Endovascular therapy

Endovascular therapy (EVT) is an intra-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 (intra-arterial thrombolysis) or removing the clot mechanically from the site of vessel occlusion (mechanical thrombectomy, MT), or both.1

A shift in therapy

The ESO-Karolinska group updated their consensus statement in 2016 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.2

Two of the ten recommendations pertain to EVT and IVT:2

  • 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).”

In 2019, the ESO-ESMINT (European Stroke Organisation – European Society for Minimally Invasive Neurological Therapy) issued guidelines to treat patients with ischaemic stroke caused by a large vessel occlusion (LVO) using mechanical thrombectomy (MT) in association with best medical management (BMM) including intravenous thrombolysis where indicated. This is applicable to acute ischaemic stroke patients presenting within 0-6 hours after symptom onset as well as to selected patients presenting at 6-24 hours since time last seen well:3

  • “In adults with anterior circulation LVO-related acute ischaemic stroke presenting within 6 hours after symptom onset, we recommend MT plus BMM, including IVT whenever indicated, over BMM alone to improve functional outcome.” (Quality of evidence, HIGH; strength of recommendation, STRONG)3
  • “In adults with anterior circulation LVO-related acute ischaemic stroke presenting between 6 and 24 hours from time last known well and fulfilling the selection criteria of DEFUSE-34 or DAWN5, we recommend MT plus BMM over BMM alone to improve functional outcome.” (Quality of evidence, MODERATE; strength of recommendation, STRONG)3
  • *DEFUSE-3: 6 to 16 hours since time last known well: Age ≤90 years and NIHSS ≥6: infarct core volume <70 ml and penumbra volume >15 ml and penumbra volume/core volume >1.8.
  • **DAWN: 6 to 24 hours since time last known well:
    Age <80 years: infarct core ≤30 ml if NIHSS ≥10; infarct core ≤51 ml if NIHSS ≥20.
    Age ≥80 years: infarct core ≤20 ml and NIHSS ≥10

In 2019, the American Heart Association/American Stroke Association (AHA/ASA) also updated their guidelines on endovascular therapy and rt-PA6

  • “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 guidelines)
  • “In patients under consideration for mechanical thrombectomy, observation after IV alteplase to assess for clinical response should not be performed. (Class III; Level of Evidence B-R).” (Unchanged from the 2015 guidelines)
  • NEW recommendation, 0-6 hours
    “Patients should receive mechanical thrombectomy with a stent retriever if they meet all the following criteria: (1) pre-stroke mRS score of 0 to 1; (2) causative occlusion of the internal carotid artery or MCA segment 1 (M1); (3) age ≥18 years; (4) NIHSS score of ≥6; (5) ASPECTS of ≥6; and (6) treatment can be initiated (groin puncture) within 6 hours of symptom onset (Class I, Level of Evidence A).”
  • NEW recommendation, 6-16 hours:
    “In selected patients with AIS within 6 to 16 hours of last known normal who have LVO in the anterior circulation and meet other DAWN or DEFUSE 3 eligibility criteria, mechanical thrombectomy is recommended (Class I, Level of Evidence A).”
  • NEW recommendation, 16-24 hours: “In selected patients with AIS within 16 to 24 hours of last known normal who have LVO in the anterior circulation and meet other DAWN eligibility criteria, mechanical thrombectomy is reasonable (Class I, Level of Evidence B-R).”

The importance of time: Endovascular therapy

Saver et al.7 analysed the data from five clinical trials1,8–11 using the latest stent-retriever devices to find whether there is a relationship between time to treatment and patient outcome measures.

The results show no statistical difference in improved disability outcome between EVT combined 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 increased with each hour of treatment delay, although no difference was seen in mortality with respect to time (see Table 1).7

As with thrombolysis alone, patients benefit from timely EVT 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

Table

Recent clinical trials and registries

Recent guideline recommendations favour early EVT in addition to intravenous thrombolysis (IVT) with rt-PA in select populations of stroke patients.2,3,6 Five clinical trials (MRCLEAN8, EXTEND-IA9, ESCAPE10, SWIFT-PRIME1, and REVASCAT11) form the basis for the guideline recommendations, as they reported EVT added to standard acute ischaemic stroke care (usually involving intravenous 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.1,8–11

More recent clinical studies, such as the THRACE study12, were able to increase the benefit of EVT using improved image-based patient selection, more modern stent-retriever devices, and the increased awareness of the importance of time13, and the PISTE study14 demonstrated that rapid implementation of mechanical thrombectomy following intravenous thrombolysis improves functional outcome.

MR CLEAN (Multicenter Randomised Clinical trial of Endovascular treatment for Acute ischaemic stroke in the Netherlands)8

Objective

To assess the effect of intra-arterial treatment (arterial catheterisation with a microcatheter (MERCI stent retriever) to the level of occlusion plus delivery of a thrombolytic agent, mechanical thrombectomy, or both) within 6 hours of symptom onset against ‘usual care alone’ (usually involving IV rt-PA).

Results

500 patients were included: 233 were assigned to the intra-arterial group and 267 to usual care alone. 89% of patients received IV rt-PA prior to randomisation.

The odds ratio for achieving the primary outcome of a lower mRS (shift analysis) at 90 days was 1.67 (95% confidence interval, 1.21 – 2.30) in favour of IVT+EVT.

32.6% of intra-arterial treated patients had a good functional independence (mRS 0-2), compared to 19.1% for ‘usual care alone’: an absolute difference of 13.5%.

The safety endpoints of mortality, symptomatic intracerebral haemorrhage and serious adverse events, did not significantly differ between the groups.

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

mRS: Mr. Clean

Conclusion

The vast majority (approximately 90%) of patients included in the MR CLEAN study also received rt-PA. The study shows 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)9

Objective

To assess the effectiveness (improved reperfusion and early neurologic improvement) of early EVT (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 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 and 35 to the rt-PA plus EVT.

This trial was halted because of significant benefit in the EVT arm.

EVT 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).

EVT 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 EVT (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

mRS EXTEND IA

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 EVT after treatment with IV rt-PA.

ESCAPE (Endovascular treatment for Small Core and Anterior circulation Proximal occlusion with Emphasis on minimising CT to recanalization times)10

Objective

To assess the efficacy of rapid EVT using contemporary endovascular techniques* plus guideline-based care (IV rt-PA within 4.5 hours of symptom onset) in acute ischaemic stroke, 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, one patient did not provide proper consent. 120 patients in the intervention group received rt-PA.

Overall results were favourable for combined EVT plus guideline-based care compared to guideline-based care alone. For example, the proportion of patients with a mRS 0-2 at day 90 was 53.0% vs 29.3% for the intervention and control groups, respectively (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. ESCAPE: mRS at 90 days in the intention-to-treat population

mRS ESCAPE

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) 1

Objective

To assess the efficacy and safety of rapid EVT (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).

Figure 4. mRS at 90 days in the intention-to-treat population

mRS: SWIFT PRIME

Conclusion

Treatment with a stent retriever after intravenous rt-PA resulted in significantly improved functional outcomes at 90 days, confirming 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)11

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

The study included 206 patients (103 in each study arm). Efficacy outcomes significantly favoured thrombectomy plus medical therapy over medical therapy alone, including mRS at 90 days, the proportion of patients with a mRS <2 (43.7% vs. 28.1%), and an improvement in neurologic function at 24 h.

Safety was comparable between the two treatment arms.

Figure 5. Modified Rankin Scale Scores (mRS) at 90 days in the intention-to-treat population

mRS: REVASCAT

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.

THRACE (THRombectomie des Artères CErebrales) trial12

Objective

To compare intravenous thrombolysis alone (IVT) vs. intravenous thrombolysis plus mechanical thrombectomy (IVT+MT) with the latest devices on the effect on 3-month functional independence outcomes in patients with moderate-to-severe stroke (confirmed on CT or MRI) treated within 4 hours of symptom onset (thrombolysis) or 5 hours (thrombectomy).

Results

Analyses are based on data from 402 patients total, (IVT=202 and IVT+MT=200).

IVT+MT showed significant benefits over IVT alone for functional independence (mRS 0-2) (OR: 1.55, 95% CI: 1.05-2.30; p=0.028); mean NIHSS score (mean NIHSS 4 points lower for IVTMT vs. IVT at discharge/day 7; p=0.001); and Barthel index at 3 months (OR: 1.59, 95% CI: 1.02-2.49; p=0.04).

There were no significant differences in mortality at 3 months, or in symptomatic or asymptomatic haemorrhage at 24 hours.

Discussion and conclusions

The design of the THRACE study is very similar to that of the IMS III trial15, 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.

PISTE (Pragmatic Ischaemic Stroke Thrombectomy Evaluation) trial14

Objective

To compare 90-day independence outcomes (mRS 0-2) following intravenous thrombolysis alone (IVT) vs. intravenous thrombolysis plus mechanical thrombectomy (IVT+MT) in patients with large artery occlusion causing an anterior circulation ischaemic stroke, defined on CT. In the IVT+MT group, MT was initiated as soon as possible and within 90 minutes after IVT administration was started.

Results

65 patients from 10 UK centres were randomised to IVT (n=32) or IVT+MT (n=33). Although patients in the IVT+MT group had more severe strokes, increased vascular risk, higher pre-stroke functional impairment (mRS), they also had more favourable ASPECT and collateral scores, and there was a higher number of female patients.

There was no significant difference in the primary outcome in the intention-to-treat analysis between the two treatment groups (absolute difference 11%, adjusted OR 2.12, 95% CI 0.65 to 6.94, p=0.20). A significant benefit was shown for full neurological recovery (mRS 0-1) with IVT+MT at 90 days (OR 7.6, 95% CI 1.6 to 37.2, p=0.010).

The per-protocol population (n=58) demonstrated significant benefits of IVT+MT for both the primary and most secondary endpoints (22% absolute difference in mRS 0-2; adjusted OR 4.9, 95% CI 1.2 to 19.7, p=0.021).

There were no significant differences between the groups in the ITT or PP populations for any of the safety outcomes, including SICH or death.

Table 2: Primary and secondary outcomes in the ITT and PP population

Table

Discussion and conclusions

In contrast to other studies, which first assessed the outcome of IVT before progressing to MT, the PISTE study focussed on rapid initiation of MT after IVT.

This study confirms the efficacy and safety of IVT+MT in patients with a large anterior ischaemic stroke and emphasises the benefit of keeping the time delay between IVT and MT to a minimum, in order to achieve improved functional outcome.

Further support for the use of combined IVT+EVT is provided by data from registries, which have demonstrated improved clinical outcomes of patients treated with IVT followed by MT versus primary MT alone.16-18

These data indicate that combined IVT and MT could be associated with lower probability of death or severe dependency after three months from stroke due to large vessel occlusion, supporting the current guidelines of treating eligible patients with IVT before MT. 16-18

Italian Registry:Combined IVT and EVT versus primary mechanical thrombectomy16

Objectives

Comparison of combined IVT + EVT with primary mechanical thrombectomy (MT) in patients in the Italian Registry of Endovascular Stroke Treatments with AIS due to proximal intracranial artery occlusion, who were eligible for IVT according to current guidelines.

Results

A shift in the 90-day mRS distributions toward a better outcome was found in favour of the combined treatment. Subjects who underwent combined treatment had higher probability of survival (with mRS 0–3) and lower case fatality rate. Haemorrhagic transformation did not differ between the two groups.

Conclusion

Combined IVT + EVT is associated with lower probability of death or severe dependency after three months from stroke due to large vessel occlusion.

MR CLEAN Registry: Endovascular Treatment With or Without Prior Intravenous Alteplase for Acute Ischaemic Stroke17

Objectives

The aim of the study was to compare clinical and procedural outcomes, safety, and workflow between acute ischaemic stroke patients with a large vessel occlusion treated with IVT prior to EVT to those treated with EVT alone using data of the MR CLEAN (Multicenter Randomised Controlled Trial of Endovascular Treatment for Acute Ischaemic Stroke in the Netherlands) Registry.

Results

Out of 1,485 patients included in the study, 1,161 (78%) were treated with IVT+EVT and 324 (22%) with EVT alone. The patients in the combined approach arm were younger (70 vs. 72 years), had less severe deficits (NIHSS) on presentation, a lower rate of atrial fibrillation (16% versus 44%) and fewer previous strokes than those treated with EVT alone, as well as better pre-stroke mRS.

At 90 days, mRS was better in the IVT+EVT group vs. EVT alone, with 41% vs 29% of patients, respectively, reaching functional independence. Mortality was also improved in the IVT + EVT group vs EVT. Overall, procedure time was shorter in the IVT+EVT group, although non-transferred IVT+EVT patients had longer door-to-groin-puncture times compared to EVT. Successful reperfusion, first-pass effect, and symptomatic intracranial haemorrhage did not differ between groups.

Conclusion

In this observational study, patients treated with IVT+EVT demonstrated better clinical outcomes than patients who received EVT alone.

NASA Registry: 'Real world' applicability of endovascular therapy18

Objective

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.

Results

Using the same inclusion criteria as the IMS-III study15 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.18

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 stroke 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.18

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.18

Conclusion

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.18

Meta-analyses

Subsequent meta-analyses of 8 clinical trials confirmed the results of the recent individual studies.2,19,20 Steiner et al.2 and Sardar et al.19 also analysed the pooled data by study date (2015 trials vs. the 3 earlier trials) and found even stronger support for endovascular therapy (EVT) in combination with intravenous thrombolysis (IVT).2,19 A further meta-analysis that pooled results from 5 of the clinical trials reports similar results.21

The following tables provide the odds ratios and 95% confidence intervals by outcome measure (endovascular vs. standard treatment and/or IV thrombolysis alone).

Table 2. Mortality (90 days)

Mortality (90 days)

Table 3. mRS 0-2 (90 days)

mRS 0-2 (90 days)

Table 4. Symptomatic ICH

Symptomatic ICH

All of the above meta-analyses show a significant increase in the rate of independence at 90 days (measured by mRS scores 0-2) with EVT 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.

Similarly, a large meta-analysis by Katsanos et al. investigated the use of bridging therapy (BT; IVT followed by MT), and found it to be associated with improved functional independence (without evidence for safety concerns) as compared to direct MT, for AIS patients with LVO.22

Bridging therapy: IV Thrombolysis prior to Mechanical Thrombectomy in Large Vessel Occlusions22

Objectives

This systematic review and meta-analysis included observational studies and post-hoc analyses from RCTs that provided data on the outcomes of patients with acute ischaemic stroke (AIS) due to large vessel occlusions (LVO), stratified by the intravenous thrombolysis (IVT) treatment status prior to mechanical thrombectomy (MT), and aimed to investigate the comparative safety and efficacy of bridging therapy (BT), consisting of IVT followed by mechanical thrombectomy (MT) and direct mechanical thrombectomy (dMT).

Results

38 studies were included in the meta-analysis. In unadjusted analyses, BT was associated with a higher likelihood of 90-day functional independence (mRS 0-2 at 90 days or discharge), functional improvement, successful recanalisation, and successful recanalisation with less than two device passes compared to dMT. BT was also related to a lower risk of mortality at 90-days or discharge.

Adjusted analyses at 90 days showed BT was independently associated with higher incidence of functional independence and a lower mortality compared to dMT. The two groups did not differ in functional improvement or symptomatic ICH.

Conclusions

Bridging therapy, using IVT prior to MT, appears to be associated with improved functional independence and lower risk of mortality without an increased risk of safety concerns, compared to dMT, for AIS patients with LVO.

Overall conclusions

Results of 5 clinical trials1,8–11 demonstrated that the combination of guideline-based care (intravenous rt-PA within 4.5 hours of onset of stroke symptoms in eligible patients) plus endovascular therapy (EVT) can be highly beneficial, compared to standard stroke care alone. These studies are the basis of the ESO-Karolinska consensus statement2 as well as the updated ESO-ESMINT3 and the AHA/ASA.6

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 EVT. Further studies are needed to clarify, how far the time window for EVT (and other stroke subpopulations) can be extended based on imaging selection criteria.

References 
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