is to promptly identify patients who have an arterial occlusion and recanalize the occluded artery. Patients presenting with hemispheric stroke signs will have an occlusion of the internal carotid artery (ICA) or middle cerebral artery (MCA) segment in approximately 3/4 cases and therefore have a potential target for recanalization.5,6 The National Institute of Health Stroke Scale Score (NIHSSS) is the initial tool for evaluating stroke patients and is predictive for large-vessel occlusion (LVO) in those patients who may be poor responders to IVT and thus better candidates for
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SERRONE ET AL
endovascular treatment. In correlating NIHSSS with magnetic resonance angiography findings, Derex et al7 found that every 1 point increase in NIHSSS had an odds ratio of 1.28 for predicting vessel occlusion. Additionally, several authors have correlated proximal angiographic occlusion (ICA, M1, M2, or basilar artery) with an increasing NIHSSS.8,9 Initial evaluation in AIS also includes a noncontrast head computed tomogram (CT) to rule out hemorrhage before considering therapy for recanalization. These studies can also reveal hyperdense intravascular clots that are predictive for occlusion, poor response to IVT, and poorer prognosis.10 At many centers, acute noninvasive vascular imaging is also performed.11 With the goal of selecting stroke patients with LVO, the recently completed IMS-3 trial selected patients for enrollment with an NIHSSS $10 or NIHSSS 8 to 9 with CT angiogram evidence of LVO.12 The next challenge in management of AIS is determining which clots will fibrinolyze with IVT and which will respond better with adjunctive endovascular management. Wolpert et al13 evaluated 93 patients with angiography acutely before and after IVT. Lesions in the ICA, M1, M2, and M3 branches recanalized at 8.7%, 28.9%, 40%, and 47%, respectively, after IVT. Saqqur et al14 had similar findings using transcranial Doppler (TCD) finding recanalization for ICA terminus, M1, and M2 occlusions at 6%, 30%, and 44%, respectively. Additionally, patients with a hyperdense MCA sign on head CT have much lower rates of recanalization.13,15 There is a direct correlation with LVO (ICA, proximal MCA), poor NIHSSS (typically $10), and poor response to IVT. This population, if any, would benefit the most from endovascular care. This is most evident comparing revascularization in IMS 3 by occlusion location. Endovascular therapy achieved recanalization of the ICA, M1, and M2 vessels at 81%, 88%, and 86% compared with respective rates of 35%, 68%, and 77% in the IVT group.12 Patients with LVO that respond poorly to IVT can be selected most quickly and efficiently with a combination of calculating the NIHSSS, a noncontrast head CT, and potentially acute vascular imaging with CT angiography or TCD.
37%, respectively. In PROACT 2, a randomized controlled trial (RCT) showing better outcomes with intra-arterial (IA) urokinase vs placebo, the median time until IA infusion beginning was 5.3 hours, with most patients (63%) achieving recanalization by at least their 1-hour angiogram (possibly earlier but not assessed).4 An absolute line for when to no longer attempt recanalization does not exist and every stroke case has to be evaluated individually. The only certainty is that the chance for a good outcome after recanalization decreases rapidly over the 6hour time period from ictus, emphasizing the urgency for the most prompt recanalization. The possibility to extend the time window of stroke intervention further with perfusion imaging to subselect patients with salvageable penumbra was not proven efficacious in a recent RCT.21 Several studies lend more support for recanalization predicting better outcome regardless of the method of recanalization (Figure 1).12,19,22,23 The angiographic grading scales used to quantify recanalization in stroke are abstracted from the Thrombolysis In Myocardial Infarction (TIMI) grading scales (Table).24 Even the Thrombolysis In Cerebral Infarction Scale (TICI) has evolved since its original description by Mori et al25 and Higashida and Furlan.26 These scales are not specific for different cerebral circulations, do not account for collaterals, and thus poorly represent perfusion to distal branches which is the ultimate goal of treatment in stroke. Since the broad acceptance of the TICI scale, most authors defined meaningful recanalization as TICI 2a (eg, perfusion into only 1 M2 branch
TIMING AND RECANALIZATION Timing from stroke onset to revascularization is paramount. Analysis of IMS 1 and 2 revealed a 10% decrease in the probability of a functional outcome for only a 30-minute delay.16 Two metaanalyses found that the therapeutic effect of IVT is greatest before 1.5 hours, still substantial before 3 or 4.5 hours, but has little if any benefit after 4.5 hours.17,18 Christou et al,19 evaluating the time until recanalization using TCD, found that no patient recanalizing after 300 minutes had a complete recovery. In a prospective evaluation of IVT and intra-arterial thrombolysis (IAT) followed by mechanical therapy if needed, Mazighi et al20 found that favorable outcomes (modified Rankin Scale [mRS] #2) in patients recanalized at ,210 minutes, between 210 and 260 minutes, and .260 minutes occurred in 93%, 67%, and
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FIGURE 1. Chronological comparison of recanalization rates (reported as TICI 2a or better) to neurological outcomes (mRS #2) of 14 randomized controlled trials evaluating interventional therapy in ischemic stroke. Of note, subsequent data have shown that clinical outcomes correlate better with TICI 2b recanalization. mRS, modified Rankin Scale; TICI, Thrombolysis In Cerebral Infarction Scale.
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3
3
2b ($2/3 distal territory) 2b ($1/2 distal territory) TICI
TICI
Higashida26 (2003)
Broderick12 (2013)
TIMI, Thrombolysis In Myocardial Infarction; TICI, Thrombolysis In Cerebral Infarction Scale.
TICI
1 0 Any cerebral
2a (,2/3 distal territory) 2a (,1/2 distal territory) 1 0
4 2 (,1/2 distal territory) 3 ($1/2 distal territory) 1 0
Anterior cerebral circulation Any cerebral
3 2 (slow transit time) 1 0 Coronary
for an MCA stroke) or better.27 However, recent retrospective application of the TICI scale to clinical data has begun to validate TICI 2b (perfusion into 2 or more M2 branches) or better as meaningful reperfusion, a position echoed by the IMS 3 investigators.12,28 The timing and completeness of recanalization are strong predictors of outcome in the ischemic stroke population receiving interventional therapy. Further emphasis should be given to the fact that these are the 2 main variables that interventionalists can improve. Evaluation of several studies and meta-analyses indicate that the timing for meaningful recanalization likely exists at about 4.5 hours from ictus. Recanalization to at least TICI 2b within the 4.5-hour window defines the technical goal of stroke intervention.
RECANALIZATION STRATEGIES
TIMI Study Group24 (1985) Mori25 (1992)
TIMI
No Recanalization Circulation Scale Name
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Author (year)
TABLE. TIMI and TICI Grading Systems
Recanalization, No Perfusion
Partial Perfusion
Partial Perfusion
Complete Perfusion
ROLE OF ENDOVASCULAR THERAPY IN TREATMENT OF ACUTE ISCHEMIC STROKE
As outlined above, the technical goal of treatment of AIS is reperfusion to TICI 2b-3 in 4.5 hours or less. Assessing the efficacy of different acute stroke therapies for recanalization, Rha and Saver23 evaluated 53 studies in a meta-analysis and found the rates of recanalization were: spontaneous (24%), IVT (46.2%), IAT (63.2%), combined IVT/IAT (67.5%), and mechanical (83%). For more distal emboli, IVT is the mainstay of acute ischemic stroke treatment owing to the ease of administration as well as being the most validated in clinical trials. Although not born out in completed RCTs, endovascular therapy with the use of more efficacious modern thrombectomy devices will likely be necessary to improve outcomes in cases of ICA or proximal MCA clots because of the inability of IVT to recanalize these lesions well.29 Endovascular therapy may also be necessary in cases where contraindications to systemic fibrinolytics exist.30 Albeit statistically significant, the efficacy of IVT is not outstanding, with the absolute risk reduction of poor outcome in NINDS and ECASS 3 of only 13% and 7%, respectively. Additionally, 61% of patients in NINDS and 52.4% of patients in ECASS 3 remained with permanent disability or death.2,3 We will briefly summarize IVT and follow with more detailed discussion of endovascular treatment strategies for AIS.
INTRAVENOUS THROMBOLYSIS The benefits of IVT over endovascular treatment include the ease and speed of administration, noninvasiveness, and low cost. Recanalization with IVT is inversely proportional to the size of the clot and thus this therapy has its greatest efficacy with more distal MCA occlusion and poor efficacy with proximal MCA or ICA occlusions. Patients with distal thrombi are typically those who present clinically with lower NIHSSS.8 Although inferior to endovascular care by means of recanalization of LVO, IVT has been demonstrated to be at least equally efficacious in 3 RCTs that have selected for patients with LVO.12,21,31 IVT is thus the standard of care in patients without contraindications to systemic fibrinolysis until further studies demonstrate the superiority of endovascular therapy.
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In the early years of IVT, initial RCTs may have been unsuccessful at proving the efficacy of IVT owing to the overdosing of thrombolytics, use of thrombolytics associated with more hemorrhage, or delayed treatment.32-36 The US Food and Drug Administration (FDA) approved the use of IVT in 1996 after the NINDS rtPA Stroke Trial demonstrated the efficacy of alteplase at 0.9 mg/kg if given within 3 hours. An outcome of mRS 0 to 1 at 3 months had an odds ratio of 1.9 compared with medical management. These outcomes were superior despite the increased incidence of intracranial hemorrhage in patients receiving IVT (6.4% vs 0.6%).2 This window has been extended to 4.5 hours by the vast majority of stroke centers after ECASS 3 which demonstrated an adjusted relative risk of 7.2% for poor outcome (52.4% vs 45.2%, mRS # 1).3 Further extension of the time window for administration of IVT to 6 hours has little support in clinical trials.37 Guidelines for stroke management by the American Heart Association/American Stroke Association recommend administration of IVT to stroke patients up to 4.5 hours from ictus.38
INTRA-ARTERIAL THROMBOLYSIS ALONE The option of IAT offers a more direct instillation of thrombolytics to the offending clot and allows the use of mechanical devices, if needed, because the catheter is already placed in the occluded artery. The drawbacks to IAT compared with IVT include the invasiveness of the therapy with associated vascular complications, costs, and the time delay in obtaining endovascular access while trying to achieve a time-sensitive goal. Although recanalization rates are superior with IAT, if IVT is not also used, the increased infarction that occurs awaiting endovascular access may be too costly to provide clinical benefit. This concern is negated with combination IVT/IAT as discussed later. Support for IAT alone for anterior circulation strokes is derived from 2 RCTs using IA urokinase with placebo controls.4,39 Both trials treated MCA strokes only and had placebo control (ie, not receiving IVT). PROACT 2 randomly assigned 180 of 12 323 (1.4%) screened patients and found better recanalization rates (TIMI 2-3, 66% vs 18%; TIMI 3, 19% vs 2%) and better outcomes (mRS 0-2, 40% vs 25%, P = .04) with IAT than placebo, especially in patients with NIHSSS 11 to 20 (odds ratio = 2.58).4 Similar in design to PROACT 2, the Middle Cerebral Artery Embolism Local Fibrinolytic Intervention Trial (MELT) found better excellent outcomes (mRS 0-1, 42.1% vs 22.8%, P = .045), but good outcomes (mRS 0-2) did not reach statistical significance (49.1% vs 36.8%, P = .35).39 A meta-analysis of 5 RCTs comparing IAT with placebo, which includes the 2 abovementioned trials, found IAT to achieve TIMI 2a-3 recanalization rates of 64.6% and TIMI 3 rates of only 17.8%.40 Despite moderate clinical success, the marginal complete recanalization rates from these trials lends support to mechanical intervention in patients with LVO. IAT without preceding IVT, as used in the PROACT trials and MELT, likely only has a role in patients with relative contraindications to IVT such as recent surgery.41
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COMBINED IVT/IAT AND THE EVOLUTION OF MECHANICAL METHODS Combined use of IVT followed by IAT is attractive to many, because it may take advantage of the rapid administration of the former and the higher recanalization rates of the latter. Additionally, once a catheter is placed in an artery harboring a thrombus, devices for mechanical disruption of the thrombus can be used. Early in the use of thrombolytics for stroke, the Emergency Management of Stroke (EMS) Bridging Trial compared IVT/IAT with placebo/IAT in AIS presenting before 3 hours. IAT was given only proximal to the thrombus with no mechanical disruption of the clot reported in this study. Recanalization was much better in the IVT/IAT group (TIMI 3 recanalization in 54.5% [6/11] vs 10% [1/10]; P = .05).42 In the first report of intentional mechanical disruption for stroke thrombolysis, Ringer et al43 reported that balloon angioplasty resulted in successful recanalization in cases that did not respond to IVT/IAT. A finding corroborated in the RECANALIZE study where investigators found statistically higher TIMI 2a-3 recanalization of 87% vs 52% when IAT with mechanical disruption was used.42 The first Interventional Management of Stroke (IMS-1) study gave 2/3 dose IVT (alteplase, 0.6 mg/kg) followed by IA distal, into, and proximal to the thrombus. The catheter and microwire created mechanical disruption of the thrombus during placement of the catheter.45 IMS-2 trial had a similar design to IMS-1 with the addition of an ultrasound catheter to facilitate clot fragmentation. The IMS 1 and 2 trials achieved TICI 2a-3 recanalization of 56% and 61%, respectively.12,44 Shaltoni et al46 prospectively evaluated the use of full-dose IVT (alteplase, 0.9 mg/kg) followed by IAT with guidewire and catheter mechanical disruption. Despite a majority of their enrolled population having LVO (72.1% with ICA or M1 occlusion, 98.5% ICA, M1, or M2 occlusion), they were able to achieve recanalization of TICI 2a-3 in 72.5%. This recanalization rate was substantially better than the IMS 1 and 2 trials likely because of the use of full-dose IVT; however, intracerebral hemorrhage rates were not increased. In a retrospective review, Levy et al47 demonstrated TIMI 2/3 recanalization in 79% of patients with AIS using stents achieving mRS #3 in 29% of patient recanalized. Although these methods demonstrate improved recanalization rates with mechanical disruption, they have become historic with the advent of devices specifically designed for thrombectomy that have shown superior recanalization results. Mechanical Thrombectomy Devices Devices for embolectomy have been implemented in trials looking at the efficacy of endovascular management of stroke since the Merci retrieval device in 2004.48 The highest recanalization rate of any method has been seen with the newest aspiration devices (Penumbra) and stent-triever devices (Solitaire, Trevo).49-53 The 3
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ROLE OF ENDOVASCULAR THERAPY IN TREATMENT OF ACUTE ISCHEMIC STROKE
recently published RCTs enrolled patients during years that these devices were being approved for use and thus were on the front wave of this technology. Of the 660 patients randomly assigned to endovascular treatment in IMS 3, Synthesis, and MR Rescue trials, device use for thrombectomy was as follows: Merci 18.0%, Prenumbra 10.9%, Solitaire 3.3%, and Trevo 0.8%.12,21,31 Just including second-generation thrombectomy devices (Penumbra, Solitaire, and Trevo), only 99 of 660 patients (15%) had 1 of these devices used. One could argue that these trials may have shown better outcomes had they been performed after the approval of these devices, which would have allowed their more frequent use and better recanalization results. MERCI The Mechanical Embolus Removal in Cerebral Ischemia (MERCI) retrieval system (Concentric Medical Inc, Mountain View, California) was FDA approved in 2004 for patients who fail or are ineligible for IVT.48 It is a flexible corkscrew-shaped nitinol wire delivered through a 2.4F microcatheter distal to the occluded segment of the vessel. When deployed, it expands to its preshaped form and engages the thrombus. The retriever is then pulled into the balloon guide catheter (8F or 9F) under proximal flow arrest and/or active suction. Multiple generations of MERCI devices have been available. They differ from having a basic nitinol wire with helical tapering coil loops (X5 and X6) to the addition of arcading filaments to a nontapering coil loop (L4, L5, and L6) or by having variable pitch loops with attached filaments (V series, latest generation) (Figure 2).54 The MERCI trials were prospective single-arm trials with historical controls, in which the device was used in LVO within 8 hours of stroke onset. The revascularization rate (TIMI 2/3) before any adjuvant treatment in the initial phase MERCI trial and Multi MERCI studies was 48% and 55%, respectively.55,56 Two recent studies, using the TICI scale as opposed to the TIMI scale, reported higher recanalization rates of 60% and 73%.12,57 The rate of good outcome (mRS 0-2) 90 days after ictus was as follows: initial MERCI trial 27.7%, Multi MERCI trial 36%, and Merci retriever in the TREVO 2 trial 22%. Mortality rates in AIS trials using the MERCI device have decreased over time (MERCI 43.5%, Multi MERCI 34.0%, and TREVO 2 trial 24%).55-57 These results could be related to better device safety, practitioner experience, or patient selection. The rate of intracerebral hemorrhage using the Merci retriever was as follows: MERCI trial 7.8%, Multi-MERC trial 9.8%, and TREVO 2 trial 9%.55-57 One of the drawbacks of using Merci retrievers is the rate of vessel perforation, which is 10 times more common with the Merci retriever (10%) than the newer Trevo stent-triever (1%; P = .018).57 This unwanted event may be the result of the active pushing required to deploy the device out of the microcatheter in addition to the higher outward forces, concentrated on the smaller amount of device loops. We currently do not use the Merci device at our institution, in part, owing to the safety profile.
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FIGURE 2. Merci V-series retriever with 7 loops of platinum filaments. Reproduced with permission.
THROMBOASPIRATING DEVICES Devices using suction are theoretically amenable for fresh nonadhesive thrombus. These devices debulk and extract the clot from proximal to distal with the theoretical advantage of fewer embolic debris and less vasospasm.54,58,59 The main disadvantage is the navigability in intracranial vessels. The better known devices in this category are the Penumbra system (Penumbra Inc, Alameda, California) approved in 2008, and the Angiojet/ Neurojet System (Possis Medical, Minneapolis, Minnesota), which is no longer produced because of the safety concerns with early models. The Penumbra system consists of a reperfusion catheter and a microwire (separator) of various sizes with an oliveshaped tip that is used to disrupt the thrombus during aspiration (Figure 3).60 In addition, balloon occlusion at the proximal guide catheter with aspiration to promote flow reversal also facilitates clot extraction.54 In some cases, a second retriever device resembling a stent attached to a guidewire is used to remove the resistant clot. It has proven promising and efficacious in revascularization in both the anterior and posterior circulation.61,62 A multicenter, single-arm pilot trial evaluated the safety and efficacy of the Penumbra system in AIS. The primary outcome was the rate of revascularization (TIMI 2/3). Of 23 patients enrolled in the study, 20 underwent thrombectomy with 100% revascularization. At
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FIGURE 3. Three sizes of the Penumbra MAX system of aspiration catheters with separator devices. Reproduced with permission.
30 days postprocedure, good outcome (mRS #2 or NIHSSS improved $4) was achieved in 45% and all-cause mortality was 45%.61 The Penumbra Pivotal Stroke Trial was a single-arm trial that included 125 patients who presented within 8 hours of stroke with an NIHSSS $8. Recanalization (TIMI 2/3) was achieved in 81.6% with an intracerebral hemorrhage rate of 11.2%. Good outcome (mRS #2) at 90 days was 25% with a mortality rate of 32.8%.52 The Penumbra POST trial reported postmarket results in 157 patients with AIS presenting within 8 hours with LVO. TIMI 2 to 3 occurred in 87% of patients, mRS #2 at 90 days was 41%, procedural adverse events occurred in 5.7%, and all-cause mortality was 20%.53 A modified technique using the Penumbra system involves wedging the tip of the reperfusion catheter to the proximal part of the clot followed by manual suction using a 20- or 50-mL syringe. The separator mechanism is not used in this technique. Twentytwo consecutive patients with LVO were reviewed with TICI 2b-3 results in 81.9% and good outcome (mRS #2) at 3 months in 45.5% of patients.63 Similarly, the simplified application of the penumbra system termed the ADAPT technique reported by Turk et al64 achieved TICI 2b-3 results in 75% of patients at a mean treatment time of 28.1 minutes. This thromboaspirating device along with the next-mentioned stent-trievers may contribute to future improvements in recanalization rates and hopefully clinical improvements.
STENT-TRIEVERS Stent-trievers are among the newest and most efficacious devices. These devices apply a radial force in the center of the thrombus along its whole length. Animal studies have demonstrated high recanalization rates without the loss of vascular integrity.65 Typically, the technique involves proximal flow arrest by using an 8F or 9F balloon guide catheter. A microcatheter is passed through the thrombus to deliver a nitinol stent. The stent is
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then deployed, resulting in the displacement of the thrombus against the blood vessel and integration into the stent-triever. After 3 to 5 minutes, the stent is retrieved. During retrieval, continuous aspiration with a large syringe or a vacuum apparatus is performed.50,66 The current FDA-approved stent-trievers are the Solitaire and Trevo systems, which differ in the clot integration technique. The Trevo device has vertically oriented struts allowing for efficient clot integration (Figure 4A). The Solitaire has a circumferential overlapping design allowing for multiple contact planes with the thrombus (Figure 4B–C). With regard to diameter, the spectrum of vessel size for Trevo and Solitaire is 1.5 to 4 mm and 1.9 to 5.5 mm, respectively. The Trevo device can be used for up to 3 passes per device and 6 passes per vessel, whereas the Solitaire can be used for 2 passes per device and 3 passes per vessel.66 Various studies have demonstrated adequate safety and superiority in recanalization and reperfusion of stent-trievers in comparison with the Merci device.49,51,67 The Solitaire with Intention for Thrombectomy (SWIFT) trial was a randomized, noninferiority trial that compared the efficacy and safety of Solitaire with the Merci Retrieval System.51 This study was stopped early after enrollment of 126 of 250 planned patients because of a significantly higher mortality rate in the Merci arm (17% vs 38%; P = .02). Solitaire showed better TIMI 2 to 3 flow (61% vs 24%, P = .001) and better 3-month clinical outcomes (58% vs 33%, P = .02). A separate analysis also revealed greater rates of TICI 2b-3 reperfusion in the patients treated with the Solitaire device (76% vs 41.5%) and TICI 3 (52% vs 19%).68 As reported by Mokin et al,69 the Solitaire device has commonly been used in combination with the Penumbra aspiration device for the so-called “Solumbra” technique. The Trevo 2 trial was an open-label RCT of Trevo (n = 88) and Merci (n = 90) treated within 8 hours. This trial is the only device publication offering TICI 2b results, and the authors used a more strict definition of $2/3 MCA territory perfusion. TICI 2b-3 flow was achieved in 68% of patients in the Trevo group vs 44% in the Merci group. Complications did not differ between groups (Trevo 15% vs Merci 23%; P = .185). Trevo-treated patients had better 90-day clinical outcomes (mRS ,2, 40% vs 22%, P = .013).49 A study by Broussalis et al67 of 120 patients treated with either stenttrievers (Solitaire and Trevo devices) or Merci system found that successful recanalization (TICI 2b-3) was achieved in 82% of patients treated with stent-trievers compared with 62% of patients treated with the Merci device (P = .016). The mRS 0 to 2 at 90-day clinical outcomes were also better in the stent-triever arm (mRS ,2, 65% vs 35%, P = .002). Severe hemorrhage in this study occurred less frequently in the patients treated with the stent-trievers (10% vs 28%, P = .01). Results from stent-triever trials appear quite promising as a method for acute intracranial revascularization. Current Therapy and Ongoing Trials In light of the most recently published RCTs, IVT remains the standard treatment for acute ischemic stroke. Endovascular
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FIGURE 4. A, Trevo ProVue self-expanding stent-triever device. Reproduced with permission. B, Solitaire self-expanding stenttriever device. Reproduced with permission. C, balloon guide catheter with aspiration during thrombectomy with Solitaire stenttriever. Inset, clot integrated into Solitaire stent-triever device. Reproduced with permission.
therapy with stent-retrievers and thrombo-aspirating devices outside of patients enrolled in new trials may not be warranted given the results of RCTs to date. Exceptions to this include patients that present in the 4.5-hour window but have contraindications to systemic thrombolytics (eg, recent trauma, surgery, or gastrointestinal bleeding). Continued enrollment into RCTs is justified by the facts that (1) revascularization is positively associated with outcome, (2) second-generation thrombectomy devices are superior to all other methods of revascularization, and (3) second-generation devices were scarcely used in current trials comparing IVT with adjunctive endovascular therapy with IVT alone. Beginning in 2012, 2 trials started randomly assigning patients to IVT or IVT plus adjunctive mechanical thrombectomy with second-generation devices. Inclusion criteria for both trials were age 18 to 85, NIHSSS $8, and required IVT administration before 4.5 hours. The THERAPY trial is sponsored by Penumbra Inc. This study uses the penumbra clot aspiration system with a Separator 3D device as the adjunctive mechanical therapy. Patients must have
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a proximal anterior circulation clot at least 8 mm in length by noncontrast head CT.70 The SWIFT PRIME trial is sponsored by Covidien. This study uses the Solitaire stent-retriever device for adjunctive therapy. Patients are selected by CT angiogram or magnetic resonance angiography demonstration of TICI 0 to 1 occlusion of the MCA or ICA. Additionally, patients are excluded based on CT or MR perfusion imaging demonstrating large areas of infarction relative to penumbra.71 Both studies are early in enrollment with estimated completion dates in 2016 to 2018.
CONCLUSION The technical goal of any revascularization strategy is to achieve TICI 2b-3 recanalization as soon as possible. Although superior recanalization rates have been demonstrated with second-generation thrombectomy devices, the future of endovascular management of stroke may hinge on proving superior outcomes in patients treated with these new devices. Because of the lack of use of secondgeneration thrombectomy devices in current RCTs, clinical
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equipoise exists for treating AIS by using IVT with or without adjunctive second-generation thrombectomy devices. The authors remain optimistic that clinical outcomes will improve as interventional techniques evolve, and therefore believe patients with LVO should be enrolled into clinical trials to determine whether clinical outcomes can be improved upon what is achieved with IVT alone. Disclosure Dr Ringer has received consulting fees from Stryker, Microvention, and Covidien/eV3, but not for any product discussed in this article. The other authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article.
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VOLUME 74 | NUMBER 2 | FEBRUARY 2014 SUPPLEMENT | S141
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