Endovascular Embolectomy for Emergent Large Vessel Occlusion: A Historical Perspective

The role of imaging

The noncontrasted head computed tomography (NCCT) is the workhorse of neuroradiology, and stroke imaging is no exception. On arrival to a PSC or CSC, the patient should be directed immediately to the CT scanner to exclude the presence of intracranial hemorrhage, which would render the patient ineligible for either IV tPA or endovascular embolectomy and lead the treatment team down the path of hemorrhagic stroke. In addition, the presence of a hyperdense vessel segment or parenchymal abnormalities such as sulcal effacement, loss of gray-white differentiation, or hypoattenuation in a vascular distribution may indicate ELVO.^[18]

The Alberta Stroke Programme Early CT Score systematically quantifies early ischemic changes in the MCA territory by dividing it into 10 regions.^[19] The score is used on a baseline NCCT obtained before the administration of any thrombolytic. For each affected region, a point is subtracted from the best possible score (10); a score of 0 indicates diffuse MCA distribution ischemia. The ASPECT scoring system was found to be inversely related to stroke severity, and predictive for both functional outcome and symptomatic hemorrhage. In general, if more than one-third of the MCA territory (ASPECT score ≤7) is affected, thrombolysis is not offered, although the authors are quick to state that based on the available data an ASPECT score ≤7 should not in itself be the excluding criterion for thrombolysis.

Although NCCT can aid in determination of eligibility for IV tPA, often more information is needed to evaluate candidacy for endovascular intervention. Patients who benefit most from endovascular therapy have a proximal occlusive lesion and a high penumbra-to-core infarct ratio; however, the best method to determine these characteristics is unclear. In addition to NCCT, imaging modalities used to aid in the assessment of stroke include CT angiography, perfusion CT (CTP), and magnetic resonance imaging. As of yet, there is no standard set of neuroimaging that has been proven to diagnose ELVO and best predict response to endovascular treatment, and imaging protocols are determined by the availability of each modality at a given CSC. The current AHA/ASA guidelines state that noninvasive intracranial vascular imaging should be performed as soon as possible if endovascular therapy is being considered but should not delay the administration of IV tPA.^[7] The specific inclusion criteria for endovascular embolectomy are listed in Table 2.

With the implementation of endovascular therapies came the need to assess posttreatment efficacy. In 2003, Higashida et al. proposed a grading system to assess angiographic response to endovascular treatment^[20] based on the thrombolysis in myocardial infarction (TIMI) grading system used to assess coronary blood flow after percutaneous coronary angioplasty. The Thrombolysis in Cerebral Infarction (TICI) grading system has been inconsistently defined and applied in various trials;^[21] however, it has since been modified by a consensus group in 2013 (mTICI, Table 3).^[22]

Directed intraarterial (IA) thrombolysis

Enrollment began for the Prolyse in Acute Cerebral Thromboembolism (PROACT) trial in 1994, around the same time as the approval process for IV tPA was underway. PROACT showed that IA recombinant prourokinase could be delivered to recanalize occlusions of the MCA.^[23] The later PROACT II trial, published in 1999, demonstrated that IA thrombolysis achieved higher rates of recanalization compared to systemic anticoagulation with heparin (66% vs. 18%; P < 0.001) and also conferred a functional benefit, measured by the mRS 90 days after injury.^[24] The control arm of PROACT II would also become the historical “control” to which later, single-armed trials were compared.

The Italian synthesis expansion: A randomized controlled trial on IA versus intravenous thrombolysis in acute Ischemic stroke (synthesis expansion) trial, published in 2013, aimed to determine the superiority of IA thrombolysis compared to IV tPA with regard to survival free of disability (mRS 0-1) at 90 days.^[25] Patients assigned to the endovascular treatment arm did not receive IV tPA and were treated with up to 0.9 mg/kg IA tPA into the thrombus. Although primarily a comparison between the two delivery methods (IV vs. IA) of tPA, the investigators considered this a comparison between systemic and endovascular treatment. Patients treated with IA tPA could also receive additional endovascular procedures such as mechanical disaggregation, retraction, or aspiration of the thrombus per the discretion of the intervention a list; a device was used in 56 out of 165 patients. Synthesis expansion concluded that endovascular interventions were not superior to IV tPA; 30.4% of patients in the endovascular group and 34.8% of patients in the IV tPA group were alive without disability at day 90, and each treatment group experienced symptomatic intracranial hemorrhage at a rate of 6%.

The early era of mechanical embolectomy

The era of mechanical embolectomy began with the invention of the Mechanical Embolus Removal in Cerebral Ischemia (MERCI) coil retriever (concentric medical/Stryker neurovascular, mountain view, CA, USA), also known as the MERCI device, a corkscrew-shaped, nickel titanium wire deployed at the site of the thrombus to ensnare and subsequently remove it (Figure 1). Studying the device in patients ineligible for IV tPA, investigators of the MERCI trial sought to determine whether embolectomy using the MERCI retriever could restore flow in patients presenting within 8 h of an acute ischemic stroke.^[26] The TIMI score was used to assess recanalization, and treatable vessels included the intracranial vertebral artery, basilar artery, ICA, ICA terminal bifurcation, and MCA. While MERCI included more vessels than were studied in PROACT II, it demonstrated that use of the device restored vascular patency (TIMI 2-3) in 46% of patients on intention to treat analysis compared with the 18% who spontaneously recanalized in the control arm of PROACT II.^[24] In 2004, the FDA approved the MERCI retriever for the “[removal of] blood clots from the brain in patients experiencing an ischemic stroke.”^[27] The MERCI Retriever was billed as a complement to IV thrombolytics, which work well on small, distal clots not accessible by the device.^[28] MERCI met its primary endpoint, determining that patients retreated with the retriever experienced greater rates of recanalization. Its secondary endpoint was neurological outcome, as determined by mRS at day 90. Despite higher rates of revascularization, mRS ≤2 was achieved in only 27.7% of MERCI patients, comparable to 25% of control patients in PROACT II.^[24,26] For many years, contention would exist regarding whether embolectomy yielded functional benefits in patients with acute ischemic stroke over standard care despite its success in revascularization.

Close

Figure 1

87-year-old woman presented with left middle cerebral artery (MCA) syndrome, National Institutes of Health Stroke Scale score of 24. Road map in AP projection from digital subtraction cerebral angiogram shows a Merci coil retriever (arrow; concentric medical/stryker neurovascular, mountain view, CA, USA) deployed within a clot in the M1 segment of the left MCA. Thrombolysis in Cerebral Ischemia grade 2b reperfusion was attained

Export to PPT

The first randomized study attempting to prove the superiority of endovascular embolectomy began enrollment in 2004, although it was not published until 2013. Mechanical Retrieval and Recanalization of Stroke Clots Using Embolectomy (MR RESCUE) sought to determine whether patients with anterior circulation strokes and a favorable “penumbral” imaging pattern would benefit from mechanical embolectomy - first using the MERCI retriever, and including newer retrieval devices later in the trial.^[29] A penumbral pattern was defined as an infarct core ≤90 ml and <70% of the region at risk. Patients with a nonpenumbral pattern had a significant infarct core ≥90 ml or a small/ absent penumbra. MR RESCUE’s primary endpoint was the shift in disability levels (mRS) at day 90; secondary endpoints included good neurological outcome (mRS ≤2), revascularization determined by the thrombolysis in cerebral infarction (TICI) scale (2a-3), and reperfusion determined by CT or MR perfusion as a reduction of ≥90% in volume of the perfusion lesion. MR RESCUE found that embolectomy was not superior to standard care overall, not even in patients with a favorable penumbral pattern - regardless of treatment, patients with a penumbral pattern had lower day 90 mRS and smaller final infarct volumes.

Around the time of MR RESCUE, two other randomized and controlled trials - synthesis expansion and the third iteration of the Interventional Management of Stroke trial (IMS III) - seemed to strike down endovascular therapy as a complement or alternative to IV tPA despite improved revascularization. Synthesis expansion, described earlier, compared endovascular to systemic treatment, and determined that endovascular treatment was not superior to IV tPA on the basis of clinical benefit. IMS III sought to test the benefit of IV tPA followed by endovascular treatment compared to IV tPA alone.^[30] Endovascular intervention in this trial consisted primarily by the MERCI retriever but also included IA delivery of tPA as well as other endovascular devices available at the time. The study began enrolling patients 2006 and was stopped due to futility in 2012 after finding no differences in patients’ day 90 mRS. The study did note similar safety profiles in both groups and that successful endovascular recanalization was associated with improved functional outcomes. Endovascular therapy resulted in partial to complete reperfusion in 81% of MCA occlusions (TICI 2-3) compared to previous studies reporting a 40% success rate in MCA recanalization after IV tPA.^[31-33]

In the wake of multiple, negative endovascular studies, it was declared that “[t]he myth has been debunked, but the challenge is still present.”^[34] Despite some technical successes in restoring vessel patency, it appeared that endovascular treatments, both IA thrombolysis and mechanical embolectomy, were not superior to standard treatment. Still, others championed the cause and blamed study design for the failure of these influential trials. Parsons and Albers believed there to be an enrollment bias in MR RESCUE with a preference for patients with larger infarcts.^[35] They also cited the 2-h delay between imaging and the start of endovascular treatment, which could affect a patient’s penumbra to core ratio. The diffusion and perfusion imaging evaluation for understanding stroke evolution 2 (DEFUSE 2) study found favorable clinical outcomes in patients with a target mismatch (small diffusion-weighted imaging lesion compared to perfusion-weighted imaging lesion) in whom endovascular therapy was initiated early (median = 4.8 h from symptom onset).^[36] In MR RESCUE, the mean time from last known well time to groin puncture was 6.35 h.^[29] The target mismatch group in DEFUSE 2 also had an estimated core volume of 13 ml, while estimated core volumes in the penumbral pattern groups were 36 ml (embolectomy) and 37 ml (standard care). Parson and albers cited the echoplanar imaging thrombolysis evaluation trial, which suggests that good neurological outcomes were less likely to be achieved in patients with core volumes exceeding 25 ml.^[37] Also of note, only 19% of embolectomy patients achieved day 90 mRS of 0-2 in MR RESCUE, compared with 44% of patients in synthesis expansion and 42% in IMS III.^[25,30,38]

Promising results with stent retrievers

In IMS III, MERCI was the only retriever used for a significant part of the trial, and newer stent-like retrievers (“stentrievers”) were only utilized in a few cases before the trial was stopped.^[30] Those who believed in the potential of endovascular therapy were hopeful after the advent of stentrievers, which seemed more promising than MERCI. Stentrievers apply a radial force along the length of the thrombus and incorporate clot material into stent struts on deployment (Figure 2). In 2012, two stentriever studies - the SOLITAIRE with the intention for thrombectomy (SWIFT) study and the thrombectomy RE vascularization of large vessel occlusions in acute Ischemic stroke (TREVO II) study - were published concurrently in the Lancet, which has the second-highest impact factor among medical journals. This cushioned the blow when the negative results of MR RESCUE, synthesis expansion, and IMS III were published the following year.

Close

Figure 2

77-year-old woman presented with left middle cerebral artery (MCA) syndrome, National Institutes of Health Stroke Scale score of 20. Initial precontrast image in AP projection from digital subtraction cerebral angiogram shows a Trevo stent retriever (arrow; stryker neurovascular, mountain view, CA, USA) deployed within a clot in the M1 segment of the left MCA. Thrombolysis in cerebral Ischemia grade 2b reperfusion was attained

Export to PPT

SWIFT was a noninferiority trial comparing the safety and efficacy of the Solitaire Flow Restoration Device (Covidien/ ev3, Dublin, Ireland) with the MERCI Retriever.^[39] Beginning in 2010, SWIFT enrolled patients who had a persistent occlusion after treatment with IV tPA or were ineligible for IV tPA. Its primary efficacy endpoint was vascular patency (TIMI 2-3) without need for rescue therapy with another thrombectomy device and without symptomatic intracranial hemorrhage. Time to achieve recanalization and good neurological outcome at day 90 (mRS ≤2 or NIHSS improvement of ≥10 points) were secondary endpoints. SWIFT’s primary efficacy endpoint was achieved more often with solitaire (61% compared to 24% with MERCI). More patients had favorable neurological outcomes at day 90 with solitaire, and day 90 mortality was also lower in patients in the solitaire arm.

TREVO II was another randomized, noninferiority trial that began enrollment after the single-arm TREVO trial, which found that treatment with the TREVO Retriever (Stryker Neurovascular, Mountain View, CA, USA) achieved a 92% recanalization rate and that 55% of patients had good functional outcomes (mRS ≤2) at day 90,^[40,41] TREVO II found that 86% of patients in the TREVO group met the primary recanalization endpoint (TICI 2-3) while 60% of patients in the MERCI group met this endpoint. Rescue therapy was required more often in the MERCI group, and vessel perforations were 10 times more common with the MERCI device, likely due to the more even force applied by the TREVO Stentriever. 40% of patients in the TREVO group had favorable outcomes at day 90 compared to 22% of patients in the MERCI group, although there were no significant differences in mortality at day 90.

2015: The year of endovascular embolectomy

SWIFT and TREVO demonstrated the superiority of stentrievers over the original MERCI coil retriever, but the superiority of endovascular therapy over IV tPA had not yet been determined. The first trial to tackle this feat since MR RESCUE was the multicenter randomized clinical trial of endovascular treatment for acute ischemic stroke in the Netherlands (MR CLEAN).^[42] MR CLEAN enrolled patients between 2010 and 2014 and assessed whether endovascular treatment plus standard care would improve functional outcomes compared to standard care alone. Mechanical embolectomy included thrombus retraction, aspiration, wire disruption, or use of a retrievable stent. The study’s primary endpoint was functional outcome, assessed by mRS shift at day 90. MR CLEAN found that 32.6% of patients undergoing IA treatment were functionally independent (mRS ≤2) compared to 19.1% of patients who received standard care. All clinical and imaging secondary outcomes favored IA intervention including NIHSS at day 5-7, the absence of residual thrombus at the site of occlusion, final infarct volume, and good perfusion (TICI 2b-3). In this study, stentrievers were used in 81.5% of patients, and additional IA thrombolytics were given to 10.3% of patients.

Next came the endovascular treatment for small core and anterior circulation proximal occlusion with emphasis on minimizing CT to recanalization times (ESCAPE) trial and the extending the time for thrombolysis in emergency neurological deficits with IA therapy (EXTEND IA) trial, both published in the same issue. ESCAPE included patients with ELVO presenting within 12 h of symptom onset with NIHSS score >5 and ASPECT score >5.^[43] Patients were randomized to either embolectomy with any available devices (stentrievers were recommended) along with guideline-based therapy or guideline-based therapy alone, with emphasis on rapid imaging-to-treatment times; median time from imaging to groin puncture was 51 min. The addition of embolectomy improved outcomes with an odds ratio of 1.7; 53% of patients in the intervention arm achieved a 90-day mRS ≤2, as opposed to 29% of patients who received guideline-based therapy alone. EXTEND IA included patients with anterior circulation occlusion who had received IV tPA and had a favorable imaging profile based on advanced CT or MR imaging;^[44] of the 70 patients enrolled, half also underwent embolectomy with the Solitaire stentriever. Of those who received embolectomy, 71% achieved a mRS ≤2 and none experienced symptomatic hemorrhage, as opposed to 40% and 6%, respectively, who received only IV tPA.

Two more studies were published shortly thereafter - the solitaire FR with the intention for thrombectomy as primary endovascular treatment for acute Ischemic stroke (SWIFT PRIME) trial and the randomized trial of revascularization with solitaire FR device versus best medical therapy in the treatment of acute stroke due to anterior circulation large vessel occlusion presenting within 8 h of symptom onset (REVASCAT) trial - with similar results. SWIFT PRIME compared IV tPA with embolectomy using the solitaire device compared to IV tPA alone.^[45] The study’s primary endpoint was mRS at day 90, which was 2 in patients receiving IV tPA and embolectomy and 3 in patients receiving IV tPA alone. 60% of patients treated with solitaire achieved functional independence (mRS ≤2) at day 90, compared to 35% of patients who received IV tPA alone. REVASCAT randomized patients presenting within 8 h of symptom onset to either best medical therapy or embolectomy in addition to best medical therapy.^[46] Regarding the primary outcome, 43.7% of patients who received embolectomy had a mRS ≤2 as opposed to 28.2% of patients who did not receive embolectomy; the secondary outcome of vessel revascularization favored embolectomy. In addition, there was no difference between the two groups in terms of symptomatic intracranial hemorrhage or other significant adverse events.

The highly effective reperfusion evaluated in multiple endovascular stroke trials (HERMES) collaboration undertook a metaanalysis of all phase three trials involving stent retrievers or other second-generation embolectomy devices.^[47,48] The goal was to pool the data of all the recent trials to address two questions: (1) The degree of benefit of performing mechanical embolectomy within the established 6-h window and (2) whether mechanical embolectomy past six ours was beneficial. The HERMES collaborators concluded that earlier endovascular embolectomy along with medical therapy was associated with better functional outcome at 90 days and that this became nonbeneficial after 7.3 h as compared to standard medical therapy alone.