Year : 2015 | Volume
: 1 | Issue : 1 | Page : 9--13
A review of current clinical studies leading to improved outcomes in patients treated with newer-generation thrombectomy devices
Yaser Carcora1, Mohammed Hussain1, Xiaokun Geng2, Yuchuan Ding2,
1 Department of Neurological Surgery, Wayne State University School of Medicine, Detroit, Michigan, USA
2 Department of Neurological Surgery, Wayne State University School of Medicine, Detroit, Michigan, USA; Department of Neurology, China-America Institute of Neuroscience, Luhe Hospital, Capital Medical University, Beijing, China
Department of Neurological Surgery, Wayne State University School of Medicine, 550 E Canfield, Detroit - 48201, Michigan, USA
Treatment with endovascular treatment in conjunction with intra-venous Tissue Plasminogen Activator (IV tPA) under specific clinical situations leads to improved functional outcomes in patients. This review addresses the efficacy of endovascular stroke treatment in patients selected under ideal inclusion criteria and treated with the most up to date embolectomy devices. Recent trials such as ESCAPE, MR CLEAN, EXTEND IA and SWIFT PRIME showed that demonstration of proximal vessel occlusion in CT scans, stratification of penumbral patterns, along with expedient recanalization with the most up to date embolectomy devices leads to a statistically significant improvement in function, NIHSS scores, and mortality in patients treated with endovascular tPA. SWIFT PRIME, in particular, demonstrated that patients demonstrated a 4.5 point improvement in NIHSS scores 27 hours after treatment and decreased mortality along with an increased number of patients with a Rankin score of 1-2 90 days after therapy. Evidence shows that endovascular stroke treatment leads to improved outcomes in patients who are selected based on refined CT guided inclusion criteria and rapid revascularization by newer generation embolectomy devices in conjunct with IA tPA.
|How to cite this article:|
Carcora Y, Hussain M, Geng X, Ding Y. A review of current clinical studies leading to improved outcomes in patients treated with newer-generation thrombectomy devices.Brain Circ 2015;1:9-13
|How to cite this URL:|
Carcora Y, Hussain M, Geng X, Ding Y. A review of current clinical studies leading to improved outcomes in patients treated with newer-generation thrombectomy devices. Brain Circ [serial online] 2015 [cited 2022 Nov 26 ];1:9-13
Available from: http://www.braincirculation.org/text.asp?2015/1/1/9/166352
An average of 130,000 Americans die from stroke every year.  Ever since the National Institute of Neurological Disorders (NINDS) trial showed the benefit of intravenous tissue plasminogen activator (IV tPA), its application has been ubiquitous in the realm of acute ischemic stroke treatment.  Subsequent randomized, controlled trials such as Assessment of Small Airways Involvement in Asthma (ATLANTIS), European Cooperative Acute Stroke Study (ECASS 1, 2, and 3), Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET), and the third International Stroke Trial (IST-3) showed that administering IV tPA within 3-4.5 h, in patients with symptoms of stroke, led to an overall increased degree of functional independence at 3 months.  Over time, clinicians and investigators began incorporating intraarterial techniques into their treatment modality. This encompassed the application of intraarterial thrombolysis along with the use of embolectomy devices. The birth of modern-day interventional neurology from a historical perspective began with Dr. Egas Moniz publishing Diagnostic des Tumeurs Cérébrales et Epreuve de L'encéphalographie Artérielle in 1931, documenting his experience with cerebral angiograms. For the next few decades, the basic tenets of endovascular therapies underwent constant revision from early works contributed by innumerable physicians that have culminated in the modern-day standard femoral approach-mediated procedures. A considerable degree of excitement in the endovascular community was palpable in 1998 after the Prolyse in Acute Cerebral Thromboembolism (PROACT) 2 trial showed a favorable profile of endovascular prourokinase infusion leading to higher rates of revascularization. The PROACT 2 trial was followed by a multitude of trials that tested and retested different applications of endovascular modalities in ischemic stroke treatment. This spanned from the pivotal Penumbra trial to the trials multi- Mechanical Embolus Removal in Cerebral Ischemia (MERCI), Interventional Management of Stroke (IMS I, II, and III), and Local Versus Systemic Thrombolysis for Acute Ischemic Stroke (SYNTHESIS) Expansion. It should be noted that the results of IMS III, Mechanical Retrieval and Recanalization of Stroke Clots Using Embolectomy (MR RESCUE), and SYNTHESIS failed to show a statistically significant improvement in patients treated with endovascular recanalization when compared to IV tPA, thus curbing the enthusiasm for endovascular treatment. ,, Small sample size, older-generation embolectomy devices, intermittent use of imaging modalities along with longer door-to-needle times ultimately compromised endovascular treatment. ,, A more balanced investigation of the efficacy of endovascular treatment required further study. Recent studies have shown that the demonstration of proximal vessel occlusion in computed tomography (CT) scans, stratification of penumbral patterns, along with expedient recanalization with the most up-to-date embolectomy devices leads to a statistically significant improvement in function, National Institutes of Health Stroke Scale (NIHSS) scores, and mortality in patients treated with endovascular techniques. Reviewing these different trials in terms of their inclusion criteria, treatment time, and device use will allow for an improved understanding of how endovascular treatment modalities lead to lower mortality and higher functional independence in stroke patients.
NIHSS score as a basis for inclusion
Earlier trials of endovascular stroke treatment utilized different inclusion criteria to enroll patients. For instance, NIHSS scores rather than isolated ischemic lesions on CT scans were the basis of inclusion. This was due, in part, to underutilization of the CT scan-related Alberta Stroke Program Early CT Score (ASPECTS), CT perfusion, and CT angiography (CTA). For example, the IMS III trial selected patients on the basis of the criterion of an NIHSS score of greater than 10. By doing so, the NIHSS was meant to act as a surrogate marker for large-vessel occlusion (LVO); an individual with a score of over 10 had an 80% likelihood of having an occlusion in either the anterior cerebral artery (ACA), the middle cerebral artery (MCA), or the internal carotid artery (ICA).  This method led to potential discrepancies in patient selection, as those with a high NIHSS score did not necessarily have the optimal ischemic pattern for treatment. In addition, CTA use was not ubiquitously performed in the IMS III trial. As a result, patients who presented without LVOs on angiography were included in the endovascular treatment arm. Not surprisingly, the results correlated with no dramatic changes in postinterventional modified Rankin scores (mRS) between the endovascular and control arms. 
Another trial, MR RESCUE sought to validate optimal penumbral patterns using multimodal imaging techniques such as MRI and CT perfusion scans to achieve better outcomes post endovascular treatment. However, MR RESCUE, like IMS III, selected patients based on NIHSS scores. , Individuals with a score of 6-29 were deemed eligible for the study and by extension had a high risk of LVO.  The MR RESCUE trial also showed equivocal results for endovascular treatment. A learning point gained from this trial was the importance of assessing collateral circulation and its relationship with final infarct volume. MR RESCUE demonstrated that individuals with smaller infarct cores and large amounts of collateral circulation (assessed after treatment by CT imagery) had a lower infarct volume after intervention.  The SYNTHESIS Expansion trial also reported that individuals with more salvageable tissue had better treatment outcomes with endovascular therapy.  Although these three trials (IMS III, MR RESCUE, and SYNTHESIS Expansion) failed to demonstrate a significant benefit of endovascular application, they did reveal the importance of using CT imaging to select patients with favorable penumbral patterns and robust collateral circulation. The studies disclosed that the NIHSS, by itself, is not specific enough to differentiate large-vessel ischemic strokes from small-vessel lipohyalinosis.  In essence, imaging needed to be an integral focus of the inclusion criteria.
CT-guided inclusion criteria
Every patient recruited in the recent multicenter randomized clinical trial of Endovascular Treatment of Acute Ischemic Stroke in the Netherlands (MR CLEAN) trial underwent CTA to assess for a demonstrable occlusion of the ICA, the MCA, or the ACA (defined as LVO).  The study also stratified patients based on NIHSS scores, and patients with high NIHSS scores were excluded due to the risk of hemorrhagic stroke.  Additionally, 96 % of patients had a premorbid mRS of 0-2, which equated to functional independence.  In comparison to the IMS III trial, which did not use CT imagery in the process of patient selection, there was an improvement in functional independence in the endovascular patient group. On evaluation, patients who were treated with endovascular treatment (with new-generation thrombectomy devices, predominantly stent retrievers) had a decrease in their NIHSS score by 2.9 points or more.  Additionally, there was a shift toward improved outcomes in the endovascular treatment, with 32.6% of individuals in the endovascular group attaining an mRS of 2 or less versus 19.2% in the control group.  Furthermore, 59% of patients also obtained a thrombolysis in cerebral infarction (TICI) score of 2B/3. This was in stark contrast to prior trials showing a substandard 6% ICA recanalization rate with IV tPA.  Although age, stroke severity, and serum glucose levels are important prognostic factors in stroke patients after intervention, prompt recanalization is the defining factor for postinterventional mortality.  As later studies emphasized CT and CT perfusion imaging both before and after stroke treatment, it became easier to assess recanalization after intervention. The Extending the Time for Thrombolysis in Emergency Neurological Deficits-Intra-arterial (EXTEND-IA) trial, which used CT-guided inclusion criteria, found that 92% patients in the endovascular treatment arm achieved recanalization within 24 h of treatment versus 34% in the alteplase-only treatment group. , The Randomized Trial of Revascularization with Solitaire FR ® Devices (REVASCAT) reinforced these findings, as 66% of the patients in that trial obtained an average modified TICI score of 2B/3. Furthermore, there was a 1.7-point increase in the Rankin score in patients who were selected based on proven occlusion of anterior circulation.  Thus, using CT scans in lieu of clinical stroke criteria allowed for improved selection of patients, who benefitted from endovascular treatment due to their favorable penumbral patterns.
Recanalization in optimal penumbral patterns
There are two parts of the ischemic insult that must be considered: The core infarct and the penumbral rim. The core infarct is the area of severe infarct. This is the portion of the brain that has lost many neurons and is unsalvageable. The penumbral area is the section of ischemic tissue that is marred by cerebral oligemia yet is still salvageable if treated immediately.  There is a complicated relationship between patients with a penumbral pattern and their ability to attain functional independence after recanalization. The MR RESCUE trial showed neutral results in patients with favorable penumbral patterns.  In patients with favorable penumbral patterns, embolectomy was not superior to standard care. For example, patients in the embolectomy arm showed a Rankin score of 3.9 versus 3.4 in the control arm.  However, patients with a penumbral pattern demonstrated a decreased final infarct volume after treatment. The MR RESCUE trial revealed a key teaching point: That selecting patients with favorable penumbral patterns leads to improved final infarct core volumes and a higher likelihood of reperfusion.
This learning point was incorporated into subsequent trials such as Solitaire™ with the Intention for Thrombectomy as Primary Endovascular Treatment for Acute Ischemic Stroke (SWIFT PRIME), Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion with Emphasis on Minimizing CT to Recanalization times (ESCAPE). EXTEND-IA, and REVASCAT that recruited patients with optimal penumbral profiles. ,, The ESCAPE trial excluded patients with moderate to large infarct cores defined by minimal collaterals in a region greater than 50% of the MCA territory, an infarct with an ASPECTS score of less than 6 (indicating an extensive cerebral infract), or a region of slow cerebral blood volume and flow.  The SWIFT PRIME and REVASCAT trials also excluded patients with an ASPECTS score of less than 6, , These three trials emphasized that selecting patients based on optimal penumbral patterns leads to improved functional ability both 72 h and 90 days after embolectomy treatment.
Time to treatment
In subgroup analysis, IMS 3 and SYNTHESIS demonstrated that shortening the door-to-needle time improved patient outcomes after endovascular treatment. Many randomized control trials have shown that the efficacy of IV tPA decreases the longer stroke symptoms continue.  For each 15-min reduction in the time to initiate therapy, there was a 4% decrease in odds of gait disability, a 4% decrease in death before discharge, and a 4% decrease in symptomatic hemorrhagic stroke after treatment.  The importance of minimizing the time of treatment administration was demonstrated by all the five recent multicenter randomized prospective trials (MPRCTs): SWIFT PRIME, MR CLEAN, ESCAPE, EXTEND-IA and REVASCAT.  ESCAPE was the only trial of the five studies mentioned above where time of symptom onset was the highest for inclusion (less than 12 h). This was followed by REVASCAT (less than 8 h of symptom onset), then MR CLEAN (less than 6 h of symptom onset), which was then followed by EXTEND-IA and SWIFT PRIME (less than 4.5 h of symptom onset). ,,, SWIFT PRIME had a mandatory imaging-to-mechanical embolectomy treatment time of less than 90 min, with an average treatment time of 70 min.  The study reported that 60% of endovascular candidates demonstrated functional independence (as outlined by mRS) after 90 days of discharge. The average TICI scores were also relatively higher compared to the rest of the four trials, with 88% of patients obtaining a TICI grade of 2B/3.  The patients also demonstrated a 4-5-point improvement in NIHSS scores 27 h after treatment, with an overall lower mortality rate. This ultimately translated to a decreased number needed to treat, with four patients needing to be treated in order for one patient to reach functional independence (mRS 0-2 at 90 days). Where the ESCAPE trial allowed patients to be treated up to 8 h after stroke onset, SWIFT PRIME was insistent on establishing faster access to treatment. Not only did this improve outcomes for patients, but it also revealed that the treatment plans of IMS-III, MR RESCUE, and SYNTHESIS were not fast enough for effective management. In essence, SWIFT PRIME showed that quick and efficient endovascular treatment was essential to enhance stroke outcomes.
The ESCAPE trial also reinforced the conclusions reached in the SWIFT PRIME trial. As with MR CLEAN and EXTEND-IA, patients with large infarct cores and poor collateral circulation were excluded from the study. ,, ESCAPE included 400 patients, a study sample twice the size of SWIFT PRIME, with 188 patients placed diametrically in each treatment arm. Patients were treated 2 h faster than in the IMS-III trial, with an average treatment time of 84 min  and showed a 25% improvement in Rankin scores and an 8% improvement in mortality. Moreover, the study was the first of its kind to introduce data on patients treated after 6 h of stroke onset. Although the study was not powered to assess benefit after 6 h of intervention, subgroup analysis showed a similar improvement in mRS at follow-up when compared to the IV tPA control group.
Importance of state-of-the-art thrombectomy devices
Successful treatment of large-vessel clots requires the application of the newest-generation thrombectomy devices with or without the addition of IV tPA. In the IMS III trial, approximately two-thirds of the patients in the endovascular treatment arm were treated with IA tPA alone; in those that were treated with an thrombectomy device, only relatively older first generation thrombectomy devices were used.  In the SYNTHESIS Expansion trial, only one-third of patients in the endovascular group were treated with retrievable stents. 
MR RESCUE, on the other hand, featured the ubiquitous use of thrombectomy devices. However, due to the fact that the trial took place during a time period where there was a rapid development of stent technology, first-generation retrievable stents were still used. Unfortunately, first-generation devices were vulnerable to operator failure, which is thought to have contributed to the equivocal results demonstrated in MR RESCUE. Furthermore, because the devices did not match the type of devices that are typically used in the contemporary clinical settings, the data that were derived from IMS III and the SYNTHESIS Expansion could not be applied to patient populations that are now treated with newer devices that are less susceptible to operator failure.
In comparison, recent studies such as ESCAPE and SWIFT PRIME used the newest-generation Solitaire FR thrombectomy devices (Covidien, USA). , Head-to-head comparisons in multicenter, prospective, randomized controlled trials such as SWIFT and Thrombectomy Revascularization of Large Vessel Occlusion in Acute Ischemic Stroke (TREVO) 2 have established superior recanalization and safety rates with Solitaire and Trevo (stent retrievers) compared to older-generation Merci devices. , In these current trials, retrievable stents were used on 86% of patients within the endovascular treatment arm of the ESCAPE trial, which resulted in successful recanalization in 76% of patients. Furthermore, 95% of patients in the REVASCAT trial were treated with thrombelectomy devices; as a result, over 90% of patients had at least 50% of their anterior circulation reperfused.  When considering treatment with IA tPA, the inclusion of retrievable stents as part of the treatment is integral. As earlier studies have shown, treatment with IA tPA alone leads to clinically unfavorable results. Looking forward, later trials must continue to include stent-retriever treatment along with IA tPA doses to reinforce statistically significant functional outcomes.
Sample size and randomization refinements in later trials
Although not often discussed within the conversation about endovascular treatment, sample size is still a very important criterion for reinforcing results and attaining a sense of generalizability among different population strata. As previously discussed, the inclusion criteria for a majority of the older trials were individuals 18-85 years old with an elevated NIHSS score or LVO directly confirmed by CT imaging. However, each trial had a difference in sample size. Earlier trials such as MR RESCUE and PROACT had smaller sample sizes. PROACT, for example, used only 40 patients to demonstrate the efficacy of intraarterial prourokinase. In comparison to much larger trials, the sparse sample size here served to limit generalizability to a broader population.  In addition, the earlier studies were not properly randomized. There was a 2:1 ratio of endovascular patients versus placebo; optimizing the ratios would have allowed for more consistency with the results. On the other hand, MR RESCUE increased the sample size and improved randomization; however, the study allowed up to 8 h of stroke onset before a patient could be included in the study.  This delay in stroke treatment would certainly have decreased efficacy of endovascular treatment.
In contrast, the ESCAPE trial enrolled 120 patients into the intervention group, while SWIFT PRIME and REVASCAT enrolled approximately 100 patients each into the endovascular arm. ,, The importance of the later trials was not only the increased number of patients in the endovascular treatment arm and the 1:1 ratio of the endovascular-versus-control group, but that patients were included based on imaging of LVO on CT scans. Not only were there more patients to test the efficacy of endovascular therapy, but these patients who demonstrated a large-vessel thrombus also reflected the typical profile of a stroke patient needing intervention. ESCAPE, MR CLEAN, EXTEND-IA, SWIFT PRIME, and REVASCAT were also multinational studies that were done in patients from various backgrounds. As the results were efficacious across all the patients with endovascular therapy, the results of the most recent trials can be generalizable to a broader population consisting of people of different genetic makeup. ,,
Endovascular treatment has a long and storied history in the realm of neurointervention. Studies have shown that with the demonstration of large-vessel thrombus, quick efficiency in addressing the clot, use of state-of-the-art thrombectomy devices, shorter door-to-needle time, and refined randomization criteria lead to improved mortality and functional independence in patients treated with endovascular treatment in conjunction with IV tPA. From the PROACT 2 trial to the latest REVASCAT, interventional neurology has evolved significantly. The results of the five most recent multicenter randomized control trials constituted a game-changer in how acute ischemic strokes affecting large vessels in the anterior cerebral circulation are handled. This has led to the establishment of guidelines setting endovascular intervention as the standard of care in large-vessel-related anterior ischemic strokes. Further trials are warranted at this juncture to reinforce the findings of the prior studies and also to improve morbidity and mortality after ischemic strokes.
|1||Center of Division and Prevention 'Stroke Facts Cdc.Gov'. Cdc.gov. N.p., 2015. Web. 5 Apr. 2015.|
|2||Lees KR, Bluhmki E, von Kummer R, Brott TG, Toni D, Grotta JC, et al. Time to treatment with intravenous alteplase and outcome in stroke: An updated pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials. Lancet 2010;375:1695-703.|
|3||Ciccone A, Valvassori L, Nichelatti M, Sgoifo A, Ponzio M, Sterzi R, et al. SYNTHESIS Expansion Investigators. Endovascular treatment for acute ischemic stroke. N Engl J Med 2013; 368:904-13.|
|4||Broderick JP, Palesch YY, Demchuk AM, Yeatts SD, Khatri P, Hill MD, et al. Interventional Management of Stroke (IMS) III Investigators. Endovascular therapy after intravenous t-PA versus t-PA alone for stroke. N Engl J Med 2013;368:893-903.|
|5||Parsons MW, Albers GW. MR RESCUE: Is the glass half-full or half-empty? Stroke 2013;44:2055-7.|
|6||Kidwell CS, Jahan R, Gornbein J, Alger JR, Nenov V, Ajani Z, et al. MR RESCUE Investigators. A trial of imaging selection and endovascular treatment for ischemic stroke. N Engl J Med 2013;368:914-23.|
|7||Berkhemer OA, Fransen PS, Beumer D, van den Berg LA, Lingsma HF, Yoo AJ, et al. MR CLEAN Investigators. A randomized trial of intraarterial treatment for acute ischemic stroke. N Engl J Med 2015;372:11-20.|
|8||Shi ZS, Loh Y, Walker G, Duckwiler GR. MERCI and Multi MERCI Investigators. Endovascular thrombectomy for acute ischemic stroke in failed intravenous tissue plasminogen activator versus non-intravenous tissue plasminogen activator patients: Revascularization and outcomes stratified by the site of arterial occlusions. Stroke 2010;41:1185-92.|
|9||Jovin TG, Chamorro A, Cobo E, de Miquel MA, Molina CA, Rovira A, et al. REVASCAT Trial Investigators. New England journal of medicine, thrombectomy within 8 hours after symptom onset in ischemic stroke. N Engl J Med 2015;372:2296-306.|
|10||Caplan LR, Kasner SE, Dashe JF. Etiology, classification, and epidemiology of stroke. uptodate. N.p., 2015. Web. 5 Apr. 2015.|
|11||Sue H. EXTEND-IA: 'Huge' benefit of endovascular therapy for stroke. Medscape.com. N.p., 2015. Web. 5 Apr. 2015.|
|12||Goyal M, Demchuk AM, Menon BK, Eesa M, Rempel JL, Thornton J, et al. ESCAPE Trial Investigators. Randomized assessment of rapid endovascular treatment of ischemic stroke. N Engl J Med 2015;372:1019-30.|
|13||Saver JL, Goyal M, Bonafe A, Diener HC, Levy EI, Pereira VM, et al. SWIFT PRIME Investigators. Solitaire with the intention for thrombectomy as primary endovascular treatment for acute ischemic stroke (SWIFT PRIME) trial: Protocol for a randomized, controlled, multicenter study comparing the solitaire revascularization device with IV Tpa With IV T. Int J Stroke 2015;10:439-48.|
|14||Filho JO, Koreshetz WJ. Initial assessment and management of acute stroke. UpToDate 2015. |
|15||del Zoppo GJ, Higashida RT, Furlan AJ, Pessin MS, Rowley HA, Gent M. PROACT: A phase II randomized trial of recombinant pro-urokinase by direct arterial delivery in acute middle cerebral artery stroke. Stroke 1998;29:4-11.|
|16||Cambell BC, Mitchel PJ, Kleinig TJ, Dewey HM, Churilov L, Yassi N, et al. EXTEND-IA Investigators. Endovascular therapy for ischemic stroke with perfusion-imaging selection. N Engl J Med 2015; 372:1009-18.|
|17||Saver JL, Jahan R, Levy EI, Jovin TG, Baxter B, Nogueira RG, et al. SWIFT Trialists. Solitaire flow restoration device versus the merci retriever in patients with acute ischaemic stroke (SWIFT): A randomised, parallel-group, non-inferiority trial. Lancet 2012;380:1241-9.|
|18||Nogueira RG, Lutsep HL, Gupta R, Jovin TG, Albers GW, Walker GA, et al. TREVO 2 Trialists. Trevo versus merci retrievers for thrombectomy revascularisation of large vessel occlusions in acute ischaemic stroke (TREVO 2): A randomised trial. Lancet 2012;380:1231-40.|