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THEMED ARTICLE y Stroke

Special Report

Lessons learnt from recent endovascular stroke trials: finding a way to move forward Expert Rev. Cardiovasc. Ther. 12(4), 429–436 (2014)

Mohammed A Almekhlafi1,2, Bijoy K Menon1,3–5 and Mayank Goyal*1,3 1 Department of Clinical Neurosciences, Calgary Stroke Program, University of Calgary, Calgary, AB, Canada 2 Department of Internal Medicine, King Abdulaziz University, Jeddah, Saudi Arabia 3 Department of Radiology, University of Calgary, Calgary, AB, Canada 4 Hotchkiss Brain Institute, Calgary, AB, Canada 5 Department of Community Health Sciences, University of Calgary, Calgary, AB, Canada *Author for correspondence: Tel.: +1 403 944 3379 Fax: +1 403 270 7907 [email protected]

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The advent of stentrievers provided momentum for endovascular stroke therapy. Hopes were dampened after three randomized trials showed no clear benefit of endovascular therapy. This review discusses the results of these trials results and shortcomings. A detailed discussion will follow on the design, conduct and analysis of current and future endovascular stroke trials. Steps to improve the workflow of acute stroke cases from the time they enter the emergency department until endovascular reperfusion is achieved can significantly shorten the time from onset to successful reperfusion. These factors in addition to using novel approaches to analyze data and minimize delays caused by the consent process are perceived to be sufficient to demonstrate the efficacy of endovascular stroke therapy. KEYWORDS: acute cerebral infarction • cerebrovascular disease • endovascular therapy • intravenous alteplase • stent retrievers • thrombolysis

The case for endovascular stroke therapy

Close to two decades after the approval of intravenous tissue plasminogen activator (IV tPA) acute ischemic stroke continues to be a major health burden and a leading cause of adult disability. Despite the overall benefit of IV tPA over placebo in reducing disability in all-comers with ischemic stroke when administered within 4.5 h from onset, a significant subset of patients fail to achieve independent functional outcome. This stimulated ongoing research aims to identify the reasons why these patients fail to improve with IV tPA despite timely treatment, and to explore alternative hyperacute therapies to mitigate the impending disability in this patients’ sub-group. The strongest predictor of favorable outcome in acute stroke victims is timely reperfusion [1]. Once an intracranial occlusion takes place, cerebral tissue downstream from the occlusion undergoes a chain of electrical and biological reactions which shapes their fate in one of three forms [2]. The ischemic core is the region most sensitive to ischemia which becomes irreversibly damaged even if reperfusion is restored [3]. On the one hand, the 10.1586/14779072.2014.894885

ischemic penumbral tissue loses some or all of its function but maintains its structural integrity and is salvageable only if timely reperfusion is achieved. The region of benign oligemia on the other hand is able to tolerate and to survive the consequences of the intracranial occlusion irrespective of reperfusion. This process is very dynamic and dependent on a number of factors in addition to time. This makes the identification of tissue fate following an intracranial occlusion a moving target. The region of the ischemic core continues to expand as time elapses while the salvageable penumbra shrinks until the penumbra no longer exists or is of diminutive size. At that point, reperfusion becomes futile [4]. The rate of successful reperfusion with IV tPA is dependent on the location and the clot burden of the culprit intracranial occlusion. Studies have shown that the likelihood of successful reperfusion with intracranial internal carotid artery (ICA) occlusion (with or without middle cerebral artery [MCA] involvement) is as low as 30%. Similarly, MCA occlusion, which accounts for 50% of all intracranial occlusions, has a 60% chance of reperfusion with IV tPA. Failure of reperfusion will render

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used a separator device as well as suction to break down and aspirate the clot fragments [12]. It was not long after that when the retrievable stents (stentrievers) were introduced and quickly climbed to the top as the technology of first choice for endovascular stroke therapy due to their ease of use and the high rates of fast and successful reperfusion achieved with them [13]. The Solitaire (Covidien) (FIGURE 1C) and Trevo (Stryker) devices proved superior to the Merci device in randomized trials where they proved to be safer and more efficacious than the Merci device [14,15].

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Recent endovascular trials

These high hopes for endovascular stroke therapy were halted after three large randomized trials showed no added benefit of endovascular therapy when compared to IV tPA alone: the IMS III [16], Systemic Thrombolysis for Acute Ischemic Stroke Expansion [17] and the Mechanical Retrieval and Recanalization of Stroke Clots Using Embolectomy trials [18].

Figure 1. Endovascular thrombectomy devices. The evolution of endovascular devices starting by the Merci device (A), the Penumbra system (B) and the Solitaire stentriever (C).

a significant proportion of these patients dead or in significant disability. In addition, a subset of patients with acute ischemic stroke are not considered for IV tPA due to the presence of one or more contraindication. The likelihood of grim outcome in this patient group is even higher, given the very low chance of timely spontaneous reperfusion. Endovascular therapy of acute ischemic stroke is promising to overcome a number of IV tPA limitations. Therapies are delivered to the occlusion interface to maximize the chances of successful reperfusion. However, the success rate of intra-arterial (IA) thrombolytic therapies remained relatively low. Among the first trials of endovascular stroke, therapies were the randomized PROACT and PROACT II studies that collectively recruited 239 patients with MCA occlusion [5,6]. Treatment with IA recombinant pro-urokinase plus IV heparin administered within 6 h from symptom onset resulted in superior recanalization and a significantly better outcome at 90 days compared to IV heparin alone (modified Rankin scale [mRS] of 2 or less). However, the rate of good clinical outcome (40%) remained relatively low, considering that 66% achieved successful recanalization (thrombolysis in myocardial infarction 2 or 3). This was attributed to delays in treatment (median onset to randomization of 4.7 h), low rates of complete recanalization (thrombolysis in myocardial infarction 3 in 19%) and the high rates of symptomatic intracranial hemorrhage (10%). Similarly, the Emergency Management of Stroke [7] and Interventional Management of Stroke (IMS) I [8] and II [9] trials treated patients using IA tPA in an open fashion to show better outcomes when compared to historical controls. These results motivated the large-scale randomized trial IMS III [10]. The Merci retriever (Concentric Medical) device (FIGURE 1A) revolutionized the field of endovascular stroke and renewed interest in the design of other devices [11]. This was quickly followed by the penumbra device (Penumbra) (FIGURE 1B) which 430

The Interventional Management of Stroke III

Prior to being stopped due to futility, the IMS III trial randomized in a 1:2 ratio 656 patients within 3 h from onset to receive IV tPA versus IV tPA plus endovascular therapy [16]. The primary endpoint of mRS of 0–2 at 90 days was achieved in 38.7% of the control arm versus 40.8% in the endovascular treatment arm (p > 0.05). There was no difference in mortality or the rate of symptomatic intracranial hemorrhage between the two groups, but more patients in the endovascular arm had asymptomatic ICH (27.4 vs 18.9% in the control arm, p = 0.01). Reperfusion of TICI-2b or -3 in the endovascular arm was achieved in 38% of those with terminal ICA occlusion, in 44% of those with M1 or single M2 occlusions and in 23% of those with multiple M2 occlusions. The trial did not mandate vascular imaging, and just under half of patients had computed tomography (CT) angiogram (CTA) (47%), 92% of which had occlusions. Systemic Thrombolysis for Acute Ischemic Stroke expansion

This was a multicenter trial which randomized 362 patients within 4.5 h from acute ischemic stroke onset to receive endovascular therapy alone (combination of IA tPA and/or clot disruption) versus IV tPA [17]. The trial primary outcome was the proportion of patients achieving a 90-day mRS score of 0 or 1. The study showed no difference in its primary outcome as the proportion of patients achieving the primary outcome with endovascular therapy (30.4%) was not different from those in the IV tPA arm (34.8%). Similar to IMS III trial, CTA was not mandatory and was performed in less than a third of the patients. In addition, the relatively low median National Expert Rev. Cardiovasc. Ther. 12(4), (2014)

Lessons learnt from recent endovascular stroke trials

Institute of Health Stroke Scale (NIHSS) of the enrolled patients (13) made experts suspect that a subset of patients lacked proximal arterial occlusion [19]. While IV tPA was administered within 2.75 h from onset, endovascular therapy was started within 3.75 h, that is, with an hour delay (p < 0.0001). IV tPA was not administered to the endovascular patients while they awaited. Finally, stentrievers were used in only 10% of the endovascular arm patients.

Special Report

The recent randomized endovascular stroke trials provided instrumental information to inform the conduct and design of future endovascular stroke therapies. These issues – discussed in details below – direct the attention into the importance of patients’ selection, consecutive enrollment, measurement and analysis of outcomes and the importance of stroke workflow to avoid any unnecessary delays.

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Stroke workflow & overcoming delays Mechanical retrieval & recanalization of stroke clots using embolectomy

This trial randomized 118 eligible acute ischemic stroke patients presenting outside the standard IV tPA treatment window (within 8 h from onset) to receive endovascular therapy using Merci or Penumbra devices versus standard of care [18]. Randomization was stratified by the presence of a small core and substantial penumbral tissue on perfusion imaging (referred to as a favorable penumbral pattern), which was defined using the study’s own software. This pattern was detected in 58% of patients. The primary outcome (mean 90-day mRS score) was similar in the endovascular arm versus standard of care (3.9 for both). There was no beneficial treatment effect in those with a favorable penumbral pattern. A major issue of this trial was the time delays as the mean time from onset to enrollment was 5.5 h. Following enrollment, all patients underwent perfusion imaging, with magnetic resonance (MR) being used in 80% of the study recruits. The time required for preforming, processing and interpreting perfusion imaging results was not reported. Successful reperfusion was defined as Thrombolysis in Cerebral Infarction Score of 2a to 3, unlike the conventional definition of 2b to 3. Although this was achieved in 67% of patients, the time to successful reperfusion was not reported. Lessons for moving forward

The results of these three trials may have not surprised those involved in researching hyperacute stroke therapies [4,19–24]. As presented above, the time delays, the use of stentrievers in a negligible number of patients and the selection of patients who are not likely to benefit from endovascular therapies played a major role in neutralizing any benefit of endovascular stroke interventions. In addition, these trials might have been overambitious in estimating the ability of endovascular therapy to benefit all comers with acute ischemic stroke. This latter factor was, at least in part, stimulated by the results of cohort studies that described outstanding outcomes with endovascular therapies. However, in the interpretation of these cohort studies, readers often overlook the important aspect of selection bias: among all those eligible for endovascular therapy, how often do they receive such therapy and what is the outcome of the entire cohort as opposed to the reported outcome of a selected subset of patients. This denominator fallacy [25] plagued the stroke endovascular literature and may have contributed to the demise of the recent endovascular trials that did not take into account the biased results of cohort studies and overestimated the outcomes of endovascular stroke therapies. informahealthcare.com

A substantial body of literature established the importance of timely treatments in influencing acute stroke outcome. In a pooled analysis of 3670 patients from eight randomized trials, the odds of a favorable 90-day functional outcome increased as the time from stroke onset to IV tPA treatment decreased with no benefit of IV tPA when given after 4.5 h from onset [26]. This translates to an increase of the number needed to treat by 1 for each 20-min delay in delivering IV tPA [27]. Similar results were described in various endovascular trials. Among 117 patients treated with IA tPA bridging therapy in the IMS I and II trials, time to angiographic reperfusion was an independent predictor of good clinical outcome, along with successful reperfusion and age [28]. These observations held true in the pooled analysis of the MERCI and multi-MERCI trials; the odds of mRS £2 were highest among those treated under 6 h from onset [29]. The recent STAR study data using Solitaire stent also shows that the odds of independent functional outcome decrease by 38%, with each 1-h delay in the time from stroke onset to reperfusion (or last angiographic run) [MENON B, PERS. COMM.]. In a small series, we have shown that fast reperfusion (defined as a time from CT imaging to successful endovascular reperfusion of 60 min or under) resulted in minimal expansion of the CT-defined core when compared to baseline imaging [30]. More than 80% of patients in that cohort achieved mRS of 0 or 1. Door-to-needle time

Delay can be introduced in any of the numerous steps required for a patient with ischemic stroke until reperfusion is successfully restored. Therefore, a number of time metrics were derived to measure delays along this time curve so that fast and standardized workflow can be achieved. Among candidates for IV tPA, achieving a door-to-needle (DTN) time under 60 min is a battle to be won. Just over a quarter of patients enrolled in the Get With The Guidelines stroke registry achieve this target time [31]. However, other centers published on their ability to significantly reduce and maintain their DTN time to under 60 min. In what is currently known as the Helsinki model, investigators from the Helsinki University Central Hospital reported an impressive median DTN of 20 min, with 94% of patients being treated under 60 min [27]. In their report, the investigators describe their 12-step measures that cut down the in-hospital delays including early notification of the stroke team, bypassing the emergency department and going straight to CT in patients considered for IV tPA and delivering tPA on the CT table. Many of these steps were easily implementable 431

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that they were applied successfully in Melbourne Australia and brought their DTN to 25 min in during-hours stroke patients within 4 months [32]. In our center, we implemented a similar protocol to cut the in-hospital delays. These efforts are important in minimizing delays to initiating endovascular therapies in potential candidates.

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Advanced imaging: the hard balance of time versus information

Once the decision to administer IV tPA is made, an important question arises as to whether the patient would benefit from endovascular therapy. To help answering this question, further imaging beyond plain CT head is usually required to locate the occlusion or to estimate the size of the tissue at risk of infarction if timely reperfusion is not achieved. These advanced imaging options include CTA, CT perfusion (CTP) or MR perfusion-weighted imaging. While the choice is usually dependent on the respective center practice, the added value of the information gained by these modalities should always be weighed against the time required to perform, process and interpret the yielded images. While advanced imaging with CT or MRI is useful in selected situations as in wake-up strokes [33], in our practice we find CTA-based imaging to be most efficient [34,35]. With an added time of about 5 min, CTA provides the exact site of occlusion and the detailed vascular anatomy of the patient which would serve as a roadmap for any subsequent endovascular intervention [35]. In the IMS-III trial, the use of CTA resulted in a net time saving, with a shorter door-toreperfusion and onset-to-reperfusion times compared to patients treated in centers that do not use CTA in their decision making [PERS. COMMUN.]. While MRI diffusion imaging provides an accurate estimation of the ischemic core in the early stages, CTA can estimate the core via source imaging as well as the extent of collateral circulation. This latter feature is even further expanded with the novel multiphase CTA which not only provides information on the robustness and distribution of collaterals but also gives an idea regarding the contrast transit time through these channels. In our centers, we adapt a paradigm of targeting patients with a small core and proximal occlusion for endovascular therapy using CTA. Other centers describe using MRI-based patient selection for endovascular therapy [36]. We believe that those patients are more likely to have a relatively large penumbra that is salvageable with rapid endovascular reperfusion. Imaging to endovascular arterial access time

Once a patient believed to benefit from endovascular therapy is encountered, the clock starts ticking until endovascular reperfusion is achieved. Delays can be introduced in multiple forms into the time interval from imaging completion until arterial access for the endovascular procedure is obtained. Time can be lost for the endovascular team travel to the hospital, which is inevitable outside the working hours. However, our center experience shows that such delay can be minimized with just over 20 min delay in the imaging to reperfusion time in those 432

treated outside working hours versus during working hours [37]. One important strategy is the early notification of the endovascular team of all potential endovascular stroke candidates once the CT head confirms the ischemic nature of the disabling stroke. That way, IV tPA can be administered, and the process of consenting for the endovascular procedure is started as the endovascular team travels to the hospital. These steps are extremely important and need to be run in parallel to avoid delays. In the IMS III trial, the median time from IV tPA bolus administration to arterial groin puncture was 84 min compared to 46 min in our center [38]. Consent-related issues

Some of these delays encountered in the IMS III trial might be explained by the process of consenting for a randomized trial of endovascular therapy which is more critical and time consuming than that of routine endovascular procedure, especially outside the working hours [39]. This process of consent is both indispensable and laborious and may introduce additional delays for those enrolled in trials when compared to those treated outside trials. These delays (20–30 min on average) [39] restricted to the endovascular arms might have contributed to the neutral results of the recent endovascular trials. Therefore, adaptation and innovative solutions to this problem are of paramount importance for the current randomized endovascular stroke trials. Proposed solutions include the use of an abridged consent form in the acute phase, or the deferral of consent process [39]. The latter option is used when the subject is not able to provide consent AND no family member is reachable to provide consent. In that case, dual-physician consent is obtained, and the consent process is deferred until the consent can be obtained from the subject or a surrogate. The deferral of consent process is currently offered by the ESCAPE trial [40]. While there are limitations to the current and proposed consent processes, discussions on this topic need to continue to optimize the solution for consent-related delays. Use of general anesthesia

Another potential source of delay during the time from imaging completion to arterial puncture is the use of general anesthesia as a routine practice. In addition to the time delays introduced through this, an increasing number of studies – including our center’s experience – reported on the worse outcomes of endovascular stroke patients who had general anesthesia compared to those who received none or conscious sedation [41]. In our retrospective study [42], only 15% of 48 patients receiving general anesthetic in the acute stroke setting had good functional outcome at 3 months compared to 66% of 48 patients who received conscious or no sedation. This correlated with the drop in blood pressure at the time of intubation. In that study, intubation was the only predictor of a delayed needle to puncture time. These findings should caution against the routine use of intubation in acute ischemic stroke patients. When intubation is indicated, care should be taken to avoid rapid or severe drop in mean arterial pressure during the induction phase. Another measure that Expert Rev. Cardiovasc. Ther. 12(4), (2014)

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Lessons learnt from recent endovascular stroke trials

can be instituted to minimize delay is having a basic endovascular tray ready for use in the angiography suite which will save few extra precious minutes [35]. Such tray is to be kept dry and contains syringes, hemostatic valves and the vascular access set which will be invariably used for any endovascular or interventional procedure within 24 h in case it is not used overnight for a stroke procedure.

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Transport-related issues

Another increasingly encountered aspect F D E in comprehensive stroke centers is delay introduced through patients who are referred for endovascular therapy from a distant primary stroke center. Such patients are transferred either before IV tPA was started (ship-and-drip approach) or after (drip-and-ship). To account for delays encountered in these patients, investigators devised the picture-to-puncture time metric to capture delays occurring from the time of baseline CT scan until groin puncture is done [43]. Patients with a Figure 2. An illustrative case. A middle-aged patient presented within 90 min from picture-to-puncture time over 90 min had the time of last seen normal with a severe left hemiplegia, gaze deviation to the right a significantly lower likelihood of indepen(NIH stroke scale score of 18). CT scan of the head showed early ischemic involvement dent functional recovery at 90 days. In the of the insula and lentiform nucleus with ASPECTS score of 8 (A & B). Computed IMS-III trial, patients in the drip-and-ship tomography angiogram confirmed a mid-M1-middle cerebral artery (MCA) occlusion (C). She received IV tPA in the emergency room at 12:46 p.m. After her husband’s consent, category had a delay of 21 min in the she was transferred to the angiography suite, and the arterial access was obtained at onset-to-reperfusion time versus those 1:31 p.m. Subsequently, an 8-french balloon-guide catheter was advanced over a treated in the same facility. However, diagnostic catheter into the proximal right internal carotid artery where check images there was no significant difference in the confirmed the persistent M1-MCA occlusion (D). A microcatheter was advanced beyond onset-to-reperfusion time between those the thrombus, and a 4  20 mm Solitaire Stentriever was deployed. Check images showed evidence of partial flow through the stent at 1:45 p.m. (E). The stent was left treated via a ship-and-drip approach comin place for few minutes, and then the balloon of the guide catheter was inflated and pared to patients treated in the same centhe stent was pulled out under manual suction. A large clot was retrieved on the stent. ter. These observations stress upon the Check images showed complete recanalization of the M1-MCA with normal reperfusion importance of coordinated, protocolof the MCA territory at 1:51 p.m. (F). The patient showed substantial improvement over driven steps for the expedited transport the course of the next few hours with near resolution of her deficits. IV tPA: Intravenous tissue plasminogen activator. and treatment of such patients especially when imaging needs to be repeated prior to the endovascular procedure. This issue is important as, in the are directly advanced to the target territory. In this regard, study by Sun et al. patients with an ASPECTS score of less than CTA serves a key role in providing a roadmap to the interven7 on repeat imaging in the comprehensive stroke center did not tionalists to facilitate smooth navigation to the desired territory. Once the occlusion is located, a microcatheter is advanced gather benefit from reperfusion [43]. beyond the occlusion and stentrievers are deployed. The only exception to this approach is terminal ICA occlusions for which The endovascular procedure Once the patient is on the angiography table and vascular we find manual suction using a 60 cc syringe, after inflating access is obtained, the fastest approach to achieve complete the guide catheter balloon, extremely useful [44]. Otherwise, reperfusion should be adopted. We recommend against starting once the stent is deployed, it should be kept deployed for at with a diagnostic angiogram of non-occluded territories to least 3 min in cases whenever a bypass effect is achieved, that assess collateralization to the target territory. This approach is, angiographic runs confirm the presence of forward flow would introduce delays without gaining valuable information. through the deployed stent. Subsequently, the balloon of the We utilize a co-axial system of a balloon-guide catheter guide should be inflated and manual suction applied as the advanced over appropriate diagnostic selective catheters that stent is being retrieved. It is not uncommon for the first pass informahealthcare.com

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to fail in retrieving the clot. In these instances, the same stent can be used again. Alternatively, larger size stents can be useful especially when large clot burden is anticipated as in T-type terminal ICA occlusions. The use of non-stentriever technology can be considered in these cases as a last resort. FIGURE 2 shows an illustrative case from our center with the steps timing until successful reperfusion was achieved.

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Outcomes

Following the endovascular procedure, patients are usually transferred to specialized stroke units, and shortly after the rehabilitation and recovery phase begins. The 24-h NIHSS is assessed to compare the existing deficit in comparison to admission NIHSS. This only provides a crude measure for the density, duration and the likely place for future rehabilitation. However, it is not until 90 days after stroke onset is the stroke outcome assessed by convention. The mRS is the most widely used method for that purpose. However, there is an increasing dismay with this ordinal scale that assigns functional outcome into one of seven categories, with escalating degree of disability starting from a scale of 0 which denotes the absence of any disability to a score of 6 used for death. Scores of 0–2 have been used to reflect good functional outcome, and the proportion of patients achieving these scores has been used as a primary outcome for the three recent endovascular stroke trials. This scale does not take into account any pre-existing disability nor does it account for the cognitive or quality-of-life aspects of the patients’ outcomes. The analysis of endovascular stroke trials using a dichotomous mRS outcome proved inefficient [45]. While it describes the patients’ functional independence, it fails to capture the entire spectrum of favorable effects expected with endovascular therapy. For example, a patient who would have achieved an mRS score of 5 without endovascular therapy but enjoys a 90-day mRS of 3 is considered in the same category as the patient who achieved a 90-day mRS of 5 with IV tPA therapy. While it is clear that these two outcomes are not equal both from clinical and economical viewpoints, they are noneseparable in the conventional method of outcome analysis in endovascular therapy. Many investigators criticized this conventional interpretation of stroke trials which led to the introduction of the shift analysis method. This method accounts for the magnitude of reduction of disability (shift) across different mRS strata and considers an intervention A superior when it

successfully shifts the disability from A to Z compared to an intervention B, regardless of any difference in the proportion of patients achieving mRS 0–2. This method is being utilized as the primary outcome in two of the currently enrolling endovascular trial: ESCAPE and SWIFT PRIME. Expert commentary

The field of endovascular stroke therapy, and in particular efficient workflow and fast recanalization, is currently in a state of flux. Data from recent trials have clearly once again demonstrated that ‘time is brain’ and the need for speed. We have focused, for the last several years, our efforts toward improving acute stroke workflow to minimize any delays. At the same time, it should be fully acknowledged that the field still has a long way to go, and further improvements are not only possible, they are mandatory. We hope that we have demonstrated that delays can be minimized and overcome. We hope to encourage other stroke centers to pay more attention and to further publish more data on this issue to reach the ultimate goal of improving patients’ outcomes, which is the challenge that awaits current and future endovascular stroke trials. Five-year view

Over the coming 5 years, more analyses of the completed endovascular trials will be available, and at least a few of the currently enrolling endovascular trials will be completed and their results would be published. Patient-level pooled analyses of these results will help define the patients’ population in which endovascular therapy using stentrievers will become the standard of care. Interesting data will be available describing novel and efficient imaging modalities that will facilitate patients’ selection in a more objective fashion. The imaging modalities will identify characteristics of the brain parenchyma, vascular and clot features. Financial & competing interests disclosure

B Menon is supported by a Heart and Stroke Foundation of Canada Research Scholarship. M Goyal is a co-principal investigator of the Escape trial. M Goyal has also received a research grant from/is a consultant for/ sits on the advisory board for Covidien. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

Key issues • Stroke-related disability remains an issue despite increasing use of IV tPA. • Fast and complete reperfusion is an unmet need that endovascular therapy using retrievable stents is promising to overcome. • Three recent randomized trials failed to show any benefit of endovascular therapy in acute stroke setting; other trials are currently enrolling. • Time delay in achieving reperfusion was a common factor that influenced the recently neutral trials. • While delays are inevitable, they can be minimized and overcome with efficient workflow. • Health care providers should be mindful of the trade-off between advanced imaging and time loss. • There is an increasing need for more data that will help identifying a universal time metrics in endovascular therapy.

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intra-arterial stroke therapy studies using the Merci device, Penumbra system, and retrievable stents. AJNR Am J Neuroradiol 2013;34(1):140-5

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Lessons learnt from recent endovascular stroke trials: finding a way to move forward.

The advent of stentrievers provided momentum for endovascular stroke therapy. Hopes were dampened after three randomized trials showed no clear benefi...
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