SWRCCC 2016;4(16);26-32
doi: 10.12746/swrccc2016.0416.216

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For the past two decades, intravenous tissue plasminogen activator (IV tPA) has been the gold standard treatment of acute ischemic stroke (AIS) for patients presenting to the hospital in the first 4.5 hours after symptom onset. However, in patients with AIS due to intracranial large vessel occlusion (LVO), IV tPA has very poor recanalization rates. This group of patients has significantly worse outcomes than those without LVO. Endovascular therapy has evolved significantly since the first trial in 1998. With the publication of recent trials using modern stent-retriever devices and selection of patients with LVO, endovascular therapy has become the standard of care for patients with the most severe ischemic strokes. In this article we outline the two decade evolution of this therapy.

First generation endovascular trials

In an attempt to increase recanalization rates in AIS patients, the first randomized controlled trial (RCT) using intra-arterial thrombolysis (pro-urokinase), Prolyse in Acute Cerebral Thromboembolism (PROACT), was completed in 1998.^{1 This study showed superiority in recanalization in acute LVO stroke compared with placebo but unfortunately also an increased risk of symptomatic hemorrhage. In spite of this initial result, pro-urokinase was taken off of the market.}

With the hope for better treatment options, additional trials of endovascular intervention were completed. The interventions included intra-arterial thrombolysis using alteplase tPA and the Merci thrombectomy device. In 2013, three studies were published, “IMS III, MR RESCUE, and SYNTHESIS Expansion”.^{2-4 These three multicenter, prospective RCTs showed no benefit in the intervention arm but also showed no additional risk of symptomatic bleeding after the intervention. Several concerns were raised regarding some aspects of these trials, including non-universal determination of LVO, use of first generation lower-efficacy devices such as the Merci device, the use of intra-arterial tPA without device in some trials (e.g., 66% of endovascular patients in the SYNTHESIS trial were treated with intra-arterial tPA alone), high utilization of intra-arterial tPA and heparin, and slow randomization to arterial puncture time (Table 1 and Table 2).}

Table 1 Strengths and weaknesses of first generation endovascular stroke RCTs

Strength	Weakness
Randomized evaluation	Non-universal determination of LVO
Allowed systems for endovascular clinical trials to be set up	Use of first generation lower-efficacy devices e.g. Merci
Established evidence base for IA tPA safety profile	IA tPA without device in some trials (e.g., 66% of endovascular patients)
	High utilization of IA tPA & Heparin
	Slow randomization to puncture time

LVO-Large vessel occlusion, IA- intra-arterial, tPA- tissue plasminogen activator

 

 

 

 

 

Table 2 First generation endovascular RCTs

Study	Window/Eligibility feature	LVO determination	Intervention	Comparison	Outcome	Result
PROACT 1999 1	< 6 hr	Yes	IA tPA	IV Heparin	mRS ≤ 2 at 90 days	n=180 40% vs 25% P=0.4 sICH 10% vs 2 % p=0.06
IMS III 2013 2	<3-4.5hrs But IAT in 6 hrs	Not universal	IV tPA + IAT (IA tPA, Merci)	IV tPA	mRS ≤ 2 at 90 days	n= 656 40.8% vs 38.7% CI, -6.1 to 9.1 sICH 6.2% vs 5.9%
MR RESCUE 2013 3	< 8 hr	Yes Anterior circulation	Merci/Penumbra	Standard care (IV tPA or aspirin)	Mean mRS at 90 days	n= 118 3.9 vs 3.9 Mortality 21%, sICH 4% both groups No interaction: treatment w penumbral pattern
SYNTHESIS 2013 4	<4.5hr but IAT in 6hr	No	IAT : (IA tPA full dose, Merci + Heparin 5000 IU bolus & 500iu/hr)	IV tPA	mRS ≤ 1 at 90 days	n=362 30.4% vs 34.8% sICH 6% vs 6%

Abbreviations: IAT, intra-arterial thrombolysis; LVO, large vessel occlusion; IA tPA, intra-arterial tissue plasminogen activator; IV tPA, intra-venous tissue plasminogen activator; mRS, modified ranking scale; sICH, symptomatic intracerebral hemorrhage

 

Some experts have criticized the use of SIRS criteria to identify patients with possible sepsis because these criteria focus on inflammatory markers and lack sensitivity and specificity. However, elements of SOFA (PaO₂/FiO₂

While these three trials were being conducted, two additional RCTs, SWIFT and TREVO, examined the efficacy and safety of second generation devices (stent retrievers) compared to first generation devices (Merci).^5,6 The studies demonstrated significantly better recanalization rates with the new devices without any excess in hemorrhagic complications (Table 3).

Table 3 First generation devices versus second generation devices RCTs

Study	Window/Eligibility feature	LVO determination	Intervention	Comparison	Outcome	Result
SWIFT 20125	8hrs NIHSS	Yes	Solitaire	Merci	TIMI scale ≥2	N=113 61% vs 24% OR 4·87 (14); p=0·0001
TREVO 2012 6	8hrs NIHSS 8-29	Yes	Trevo	Merci	TICI scale ≥2	N= 90 86% vs 60% OR 4·22, (12); p<0·0001

Abbreviations: NIHSS- National institute of health stroke scale; LVO- large vessel occlusion; TIMI- thrombolysis in myocardial infarction; TICI- thrombolysis in cerebral infarction

Guidelines, data synthesis and meta-analyses

Having learned the limitations in the initial studies and with cautious enthusiasm from the device vs. device trials, new endovascular stroke trials were designed and conducted. These second generation RCTs had universal determination of the presence of LVO prior to randomization. Several of the studies initiated optimized workflow protocols to achieve faster randomization to arterial puncture times, and all of the studies used second generation stent-retriever mechanical thrombectomy devices. The first of these, MR CLEAN, was published in late 2014.^{7 This study compared endovascular therapy to best medical treatment in stroke patients with LVO who presented within six hours of symptom onset. Following the presentation of this study at the 2014 World Stroke Congress, multiple endovascular trials were stopped by the respective data safety and monitoring boards due to efficacy of endovascular therapy on interim analysis. The four RCTs (ESCAPE, REVASCAT, EXTEND IA, and SWIFT PRIME) showed benefit of endovascular stroke therapy and were presented and published in 2015 (Table 4).8-11 These five studies benefited from the first generation trials by optimizing study design and conduct. However, there were still unanswered questions and limitations to these studies (Table 5).}

Table 4 Second generation endovascular RCTs

Study	Window Eligibility feature	LVO determination	Intervention	Comparison	Outcome	Result	NNTB
MR CLEAN 2014 7	≤6hr	Yes (ICA, MCA) CTA	Stent-retriever* +IV tPA	IV tPA	mRS at 90 days	n=500 32.6% vs 19.1% OR 1.67 CI 1.21 to 2.3 No difference sICH	7 for mRS 0-2 3.4 for mRS shift
ESCAPE 2015 8	≤12hr Multiphase CTA	Yes (ICA, MCA) CTA	Stent-retriever* +IV tPA	IV tPA	mRS at 90 days	n=316 53.0%, vs 29.3% OR 2.6; CI, 1.7 to 3.8; P<0.001 Death 10.4% vs 19% p=0.04 sICH 3.6 vs 2.7%	4 for mRS 0-2 3 for mRS shift
REVASCAT 2015 9	≤8hr IV tPA failure Or IV tPA contraindicated	Yes (ICA, MCA) CTA	Stent-retriever +/-IV tPA	IV tPA	mRS (shift analysis) at 90 days mRS (0-2) at 90 days	n=206 OR 1.7; CI 1.05-2.8 mRS 0-2: 43.7% vs 28.2% sICH 1.9% in both groups Death 18.4% vs 15.5%	7 for mRS 0-2
EXTEND IA 2015 10	≤4.5hr 6hr IAT CTP core <70ml	Yes (ICA, MCA) CTA	Solitaire +IV tPA	IV tPA	Reperfusion @24 & early neuro Improvement	n=70 Reperfusion: 100% vs 37% p<0.001 Early improve: 80% vs 37% mRS 71% vs 40% p=0.01 sICH & mortality no difference	NR
SWIFT PRIME 2015 11	≤4.5hr 6hr IAT CTP small core 50ml (71pts) ASPECTS ≥6 (125pts)	Yes (ICA, MCA) CTA	Solitaire +IV tPA	IV tPA	mRS 0-2 at 90 days	n=196 60% vs 35%, p<0.001 Mortality 9% vs 12% sICH 0% vs 3%	4 for mRS 0-2

 

*Allowed other devices  Abbreviations: CTA- computed tomography angiography; CTP-computed tomography perfusion; ASPECTs- Alberta Stroke Program Early CT Score; ICA- internal carotid artery; MCA- middle cerebral artery; IV tPA- intravenous tissue plasminogen activator; mRS- modified ranking scale; sICH- symptomatic intracerebral hemorrhage; NNTB- number needed to treat for benefit; NR- not reported

 

 

Table 5 Strengths and weaknesses of second generation endovascular stroke RCTs

Strength	Weakness
Established class 1 evidence for endovascular stroke intervention	Most patients treated within 8hrs of symptom onset (unclear if treatment beyond this is beneficial)
All primarily used stent-retrievers	Wake up strokes excluded in most studies
All confirmed presence of LVO	Posterior circulation strokes excluded
All treated patients quickly	Unclear if CTP is of added benefit within 6 hrs
Majority used CT/CTA based systems	Unclear if CTP is of added benefit after 6hrs
Established workable time targets

 

LVO- Large vessel occlusion, CT-computed tomography, CTA-computed tomography angiography, CTP- computed tomography perfusion imaging

 

 

Guidelines, data synthesis and meta-analyses

In the summer of 2015 the American Hearth Association/American Stroke Association guidelines were updated to reflect changes in the evidence base. The recommendations based on Class I evidence included administration of tPA in eligible patients even if endovascular therapy was considered and administration of endovascular therapy to adult patients with appropriate LVO ischemic stroke presenting within six hours of symptom onset who meet additional clinical and radiological criteria (stroke severity, CT ASPECT score ≥6). The recommendations emphasized the preference for second generation devices (stent-retrievers) over intra-arterial tPA. Also strongly recommended was the need for rapid evaluation of stroke patients with non-invasive imaging to determine presence of LVO stroke.

After the publication of the guidelines several attempts at data synthesis using traditional meta-analyses and individual patient data (IPD) meta-analysis were conducted. The traditional meta-analysis combined the results from first and second generation trials and demonstrated that the overall result still demonstrated superiority of endovascular therapy compared to best medical therapy in acute ischemic stroke.<sup>12 Subsequent to this the HERMES clinical trial collaboration pooled the results of the trials in an individual patient data (IPD) meta-analysis to address some of the subgroups who were under-represented in the individual trials (Table 5).13 The results confirmed the overall superiority of endovascular therapy. Also, the IPD meta-analysis demonstrated substantial efficacy of endovascular therapy within the late >5 hour window without an increase in symptomatic intracranial hemorrhage; most of the patients treated late were treated between 5-8 hours. Furthermore, patients who were ineligible for tPA also benefited from endovascular therapy compared with conservative management. Interestingly, the IPD meta-analysis confirmed initial observations from subgroup analysis of the individual trials in that the treatment effect was modified by age. Although the therapy was positive in all age groups, patients who were older than 80 years had an even higher benefit from endovascular therapy.

Last, it is important to note that the overall effect size of endovascular therapy is large. The number needed to treat for benefit (NNTB) for functional independence with endovascular therapy in AIS ranges from 4 in the ESCAPE and SWIFT PRIME trials to 7 in MR CLEAN and REVASCAT. When meaningful improvement in disability (modified Rankin scale shift) was used, the NNTB was 2.6 based on the HERMES meta-analysis. This contrasts with the previous standard of care, intravenous tPA vs. placebo, which had an NNTB to achieve normal functional status of 8-15 depending on the time to treatment delay. A recent study analyzing cost-effectiveness among second generation endovascular RCTs found that adding endovascular treatment to standard stroke therapy such as IV tPA is not only cost-effective but also cost saving.14

While stent retriever thrombectomy was the first endovascular technique to show efficacy in pivotal randomized controlled trials of large vessel occlusion stroke, other modern techniques have also been developed. Aspiration thrombectomy using large bore intracranial catheters either alone or in combination with stent retrievers and augmentation of stent retrievers with aspiration via balloon guided catheters have shown promising results in observational studies.15-16 The first randomized trial comparing some of these techniques with a novel stent retriever (Penumbra 3D Revascularization Device) has been completed with encouraging preliminary results, suggesting comparable efficacy of aspiration thrombectomy alone and stent retriever assisted thrombectomy.17 We await the final results and critical appraisal of this study and other ongoing studies that may inform device and technique selection for stroke thrombectomy. Expanding the armamentarium available to neurointerventionalists may increase recanalization rates and shorten arterial puncture to recanalization times. It is biologically plausible and consistent with available evidence that should these improvements be realized increased efficacy and safety of mechanical thrombectomy for large vessel occlusion stroke should be possible.</sup>

References

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Submitted: 07/11/2016
Accepted: 09/04/2016
Published electronically: 10/15/2016
Reviewer:Subasit Acharji MD
Conflict of Interest Disclosures: none

 

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