History and Overview of Endovascular Stroke Therapy

Study

Treatment modality

Age criteria (years)

Time window

Territory

NIHSS criteria

Vascular imaging

Other imaging

Number of cases

Mean age (years)

NIHSS median, (range) or [IQR]

Time onset to groin (min)

Endovascular vs control

Mean ± SD or median, [IQR]

IMS III (2013)

IV rt-PA + IA drug or any approved device vs IV rt-PA

18–82

5 h to IAT

Any

≥10 or 8–9 with occlusion

Non-contrast CT only

434/222

17 (7–40)/16 (8–30)

208 ± 47

SYNTHESIS Expansion (2013)

IA drug or any approved device vs IV rt-PA

18–80

6 h to IAT

Any

No thresholds

Non-contrast CT only

181/181

13 (2–26)/13 (9–18)

225 [194–260]

MR RESCUE (2013)

IV rt-PA + IA mechanical (Merci or Penumbra system) vs IV rt-PA

18–85

8 h to IAT (stop by 9 h)

Anterior circulation

6–29

CTA

MRI

Multimodal CT/MR for stratification

64/54

18 (12–22)/18 (11–23)

381 ± 72

MR CLEAN (2015)

IV rt-PA + IA any approved device (82% stent retriever) vs IV rt-PA

>18

6 h to IAT

Anterior circulation

CTA

MRA

233/267

17 [14–21]/18 [14–22]

260 [210–313]

ESCAPE (2015)

IV rt-PA + IA any approved device (79% stent retriever) vs IV rt-PA

>18

12 h to randomization

Anterior circulation

CTA

Multiphase CTA to identify core size and collaterals

165/150

16 [13–20]/17 [12–20)

Onset to CT 134 [77–247]

CT to groin 51 [39–68]

SWIFT PRIME (2015)

IV rt-PA + IA stent retriever vs IV rt-PA

18–80

6 h to IAT

Anterior circulation

8–29

CTA ± CTP or MRI

CT/CTP or MRI to identify ischemic penumbra (the first 71 pts) and ASPECTS ≥6 (the remaining 125 pts)

98/98

17 [13–20]/17 [13–19]

224 [165–275]

EXTEND-IA (2015)

IV rt-PA + IA stent retriever vs IV rt-PA

≥ 18

6 h to IAT

Anterior circulation

No thresholds

CTA

CTP

35/35

17 [13–20]/13 [9–19]

224 [165–275]

REVASCAT (2015)

IV rt-PA + IA stent retriever vs IV rt-PA

18–80

8 h to IAT

Anterior circulation

≥ 6

CTA ± CTP or MRI

103/103

17 [14–20]/17 [12–19]

269 [201–340]

Study	TICI 2b-3 recanalization	Time to reperfusion (min) mean ± SD or median, [IQR]	Favorable functional recovery at 3 months (mRS 0–2; endovascular vs control)	Symptomatic ICH (endovascular vs control)	Mortality at 3 months (endovascular vs control)
IMS III (2013)	41%	325 ± 52	41% vs 39% (RR 1.0, 0.8–1.2)	6.2% vs 5.9% (p = 0.83)	19% vs 22% (p = 0.52)
SYNTHESIS Expansion (2013)	NR	NR	42% vs 46% (p = not reported)	6% vs 6% (p = 0.99)	8% vs 6% (p = 0.53)
MR RESCUE (2013)	27%	NR	Used mean mRS comparison 3.9 vs 3.9 (p = 0.99)	5% vs 4% (p = 0.24)	19% vs 24% (p = 0.75)
MR CLEAN (2015)	58.7%	332 [279–394]	33% vs 19% (RR 1.7, 1.2–2.3)	7.7% vs 6.4% (p = NA)	21% vs 22% (RR 1.0, 0.7–1.3)
ESCAPE (2015)	72.4%	241 [176–359]	53% vs 29% (RR 1.8, 1.4–2.4)	3.6% vs 2.7% (p = 0.75)	10% vs 19% (RR 0.5, 0.3–0.8)
SWIFT PRIME (2015)	88%	252 [190–300]	60% vs 35% (RR 1.7, 1.2–2.3)	0% vs 3.1% (p = 0.12)	9% vs 12% (RR 0.7, 0.3–1.7)
EXTEND-IA (2015)	86%	248 [204–277]	71 vs 40% (RR 1.8, 1.1–2.8)	0% vs 5.7% (p = 0.49)	9% vs 20% (RR 0.4, 0.1–1.5)
REVASCAT (2015)	66%	355 [269–430]	44% vs 28% (RR 1.6, 1.1–2.3)	1.9% vs 1.9% (p = 1.00)	18% vs 16% (RR 1.2, 0.6–2.2)

CTA CT angiography, CTP CT perfusion, IA intra-arterial, IV intravenous, MRI MR imaging, MRA MR angiography, NR not reported, rt-PA recombinant tissue plasminogen activator

MR CLEAN (Multicenter Randomized CLinical trial of Endovascular treatment for Acute ischemic stroke in the Netherlands) was the first trial in 2015 to demonstrate the efficacy and safety of mechanical thrombectomy within a 6-h time window from stroke onset. With a cohort of 500 patients, favorable outcome defined as mRS 0–2 occurred in 32.6% of patients receiving intra-arterial treatment compared to 19.1% of patients receiving standard care alone. In addition, there were no significant differences in mortality or the occurrence of symptomatic ICH [14]. The second clear victory for mechanical thrombectomy in 2015 was the EXTEND-IA (EXtending the time for Thrombolysis in Emergency Neurological Deficits with Intra-Arterial therapy) trial, specifically for the Solitaire FR stent retriever. The trial was stopped early for ethical reasons given its efficacy. Patients in the endovascular therapy group, where the Solitaire FR was the device used, had a much higher incidence of good favorable outcome as compared to patients receiving intravenous rt-PA alone (mRS 0–2 at 90 days: 71% vs. 40%, P = 0.01) [15]. The third positive result for mechanical thrombectomy came in 2015 with the ESCAPE (Endovascular treatment for Small Core and Anterior circulation Proximal occlusion with Emphasis on minimizing CT to recanalization times) trial. Endovascular intervention with available mechanical thrombectomy devices resulted in 53% of patients with a 90-day mRS score of 0–2 versus 29.3% for patients receiving standard care in the control group (P < 0.001). In addition, there was no significant difference between groups with respect to the incidence of symptomatic ICH (3.6% vs. 2.7%, P = 0.75) [16]. The fourth large trial in 2015 was SWIFT PRIME (Solitaire With the Intention For Thrombectomy as PRIMary treatment for acute ischemic stroke). The study showed that for patients receiving intravenous rt-PA for acute ischemic stroke in the proximal anterior circulation, thrombectomy with a stent retriever within a 6-h time window from onset resulted in improved functional outcomes (mRS 0–2 at 90 days: 60% vs. 35%, P = 0.001). Like the previous 2015 trials, there was no significant difference in the incidence of symptomatic ICH (0% vs. 3%, P = 0.12) [17]. The fifth in a string of positive trials, all published in the New England Journal of Medicine in the same year, was REVASCAT (Revascularization With Solitaire Device Versus Best Medical Therapy in Anterior Circulation Stroke Within 8 h). Here, the time window was within 8 h. The safety and efficacy of mechanical thrombectomy were demonstrated as with the other trials (mRS 0–2 at 90 days: 43.7% vs. 28.2% and symptomatic ICH: 1.9% for both groups) [18]. All of these five trials provided strong evidence of benefit from mechanical thrombectomy for management of acute ischemic stroke secondary to large arterial occlusion. And, this is prompting worldwide changes in the guidelines for acute stroke care. Moreover, two more trials, THERAPY (The Randomized, Concurrent Controlled Trial to Assess the Penumbra System’s Safety and Effectiveness in the Treatment of Acute Stroke) and THRACE (Trial and Cost Effectiveness Evaluation of Intra-arterial Thrombectomy in Acute Ischemic Stroke), presented their preliminary data with similar results to the aforementioned five trials at the 2015 European Stroke Conference and will be published soon.

9.2 Indications and Considerations for Mechanical Thrombectomy

Following the lessons learned from the failure of three 2013 trials, finding good candidates for endovascular stroke therapy is very important relative to patients’ outcome. However, even in the five recent randomized controlled trials which showed the overwhelming efficacy of mechanical thrombectomy, there still existed some variation regarding the indication for recanalization procedures. They can be largely divided as clinical, radiologic, and anatomical indications. In this section, the five recent trials are revisited to find consistency and also to provide an acceptable standard of indication for mechanical thrombectomy that can be applied in real clinical practice for contemporary neurointerventional doctors.

9.2.1 Clinical Indications

9.2.1.1 Time Window

Regarding the time window from stroke onset to the initiation of endovascular recanalization therapy, there were some differences between the five major trials of 2015. MR CLEAN, EXTEND-IA, and SWIFT PRIME set the time window at 6 h from onset; on the other hand, ESCAPE had a 12-h and REVASCAT had an 8-h time window. However, those differences are less meaningful when it is considered that 84% of the patients in the ESCAPE trial had stroke onset within 6 h, and 90% of the patients in the REVASCAT trial had onset within 6 h, representing that the vast majority of patients had onset within this time window. Meanwhile, there are a few ongoing trials to extend this time window to 12 h (POSITIVE trial: PerfusiOn Imaging Selection of Ischemic STroke PatIents for EndoVascular ThErapy) and to 24 h (DAWN trial: DWI/PWI and CTP Assessment in the Triage of Wake-Up and Late Presenting Strokes Undergoing Neurointervention) through the use of more selective perfusion MR imaging protocols. Therefore, some degree of time window expansion is expected in the near future because of recent developments in stroke imaging and mechanical thrombectomy devices.

9.2.1.2 Age

Regarding age as an exclusion criterion for endovascular treatment, there has been some controversy of the upper limit, specifically for patients over the age of 80. Three of the trials had no upper age limit, though all trials had a lower age limit at 18. However, both the SWIFT PRIME trial and REVASCAT set the upper age limit at 80. It is difficult to assess the effect of setting the upper age limit on outcome. With respect to functional outcome defined as mRS 0–2 at 90 days, the differences are comparable [with age limit of 80: SWIFT PRIME (60%), REVASCAT (44%) vs. without age limit: MR CLEAN (33%), EXTEND-IA (71%), ESCAPE (53%)]. And with respect to mortality, the differences are not pronounced [with age limit of 80 SWIFT PRIME (9%), REVASCAT (18 ) vs. without age limit: MR CLEAN (21%), EXTEND-IA (9%), ESCAPE (10%)]. Further studies seem necessary to address the issue of upper age limits for endovascular treatment.

Other important practical issues related to elderly patients are long-term quality of life after endovascular recanalization therapy and procedural difficulties related with the patient’s tortuous anatomy. Patients over 80 have been shown to have a higher incidence of poor clinical outcome, even with a positive recanalization score [19]. It is also reported that patients over 80 have a higher mortality during hospitalization or immediately after release following endovascular treatment. These possibly are associated with a higher incidence of comorbid medical conditions of the elderly patients. In addition, during the mechanical thrombectomy procedure, gentle and safe advancement of the devices are strongly required for rapid and successful recanalization. Tortuous vascular anatomy and underlying atherosclerosis can potentially elevate the risk of the procedure, which can make difficulties involving advancement and stable positioning of the devices. Such vascular tortuosity and atherosclerosis are mainly caused by age and chronic hypertension. Therefore, in real practice for elderly patients, these considerations should be explained to the patient’s family during the process of consent and pre-procedural discussion.

9.2.1.3 National Institute of Health Stroke Scale (NIHSS) Score

The five trials of 2015 also showed some variation with respect to NIHSS cutoff. EXTEND-IA had no literal neurological cutoff, while SWIFT PRIME had the strictest cutoff (NIHSS≥8). MR CLEAN (NIHSS≥2), ESCAPE (NIHSS≥6), and REVASCAT (NIHSS≥6) had cutoffs between 0 and 8. On the basis of these studies, at least at the present, it may be acceptably determined that the majority of centers are using NIHSS≥6 or 8 as a cutoff value for enrolling mechanical thrombectomy for anterior circulation stroke.

9.2.2 Radiologic Considerations

Primary imaging modality used to assess stroke patients still varies from institution to institution. Each imaging modality has its strengths and weakness. The two major techniques used are MR and CT scan. Transcranial Doppler (TCD) ultrasound is offered at some institutions, usually as an adjunctive modality. MR with diffusion-weighted imaging (DWI) sequences is often regarded as the gold standard for acute stroke diagnosis and patient selection [20]. Perfusion-weighted imaging (PWI) represents brain regions with tissue at risk for neuronal death. Together, DWI and PWI are used to determine the penumbra, the area that endovascular treatment intends to preserve. Additional MR modalities include fluid-attenuated inversion recovery (FLAIR), MR angiography, and gradient recall echo (GRE). FLAIR can help demonstrate abnormal or retrograde flow, predict post-reperfusion hemorrhage, or determine the age of DWI positive infarcts [21]. Intracranial MR angiography can help demonstrate abnormal or retrograde flow surrounding a proximal occlusion. And GRE can help determine the location of a thrombus, along with preexisting hemorrhages that might serve as a contraindication of intravenous or intra-arterial thrombolytic infusion. Alternatively, CT angiography and perfusion data are sometime used in virtue of its fast imaging process. Disadvantages include that CT angiography and perfusion require a large amount of contrast, which carries additional risks. However, CT scan is useful in many contexts. For example, although it is not as precise as MR DWI and PWI penumbra mismatch identification, comparing mean transit time, cerebral blood flow, and cerebral blood volume can provide an estimate of the penumbra area [22]. CT scan may also provide information regarding the location of thrombus as well as the existing of preexisting hemorrhage. Nevertheless, MR is still considered as the gold standard in many contexts. TCD is rarely used as the primary imaging technique in an acute stroke setting, but it is sometimes useful as an adjunct. One positive benefit of TCD is that it offers real-time evaluation of recanalization, and due to the benefit, it becomes widely used for patient monitoring.

9.2.3 Anatomical Considerations

All trials included the intracranial carotid artery (ICA) and M1 segment of the middle cerebral artery (MCA). It is somewhat controversial whether or not to include the MCA M2 segment. While MR CLEAN, EXTEND-IA, and ESCAPE included MCA M2 segment in their study, SWIFT PRIME and REVASCAT did not. SWIFT PRIME had the strictest inclusion criteria across many categories among the five trials of 2015. In practice up to now, whether to recanalize an occlusion at the M2 segment strongly depends on the practitioner’s discretion on the basis of the patient’s neurologic and anatomic condition. In addition, although mechanical thrombectomy is an emerging therapeutic option for posterior circulation stroke, such as acute basilar artery (BA) occlusion, there have not been rigorously evaluated, randomized, and controlled trials regarding the efficacy of mechanical thrombectomy for stroke presented at that location. So far, most previous studies are limited as small case series or safety reports. Further studies seem necessary to address the issue of endovascular treatment for these variant of stroke.

Only gold members can continue reading. Log In or Register to continue