Endovascular therapy is an inter-arterial method that uses catheter-guided devices to assist restoration of blood flow in an occluded vessel. This is accomplished either by providing a thrombolytic agent directly to the clot or removing the clot mechanically from the site of vessel occlusion, or both.1
Recently, researchers have had a great deal of success in combining endovascular therapy with IV rt-PA in the treatment of ischaemic stroke patients.1-6 In 2015, five clinical trials (MRCLEAN3, EXTEND-IA4, ESCAPE5, SWIFT-PRIME1, and REVASCAT6) reported endovascular treatment, when added to standard stroke care (usually involving IV rt-PA) is associated with an increase in favourable outcomes (mRS 0-2) in selected stroke patients with proximal arterial occlusions compared to standard care alone. The favourable results from the recent clinical trials compared to past trials could be due to improved image-based patient selection7-9, the use of more modern stent-retriever devices7-9 and the increased awareness of the importance of time9.
Subsequent meta-analyses of 8 clinical trials (the 5 mentioned above and 3 earlier trials) confirmed the results of the recent individual studies.7,10,11 Steiner et al.11 and Sardar et al.7 also analysed the pooled data by study date (2015 trials vs. the 3 earlier trials) and found even stronger support for endovascular therapy in combination with intravenous thrombolysis.7,11 A further meta-analysis12 pooled the results from only the 5 more recent clinical trials and reports similar figures to the stratified results presented by Steiner et al.11 and Sardar et al.7
A shift in therapy
The ESO-Karolinska group updated their consensus statement on mechanical thrombectomy in acute ischaemic stroke and published 10 new or updated recommendations on the use of endovascular therapy in patients with acute ischaemic stroke.11
Two of the ten recommendations pertain to endovascular therapy and intravenous thrombolysis11:
- New: “Mechanical thrombectomy, in addition to intravenous thrombolysis within 4.5 h when eligible, is recommended to treat acute stroke patients with large artery occlusions in the anterior circulation up to 6 h after symptom onset (Grade A, Level 1a, KSU Grade A).”
- Changed: “Mechanical thrombectomy should not prevent the initiation of intravenous thrombolysis where this is indicated, and intravenous thrombolysis should not delay mechanical thrombectomy (Grade A, Level 1a, KSU Grade A).”
After the publication of the ESO-Karolinska consensus statement, the EROICAS (European Recommendations on Organisation of Interventional Care in Acute Stroke) released the collaborative recommendations from six predominate European stroke and neurological societies*.13 The recommendations cover a range of topics from “centre and operator requirements for thrombectomy” and the “candidates for thrombectomy” to “preclinical and clinical requirements in organisation before thrombectomy”, “methods for interventional treatment” and “patient care after thrombectomy”.
*European Academy of Neurology (EAN), European Association of Neurosurgical Societies (EANS), European Society of Emergency Medicine (EuSEM), European Society of Minimally Invasive Neurological Therapy (ESMINT), European Society of Neuroradiology (ESNR), European Stroke Organisation (ESO)
In light of the newly published data1,3-6, the American Heart Association/American Stroke Association (AHA/ASA) also updated their guidelines on endovascular therapy and rt-PA:14
- “Patients eligible for intravenous rt-PA should receive intravenous rt-PA even if endovascular treatments are being considered (Class I; Level of Evidence A). (Unchanged from the 2013 guideline)”, and
- “Observing patients after intravenous rt-PA to assess for clinical response before pursuing endovascular therapy is not required to achieve beneficial outcomes and is not recommended. (Class III; Level of Evidence B-R). (New recommendation)”.
Furthermore, the AHA/ASA14 provides a list of criteria for the use of endovascular therapy:
- Prestroke mRS score 0 to 1
- Acute ischaemic stroke receiving intravenous rt-PA within 4.5 hours of onset according to guidelines from professional medical societies,
- Causative occlusion of the internal carotid artery or proximal MCA (M1),
- Age ≥18 years,
- NIHSS score of ≥6,
- ASPECTS of ≥6, and
- Treatment can be initiated (groin puncture) within 6 hours of symptom onset
New recommendation: If the patient meets all of the criteria, endovascular therapy with a stent retriever is recommended (Class I; Level of Evidence A).14
The importance of time: Endovascular therapy
Saver et al.15 analysed the data from the five recent clinical trials1,3-6 using the latest stent-retriever devices to find whether there is a relationship between time to treatment and patient outcome measures.
The results show there is no statistical difference in improved disability outcome between endovascular therapy with thrombolysis versus thrombolysis alone if the delay from symptom onset to treatment is 7 hours and 18 minutes (438 minutes) or longer. Degree of disability and functional independence were affected by each hour of treatment delay, although no difference was seen in mortality with respect to time (see Table 1).
As with treatment with thrombolysis alone, patients benefit from timely endovascular intervention and therapy should begin as soon as possible after symptom onset.
Table 1. Absolute risk difference in patient outcomes for each 1-hour delay to reperfusion
Recent clinical trials & meta-analyses
The five clinical trials published in 20151,3-6 – which serve as a basis for the ESO-Karolinska consensus statement on mechanical thrombectomy in acute ischaemic stroke11, and the EROICAS recommendations13 and the AHA/ASA guideline update14 – favour early endovascular therapy in addition to rt-PA in select populations of stroke patients. The recent clinical studies and subsequent meta-analyses are summarised here.
Four independent meta-analyses7,10-12 were conducted analysing randomised clinical trials that compared manual thrombectomy vs. standard treatment with or without intravenous thrombolysis. As mentioned above, three of the analyses identified and included the same eight clinical trials7,10,11, and all four of the meta-analyses included the five most recent trials on mechanical thrombectomy. The analyses show similar results for the reported outcome measures.
The following tables provides the odds ratios and 95% confidence intervals by outcome measure (endovascular vs. standard treatment and/or intravenous thrombolysis alone). All of the meta-analyses show a significant increase in the rate of independence at 90 days (measured by mRS scores 0-2) with endovascular therapy over standard care. There were no significant differences in mortality at 90 days and in the risk of symptomatic intracranial haemorrhage (ICH) in any of the analyses.
Table 2. Mortality (90 days)
Table 3. mRS 0-2 (90 days)
Table 4. Symptomatic ICH
Patient data from the North American Solitaire Acute Stroke (NASA) registry was used to investigate whether the results from recent thrombectomy trials are applicable and generalisable in a real-world setting.16
Using the same inclusion criteria as the IMS-III study17 and only including data from patients treated with a newer generation stent-retriever device (Solitaire FR™) between March 2012 and February 2013, a NASA-IMS-III-Like group (NILG) was formed and compared to the baseline characteristics and the results of the IMS-III study as well as to the control arms of the MR CLEAN, ESCAPE, SWIFT Prime and REVASCAT trials.16
Data from 136 patients met the inclusion criteria for the NILG. Overall, there were no major differences in the patient’s baseline characteristics as far as age, sex, and comorbidities are concerned, with the exception of higher rates of atrial fibrillation, diabetes and hypertension in the NILG than in some of the clinical trial patient populations. There were some notable differences in baseline characteristics regarding clinical aspects. For example, the mean time from stoke onset to groin puncture was significantly higher in the NILG compared to the IMS-III intervention group. Furthermore, the presence and severity of intracranial occlusions was significantly different among the study groups.16
The clinical and imaging outcomes of the patients within NILG were significantly better than those of the intervention and control arms in the IMS-III study, and the control arms of the MR CLEAN, ESCAPE, SWIFT Prime, and REVASCAT trials.16
The findings support the applicability of recent thrombectomy trials in a ‘real-world’ setting, despite a greater baseline stroke severity, longer delays to treatment from symptom onset and a more proximal location of arterial occlusions in the NILG compared to the patient data from other trials.16
To compare intravenous thrombolysis alone (IVT) vs. intravenous thrombolysis plus mechanical thrombectomy (IVTMT) with the latest devices on the effect on 3-month functional independence outcomes in patients with moderate-to-severe stroke treated within 4 hours of symptom onset.
Patients were assessed for eligibility from June 2010 to February 2015. Patients were randomised to either the IVT group or the IVTMT group. Analyses are based on data from 402 patients total, (IVT=202 and IVTMT=200). The baseline characteristics and time to initiation of intravenous thrombolysis were similar for both groups.
Functional independence (defined as a modified Rankin score 0-2) significantly favoured IVTMT vs. IVT alone (OR: 1.55, 95% CI: 1.05-2.30; p=0.028). The mean NIHSS score significantly favoured IVTMT over IVT, with the mean score being 4 points lower for IVTMT vs. IVT at discharge/day 7 (p=0.001). The Barthel index at 3 months also significantly favoured the use of both intravenous thrombolysis and mechanical thrombectomy (OR: 1.59, 95% CI: 1.02-2.49; p=0.04). There were no significant differences in mortality at 3 months, nor were there any significant differences in symptomatic or asymptomatic haemorrhages at 24 hours.
Discussion and conclusions
The design of the THRACE study is very similar to that of the IMS III trial17, which did not show a benefit of mechanical thrombectomy following thrombolysis. The difference in the study outcomes is attributed to the imaging (CT or MRI) of all patients in the THRACE study to confirm and locate the arterial occlusion. Moreover, THRACE was conducted using the latest in stent retriever and aspiration devices.
The results from the THRACE study confirm the results of other recent studies on mechanical thrombectomy with standard intravenous thrombolysis, namely that the combination of the two treatments is associated with a significantly higher rate of functional independence at 3 months and does not increase mortality versus thrombolysis alone.
To assess intra-arterial treatment (defined as “arterial catheterisation with a microcatheter (MERCI stent retriever) to the level of occlusion and delivery of a thrombolytic agent, mechanical thrombectomy, or both”) against ‘usual care alone’ (which usually includes IV rt-PA, in 89% of patients in this study) following ischaemic stroke caused by an intracranial arterial occlusion within 6 hours after the onset of symptoms.
500 patients evaluated: 233 were assigned to the intra-arterial group and 267 to the ‘usual care alone’ group. 32.6% of intra-arterial treated patients had a good outcome on the modified Rankin scale (0-2), while only 19.1% for the ‘usual care alone’, for an absolute difference of 13.5%. This can be translated to an adjusted odds ratio of 2.16 (95% CI: 1.39 to 3.38).
Figure 1. Modified Rankin Scale Scores at 90 days in the intention-to-treat population
The vast majority (approximately 90%) of patients included in the MR CLEAN study also received rt-PA. The study showed intra-arterial treatment provided within 6h of symptom onset of ischaemic stroke to be safe and effective.
To assess the effectiveness (improved reperfusion and early neurologic improvement) of early endovascular thrombectomy (with the Solitaire Flow Restoration stent retriever) after IV rt-PA vs IV rt-PA alone in anterior circulation ischaemic stroke patients who are selected by a dual target of vessel occlusion and have evidence of salvageable tissue on perfusion imaging within 4.5 hours of symptom onset.
70 patients were randomised: 35 to the rt-PA-only group and 35 to the rt-PA plus endovascular therapy group. This trial was halted because of significant benefit in the endovascular therapy arm. Endovascular therapy in conjunction with rt-PA was associated with significantly greater reperfusion rates than rt-PA therapy alone (>90% reperfusion compared to 40% in the rt-PA group). Endovascular therapy plus rt-PA was also associated with a significantly greater early neurologic recovery at 3 days and a significant improvement in functional outcome, as measured by the modified Rankin scale at 90 days, over thrombolysis alone. Mortality (mRS=6) was lower with rt-PA plus endovascular therapy (n=3) vs. rt-PA alone (n=7) (p=0.18).
Figure 2. Modified Rankin Scale Scores at 90 days in the intention-to-treat population
Based on very strict patient selection criteria via imaging techniques, the investigators found ischaemic stroke patients with proximal cerebral arterial occlusion and salvageable tissue benefited significantly from early endovascular therapy after treatment with IV rt-PA.
To assess the efficacy of rapid endovascular treatment using contemporary endovascular techniques* plus guideline-based care (IV rt-PA within 4.5 hours of symptom onset) in acute ischaemic stroke patients selected via CT and CT angiography compared to guideline-based care alone.
* Retrievable stents or balloon catheters for suction clot removal
316 patients were randomised: 165 to the intervention group, and 150 to the control group, 1 patient did not provide proper consent. 120 patients in the intervention group received rt-PA.
Overall results were favourable for combined endovascular intervention treatment plus guideline-based care compared to guideline-based care alone. For example, the proportion of patients with a modified Rankin score of 0-2 at day 90 was 53.0% vs 29.3% for the intervention and control groups respectively (the adjusted rate ratio, 1.7 (95% CI: 1.3-2.2)). Mortality (mRS=6) was significantly reduced with combined treatment vs. guideline-based care alone (10.4% vs. 19%; p=0.04).
Figure 3. Modified Rankin Scale Scores at 90 days in the intention-to-treat population
Overall, the key to successful treatment in the ESCAPE trial was the effective and efficient use of time. For example, patients in the intervention group underwent groin puncture whilst rt-PA was being infused. The primary emphasis was to achieve early reperfusion.
The investigators conclude, “The trial confirms the benefit of endovascular treatment reported recently in the MR CLEAN trial.”
To assess the efficacy and safety of rapid endovascular therapy (namely, neurovascular thrombectomy) in combination with IV rt-PA vs IV rt-PA alone in ischaemic stroke patients with an imaging-confirmed occlusion of the intracranial internal carotid artery, the first segment of the middle cerebral artery or both and the absence of large ischaemic-core lesions.
196 patients were randomised: 98 in the stent retriever plus rt-PA group and 98 in the rt-PA alone group.
The proportion of patients who were able to function independently (modified Rankin score <2) at day 90 was greater in the thrombectomy plus rt-PA group than the rt-PA alone group (60% vs. 35%).
The proportion of patients with successful reperfusion at 27 hours was also higher in the thrombectomy plus thrombolysis group (83%) than the thrombolysis alone group (40%), (RR: 2.05; 95% CI: 1.45-2.91).
Figure 4. Modified Rankin Scale Scores at 90 days in the intention-to-treat population
Treatment with a stent retriever after intravenous rt-PA resulted in significantly improved functional outcomes at 90 days.
The investigators state the findings of this study confirm the results of other recent trials.
To assess the efficacy and safety of neurovascular thrombectomy (using the Solitaire stent retriever) in addition to medical therapy (which may entail rt-PA) vs medical therapy alone in the treatment of eligible stroke cases within 8 hours of symptom onset.
206 patients were randomised: 103 in each study arm.
The efficacy outcomes significantly favoured the thrombectomy plus medical therapy arm over the medical therapy only arm, including modified Rankin scale score at 90 days, the proportion of patients with a modified Rankin score <2 (43.7% vs. 28.1%), and an improvement in neurologic function at 24 h.
Regarding safety, the results between the two treatment arms were similar.
Figure 5. Modified Rankin Scale Scores at 90 days in the intention-to-treat population
The results of this study support the use of neurovascular thrombectomy in conjunction with medical therapy in patients with an image-confirmed anterior circulation stroke treated within 8 hours of symptom onset. More than two thirds of the patients in the thrombectomy group received rt-PA as standard medical therapy.
Results of 5 recent clinical trials1,3-6 demonstrated that combination of guideline-based care (including rt-PA within 4.5 hours of onset of stroke symptoms in eligible patients) plus endovascular therapy can be highly beneficial, as compared with standard stroke care alone. Based on the results from the recent clinical trials, the ESO-Karolinska issued a consensus statement11 with new and updated recommendations on the use of mechanical thrombectomy in certain acute ischaemic stroke patients, as did EROICAS13 and the AHA/ASA14.
Recent improvements, both in stent retriever devices and imaging criteria, significantly contributed to this success. However, only a small proportion of carefully selected ischaemic stroke patients, those with large proximal arterial occlusions, may benefit from endovascular treatment. Further studies are needed to clarify, how far the time window for endovascular treatment (and other stroke subpopulations) can be extended based on imaging selection criteria.
- Saver J, et al. Stent-Retriever Thrombectomy after Intravenous t-PA vs. t-PA Alone in Stroke. N Engl J Med 2015;372:1-11. (SWIFT-PRIME)
- Abou-Chebl A. Review: Intra-arterial Therapy for Acute Ischemic Stroke. Neurotherapeutics 2011;8:400-413.
- Berkhemer O, et al. A Randomized Trial of Intraarterial Treatment for Acute Ischemic Stroke. N Engl J Med 2015;372:11-20. (MR CLEAN)
- Campbell BCV, et al. Endovascular therapy for ischemic stroke with perfusion-imaging selection. N Engl J Med 2015;372:1009-1018. (EXTEND-IA)
- Goyal M, et al. Randomised assessment of rapid endovascular treatment of ischemic stroke. N Engl J Med 2015;372:1019-1030. (ESCAPE)
- Jovin TG, et al. Thrombectomy within 8 hours after symptom onset in ischemic stroke. N Engl J Med 2015;372:2296-2306. (REVASCAT)
- Sardar P, et al. Endovascular therapy for acute ischaemic stroke: a systematic review and meta-analysis of randomized trials. Eur Heart J 2015;36(35):2373-2380.
- Bracard S, et al. Mechanical thrombectomy after intravenous alteplase versus alteplase alone after stroke (THRACE): a randomised controlled trial. Lancet Neurol 2016;15(11):1138-1147.
- Furlan A. Endovascular therapy for stroke – it’s about time. N Engl J Med 2015;372:2347-2349.
- Badhiwala JH, et al. Endovascular Thrombectomy for Acute Ischemic Stroke: A Meta-analysis. JAMA 2015;314:1832-1843.
- Wahlgren N, et al. Mechanical thrombectomy in acute ischemic stroke: Consensus statement by ESO-Karolinka Stroke Update 2014/2015, supported by ESO, ESMINT, ESNR and EAN. Int J Stroke 2016;11(1):134-147.
- Goyal M, et al. Endovascular thrombectomy after large-vessel ischaemic stroke: a meta-analysis of individual patient data from five randomised trials. Lancet 2016;387:1723-1731.
- Fiehler J, et al. European Recommendations on Organisation of Interventional Care in Acute Stroke (EROICAS). Int J Stroke 2016;11(6):701-706.
- Powers WJ, et al. 2015 AHA/ASA Focused Update of the 2013 Guidelines for the Early Management of Patients With Acute Ischemic Stroke Regarding Endovascular Treatment: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke 2015. DOI: 10.1161/STR.0000000000000074.
- Saver JL, et al. Time to treatment with endovascular thrombectomy and outcomes from ischemic stroke: a meta-analysis. JAMA 2016;316(12):1279-1289.
- Nogueira RG, et al. Rescue thrombectomy in large vessel occlusion strokes leads to better outcomes than intravenous thrombolysis alone: a ‘real world’ applicability of the recent trials. Intervent Neurol 2016;5:101-110.
- Broderick JP, et al. Endovascular Therapy after Intravenous t-PA versus t-PA Alone for Stroke. N Engl J Med 2013;368:893-903.