Endovascular Therapy

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 and/or removing the clot mechanically from the site of vessel occlusion.1

Recently, researchers have had a great deal of success in combining endovascular therapy with IV rt-PA use in the treatment of ischaemic stroke patients.1-6

In the past year, five clinical trials (MRCLEAN3, EXTEND-IA4, ESCAPE5, SWIFT-PRIME2, and REVASCAT6) have reported that endovascular treatment, when added to standard stroke care (usually involving IV rt-PA) shows increased favourable outcomes (mRS 0-2) in selected stroke patients with proximal arterial occlusions compared to standard care alone.

A shift in therapy

In a recent editorial in the New England Journal of Medicine7, Professor Anthony Furlan (Chairman of the Department of Neurology at the University Hospitals Case Medical Centre in Cleveland, Ohio, USA) attributes the newfound success of endovascular therapy in the treatment of stroke to three core elements:

  1. Advances in technology, specifically stent-retriever device technology;
  2. An increased awareness of the importance of time; and
  3. Improved neuroimaging criteria for patient selection

In the following section, you will find summaries of five recent clinical studies, which favour early endovascular therapy in addition to rt-PA in selected populations of stroke patients. You will also find that these studies do, in fact, incorporate the three aspects covered in the NEJM editorial.

Recent Clinical Trials

MR CLEAN (Multicenter Randomised CLinical trial of Endovascular treatment for Acute ischaemic stroke in the Netherlands)3

 

MR CLEAN (Multicenter Randomised CLinical trial of Endovascular treatment for Acute ischaemic stroke in the Netherlands)3

Objective:

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.

Results:

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).

Modified Rankin Scale Scores at 90 days in the intention-to-treat population

Figure 1: Modified Rankin Scale Scores at 90 days in the intention-to-treat population

Conclusion:

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.

EXTEND-IA (EXtending the Time for thrombolysis in Emergency Neurological Deficits – Intra-Arterial trial)4

Objective:

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.

Results:

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).

 

Modified Rankin Scale Scores at 90 days in the intention-to-treat population

Figure 2: Modified Rankin Scale Scores at 90 days in the intention-to-treat population

Conclusion:

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.

ESCAPE (Endovascular treatment for Small Core and Anterior circulation Proximal occlusion with Emphasis on minimising CT to recanalisation times)5

Objective:

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

Results:

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).

Modified Rankin Scale Scores at 90 days in the intention-to-treat population

Figure 3: Modified Rankin Scale Scores at 90 days in the intention-to-treat population

Conclusion:

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."

SWIFT-PRIME (Solitaire With the Intention For Thrombectomy as PRIMary Endovascular treatment)2

Objective:

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.

Results:

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).

 

Modified Rankin Scale Scores at 90 days in the intention-to-treat population

Figure 4: Modified Rankin Scale Scores at 90 days in the intention-to-treat population

Conclusion:

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.

REVASCAT (randomised 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 eight hours of symptom onset)6

Objective:

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.

Results:

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.

 

Modified Rankin Scale Scores at 90 days in the intention-to-treat population

Figure 5: Modified Rankin Scale Scores at 90 days in the intention-to-treat population

Conclusion:

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.

Overall conclusions

Results of 5 recent clinical trials 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. 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.

References 
  1. 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.
  2. Rijken DC and Sakharov DV. Basic Principles in Thrombolysis: Regulatory Role of Plasminogen. Thromb Res 2001;103:41-49.
  3. Wardlaw J, et al. Recombinant tissue plasminogen activator for acute ischaemic stroke: an updated systematic review and meta-analysis. Lancet 2012;379(9834):2364-2372.
  4. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med 1995;333(24):1581-1587.
  5. Abou-Chebl A. Review: Intra-arterial Therapy for Acute Ischemic Stroke. Neurotherapeutics 2011;8:400-413.
  6. Berkhemer O, et al. A Randomized Trial of Intraarterial Treatment for Acute Ischemic Stroke. N Engl J Med 2015;372:11-20.
  7. Campbell BCV, et al. Endovascular therapy for ischemic stroke with perfusion-imaging selection. N Engl J Med 2015;372:1009-1018.
  8. Goyal M, et al. Randomised assessment of rapid endovascular treatment of ischemic stroke. N Engl J Med 2015;372:1019-1030.
  9. Jovin TG, et al. Thrombectomy within 8 hours after symptom onset in ischemic stroke. N Engl J Med 2015;372:2296-2306.
  10. Furlan A. Endovascular therapy for stroke – it’s about time. N Engl J Med 2015;372:2347-2349.
  11. Casaubon LK, et al. Canadian Stroke Best Practice Recommendations: Hyperacute Stroke Care Guidelines, Update 2015. Int J Stroke 2015;10:924-940.
  12. 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. Stroke 2015;46:000-000. DOI: 10.1161/STR.0000000000000074.
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