4.1.1 Clinical Presentation

A 79-year-old female, previously well, was undergoing rehabilitation on the ward post elective right knee replacement. She developed sudden left hemiparesis and aphasia. A stroke code was called; the patient was not a candidate for tissue plasminogen activator (tPA).

4.1.2 Imaging and Workup

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  Noncontrast CT head was performed, which demonstrated hyperdense right M1 sign.

  
  
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  CT angiography demonstrated proximal vessel occlusion, with mismatch on CT perfusion.

  
  
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  Decision was made to take the patient urgently to the angio suite for mechanical thrombectomy. Risks include death, hemorrhage, reperfusion injury, pseudoaneurysm, hematoma, and vascular injury, and informed consent was obtained.

4.1.3 Diagnosis

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  Right middle cerebral artery (MCA) M1 segment occlusion.

4.1.4 Technique

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  Right femoral single-wall puncture after standard prep and drape.

  
  
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  Under ultrasound guidance, 5 to 7 Fr dilators were used with 8-Fr sheath. 2,000 units of heparin was infused.

  
  
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  Considering the tortuous anatomy off the aortic arch and great vessel origins, Mani catheter with a Terumo advantage exchange wire was used to gain access to the right external carotid artery.

  
  
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  Concentric balloon catheter of 8 Fr was then exchanged up, and positioned into the proximal right internal carotid artery (ICA).

  
  
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  Initial anteroposterior (AP), lateral angiograms demonstrated a proximal right M1 occlusion, with cross-filling into the left anterior cerebral artery territory, and cortical collateral filling at a very delayed stage.

  
  
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  Trevo 18 microcatheter was then prepared, using a transcend soft tip microguidewire, and gained access into right M2 segment, with microcatheter injection demonstrating intraluminal position (Fig. 4.1).

  
  
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  Trevo ProView mechanical thrombectomy stent was then deployed, with single shot angiogram demonstrating appropriate expansion of the stent. This was incubated for 5 minutes.

  
  
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  With the stent in situ, transient bypass effect with observed on AP and lateral angiograms.

  
  
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  The stent was pulled back with inflation of the concentric balloon guide catheter, and simultaneous suction to obtain flow arrest.

  
  
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  Repeat angiogram demonstrated recanalization of the M1, and the superior M2 branch, with occlusion of the inferior M2 branch persisting.

  
  
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  Recanalization of the inferior branch was not pursued. The sheath was sewn in.

  

4.1.5 Outcome

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  Immediate neurological assessment was performed, which showed motor improvement.

  
  
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  The patient was discharged home on postoperative day 3 with an NIHSS score of 0.

  
  
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  At 6-month follow-up in the neurointerventional clinic, her NIHSS and modified Rankin scale scores were 0.

4.1.6 Discussion

The next-generation RCTs were conducted with lessons from IMS III, SYNTHESIS, and MR RESCUE. Since the publication of these negative studies, a couple of new trials were designed to primarily test the new stent retrievers, utilize baseline imaging as an inclusion criteria, and aim for a faster stroke onset to procedure time. These trials included MR CLEAN, ESCAPE, EXTEND IA, SWIFT PRIME and REVASCAT, THRACE, and THERAPY. With the exception of THERAPY, which was underpowered at the time of its termination, all of these trials yielded conclusive positive results that favored mechanical thrombectomy.

The MR CLEAN was a Dutch trial wherein 233 patients were randomized to intra-arterial (endovascular) treatments with usual care and 267 were randomized to usual standard of care alone. Out of those in the endovascular arm, 196 underwent endovascular treatment, of which 190 were treated with modern stent retrievers. Patient inclusion criteria involved a large vessel occlusion in the anterior circulation as confirmed via CTA, feasibility of endovascular treatment within 6 hours of stroke onset, and NIHSS of ≥ 2. There were significant differences observed among the patients who achieved a good functional outcome (modified Rankin scale [mRS] ≤ 2): 32.6% in the endovascular arm vs. 19.1% in usual care. The adjusted odds ratio was 1.67 (95% confidence interval [CI]: 1.21–2.30). There were no significant differences in mortality, rate of symptomatic intracerebral hemorrhage (SICH), or other serious adverse events. ¹ The positive result of MR CLEAN owes itself to the use of stent retrievers and baseline imaging. Other factors were contributory as well; for instance, most patients in the trial were included after they have failed to respond within 1 hour of IV-tPA. It was then not surprising that usual care would be less effective than expected. Moreover, the Dutch health system allowed only endovascular therapy for acute ischemic stroke to be performed within the trial. This avoided the biased selection of patients who were easy to treat, making it more congruent with the reality of stroke care. Lastly, the safety result of the trial demonstrated that all the intervention procedures were performed in a safe manner. ² Though the MR CLEAN results were positive, it should be mentioned that they are not as frankly so as the other four positive trials discussed, perhaps owing to the long stroke onset to groin puncture time of 260 minutes. ^{2 ,​ 3} Regardless of its limitations, the MR CLEAN demonstrated the safety and effectiveness of endovascular therapy in acute ischemic stroke involving a large artery occlusion of the anterior circulation within 6 hours of stroke onset.

Similar to MR CLEAN, ESCAPE is a trial that compared endovascular treatment plus standard care with standard care alone. This international trial randomized 165 patients to the endovascular plus standard care arm and 150 patients to the standard care arm. Also akin to MR CLEAN, patients were enrolled with proximal intracranial occlusions in the anterior circulation, but the timeline was extended to within 12 hours of symptom onset. The inclusion criteria specified patients with small infarct cores, occlusion in proximal anterior circulation artery, and moderate-to-good collateral circulation as identified via noncontrast CT and CTA. The trial was stopped early due to demonstrable efficacy. Significantly more proportion of patients in the endovascular group achieved functional independence (mRS ≤ 2) at 90 days (53.0 vs. 29.3%). The common OR was 2.6, favoring the intervention. The number needed to treat (NNT) to achieve one more independent functional outcome was only 4. Moreover, there was also significantly reduced mortality (10.4 vs. 19%) associated with intervention, while the SICH rate was not significantly different between the groups. Better results were gained from ESCAPE than from MR CLEAN. ESCAPE also used baseline imaging and the majority of patients were treated with stent retrievers. However, a few key differences were notable. The investigators of the ESCAPE trial emphasized efficient workflow, setting time targets for CT to groin puncture and reperfusion times. The mean time from symptom onset to groin puncture was 185 minutes, which is significantly shorter than the 260 minutes of MR CLEAN. ^{2 ,​ 3} Moreover, imaging was used to exclude patients with large infarcts and poor collateral circulation. This selection process allowed patients who would most likely to benefit from endovascular therapy. There was also an emphasis on decreasing the use of general anesthesia. As such, complications due to general anesthesia were less likely to occur. With an emphasis on efficient workflow, innovative patient selection, a decreased use of general anesthesia, and the use of stent retrievers, the ESCAPE trial was able to demonstrate both an increase in functional outcome and a decrease in mortality favoring endovascular therapy. ³

EXTEND IA, SWIFTPRIME, and REVASCAT were trials that compared the effectiveness of Solitaire plus IV-tPA and IV-tPA alone. EXTEND IA was conducted in Australia and New Zealand that randomized patients already receiving IV-tPA within 4.5 hours of stroke onset to receive endovascular therapy using Solitaire or continued medical care. The plan was to enroll 100 patients with occlusions of the internal carotid or MCA and evidence of salvageable brain tissue on CT. One of the major innovations in this study is the use of RAPID software to automatically identify salvageable brain tissue, decreasing the delay to endovascular therapy. However, the trial was stopped early with 35 patients randomized to each arm due to efficacy. The co-primary outcomes of 24-hour MRI reperfusion and 3-day NIHSS both vastly favored endovascular intervention. At 24 hours, there was 100% reperfusion of the ischemic territory with Solitaire, as compared to only 37% with IV-tPA. Early neurological improvement at 3 days, defined as ≥8-point reduction on the NIHSS, or a score of 0 or 1, was achieved in 80% of Solitaire patients and 37% of IV-tPA patients. More patients in the Solitaire group also achieved a good functional outcome at 90 days than IV-tPA patients (71 vs. 40%). There were no significant differences in SICH rate or mortality. Similar to ESCAPE, this trial was also vastly more positive than the results of MR CLEAN. EXTEND IA employed CT perfusion imaging as an inclusion criteria, selecting for patients who were more likely to benefit from therapy. The time from stroke onset to groin puncture was yet again shorter than the time in MR CLEAN (210 minutes in EXTEND IA vs. 260 minutes in MR CLEAN). Another contributor to the positive result was the higher rate of revascularization (86%) achieved with Solitaire as compared with previous trials. ⁴

SWIFT PRIME was a trial conducted in the United States, Canada, and Europe that planned to randomize 477 patients who were receiving IV-tPA to either treatment with Solitaire or continued treatment with IV-tPA. Patients were included only if it was possible to perform endovascular therapy within 6 hours of stroke onset. The selection criteria included confirmed occlusions in the proximal arteries in the anterior circulation (intracranial ICA, M1, or carotid terminus) and absence of large ischemic core lesions on CTA or MRA. This trial was again stopped early due to efficacy after enrolling 196 patients with 98 in each group. The primary outcome of disability at 90 days as assessed by the mean of mRS demonstrated a favorable shift in the endovascular arm. The NNT for a less-disabled outcome was 2.6. The rate of functional independence (mRS ≤2) was achieved in 60% of the intervention group and 35% of the control, and the NNT for functional independence was 4.0. There were no differences in mortality and SICH rates. This trial had a stroke onset to groin puncture time of 224 minutes, yet again highlighting the importance of decreased time to better result. The percentage of functional independence achieved was higher than that of MR Clean and comparable to other previous trials (MR CLEAN: 33%, ESCAPE: 53%, EXTEND IA: 71%, and SWIFT PRIME: 60%). The SWIFT PRIME trial provided even more solid evidence for the use of stent retriever in treating acute ischemic stroke due to occlusions in the proximal arteries of the anterior circulation within 6 hours of onset. ⁵

The REVASCAT was a trial conducted in Spain. Its study population was those who were refractory or contraindicated to IV-tPA. In addition, patients had confirmed proximal anterior circulation occlusion. Patients were excluded if they had a large ischemic core, as identified by the Alberta Stroke Program Early Computer Tomography Score (ASPECTS) on noncontrast CT or diffusion-weighted MRI. They were randomized to receive treatment with Solitaire or medical therapy. The trial was stopped early after enrolling 206 patients due to efficacy concern, with 103 in each group. The primary outcome was reduction in severity of disability over the range of mRS. The odds ratio for 1 point improvement on the mRS scale was 1.7 (95% CI: 1.05–2.8), slightly favoring the intervention. Higher rate of functional independence (mRS ≤2) at 90 days was achieved in the intervention group (43.7%) than in the control group (28.2%). The NNT to prevent functional dependence was 6.5. Neither the rate of symptomatic hemorrhage nor death was clinically significant. This trial was similar to MR CLEAN but different from ESCAPE, EXTEND IA, and SWIFT PRIME in that it excluded patients with an early response to IV-tPA. This criteria resulted in longer times from hospital arrival to reperfusion, and thus lower rates of reperfusion in comparison to ESCAPE, EXTEND IA, and SWIFT PRIME. Moreover, patient selection in this trial was done with the ASPECTS scoring alone, which allowed the inclusion of patients with larger infarct sizes. Hence, results were positive but not as drastically positive as that of ESCAPE, EXTEND IA, and SWIFT PRIME. ⁶

While MR CLEAN, ESCAPE, SWIFTPRIME, EXTEND IA, and REVASCAT were published in 2015, the results of THRACE and THERAPY were published a year later. THRACE was a trial conducted in France. Similar to MR CLEAN and ESCAPE, this study compared IV-tPA alone with IV-tPA plus mechanical thrombectomy. The mechanical thrombectomy procedures used were primarily stent retrievers, as well as some aspiration devices. Patients were enrolled based on a confirmed occlusion in a large vessel of the anterior circulation or superior basilar artery as evident on CTA or MRA. Unfortunately only two patients were enrolled with occlusions of the superior basilar artery; thus, the results of the trial reflect strokes only in the anterior circulation. IV-tPA had to be initiated within 4 hours of stroke onset and thrombectomy within 5 hours of onset. An unplanned interim analysis was done after the results from MR CLEAN were released. This analysis showed superiority of the mechanical thrombectomy and the trial was thus stopped early. At the termination of the trial, 208 patients were randomized to receive tPA alone and 204 patients were to receive tPA plus mechanical thrombectomy. The primary endpoint of functional independence (mRS ≤ 2) at 90 days was achieved in more proportion of the patients in the intervention group (53%) compared to the control group (42%) (OR: 1.55, 95% CI: 1.05–2.30). There were no differences in mortality or SICH rates.

While the THRACE trial affirms the results of the trials published in 2015, there were some differences in its methodology. One major difference is that patient selection was not performed based on the size of the ischemic core. In THRACE, 30% of patients who scored 0 to 4 on ASPECTS achieved functional independence at 90 days. Thus, the potential benefit of treatment in this group of patients should not be overlooked. Another difference in methodology is the short delay from IV-tPA to randomization compared to other studies, and thus patients were not excluded based on their response to IV-tPA. Moreover, this resulted in a large proportion (30%) of crossover from the mechanical thrombectomy group to the control group, because many patients did not receive mechanical thrombectomy. The time from randomization to groin puncture was also longer than that of other studies. All of these factors contributed to the decreased absolute difference in functional independence as compared with other trials. Nevertheless, THRACE demonstrated the efficacy of mechanical thrombectomy without exclusion of patients with large ischemic cores and an initial response to IV-tPA.

Around the same time as THRACE, results from THERAPY were also published. This was a trial conducted in the United States and Germany with a planned enrolment of 692 patients. However, enrolment was stopped early at 108 patients after results from MR CLEAN were made available and it was subsequently considered unethical to treat patients with tPA alone. The major difference between THERAPY and other trials is that it investigated only the efficacy of the Penumbra aspiration device. It compared treatment with IV-tPA plus penumbra with IV-tPA alone. The key inclusion criterion was patients with large vessel occlusions of thrombus length ≥ 8 mm. The primary efficacy endpoint of functional independence at 90 days failed to reach significance, as the study was underpowered at the time of termination. However, the data favored intervention over control (OR: 1.76, 95% CI: 0.86–3.59). Moreover, per-protocol analyses of primary and secondary endpoints consistently favored the intervention, with some secondary endpoints reaching statistical significance. There were no differences in mortality or SICH rates. THERAPY was the first study to examine the effect of aspiration devices alone. While it was stopped early and underpowered, the results suggested a potential benefit of aspiration devices over standard medical management. What must be noted is that this trial did not answer the question of whether aspiration or stent retrievers were more efficacious, and further RCTs comparing these two currently favored procedures will be required to provide a definitive answer.

With the publication of MR CLEAN, ESCAPE, EXTEND IA, SWIFT PRIME, THRACE, and THERAPY, the case for endovascular therapy had become stronger. These trials learned from the earlier lessons of IMS III, SYNTHESIS, and MR RESCUE. Using mainly stent retrievers, stream-lining workflow to reduce door to treatment times, and employing innovating imaging techniques for optimal patient selection, these new trials had discovered a significant benefit in the functional outcomes, neurological improvement, reperfusion rates, and even mortality. The NNT to prevent one functional disability is staggeringly low, ranging from 4 to 6.5. ⁶ Moreover, endovascular therapy has consistently been proven to be just as safe as medical treatment. These results provide a strong case for using endovascular therapy as standard care for acute ischemic stroke patients.