Timely administration (<4.5 hours) of intravenous recombinant tissue plasminogen activator (IV rt-PA or tPA) improves outcomes in acute ischemic stroke.1,2 However, IV tPA is associated with early recanalization in only 21% of cases,3 with worse rates in distal internal carotid and basilar artery occlusions, and frequent re-occlusions after IV tPA in 12%.4 Furthermore, the narrow time window and strict exclusion criteria limits the opportunity for IV thrombolysis, with a significant proportion of patients found to breach criteria in a recent randomized control trial.2,5

Despite the perceived intuitive benefit of endovascular therapy of improved revascularisation and improved outcomes, three major initial randomized control trials- IMS III,6 MR RESCUE7 and SYNTHESIS8 could not demonstrate this. However, the negative findings from these studies must be interpreted in the context of several limitations. These include the use of first generation thrombectomy devices and intra-arterial thrombolytic agents to achieve recanalization,9,10 suboptimal patient selection due to the lack of sophisticated imaging techniques employed, and lengthy delays to initiation of treatment (mean time to groin puncture 208 minutes in IMS III and 381 minutes in MR RESCUE).6,7

The development of newer mechanical thrombectomy devices have resulted in superior recanalization in stroke therapy.9,10 In particular, stent retreivers such as Solitiare, TREVO and REVIVE have demonstrated markedly improved recanalization rates compared to their earlier generation counterparts.9,10,11

The incorporation of these devices, improving imaging based patient selection and more expedient treatment times has resulted in positive findings from seven trials, MR CLEAN,12 EXTEND-IA,13 ESCAPE,14 SWIFT PRIME,15 REVASCAT,16 THRACE17, and THERAPY,18 supporting the superiority of the intra-arterial approach over IV tPA. We aim in this review to outline the history of the development of different intra-arterial devices in this context.

Advantages of IA thrombolytic therapy over IV therapy include direct infusion of a highly concentrated thrombolytic drug into the occluding thrombus, permitting lower total amounts of systemic concentration of thrombolytic agent to achieve recanalization.19 Precise depiction of the arterial anatomy through angiography confers several advantages including the characterization of the obstructive lesion, assessing the extent of collateral circulation, confirmation of degree and timing of recanalization, and providing an option of employing additional mechanical thrombectomy methods to best assist with vessel recanalization.20 Conversely, the disadvantages of IA approaches include the need for a specialized neurointerventional team and endovascular facilities, additional time delays required for angiography and microcatheter placement before therapy can be commenced, and the risks of catheter manipulation.20

Different agents have been used for the thrombolytic treatment of acute ischaemic stroke. These include tissue plasminogen activator (tPA), urokinase (UK) and pro-urokinase (pro-UK).

Mechanical thrombectomy devices are divided into 2 major groups based on their mechanism of action: those that use an approach distal (retrievers) or proximal to thrombi (aspiration devices).

The MR CLEAN (Multicenter Randomized CLinical trial of Endovascular treatment for Acute ischemic stroke in the Netherlands) study was a landmark trial and the first RCT to demonstrate the superiority of intra-arterial treatment.12 Five hundred patients across 17 centers in the Netherlands who presented with clinical and radiological evidence of a proximal anterior circulation stroke within 6 hours of onset were randomized to receive intra-arterial therapy with standard care versus standard care alone.12 The intervention group received chemical and/or mechanical endovascular therapy. Intra-arterial thrombolysis was achieved using alteplase and urokinase, whilst mechanical treatment involved thrombectomy, aspiration or stenting according to neurointerventionist preference.

The primary outcome was based on 90 day mRS score, which showed a significant improvement in outcomes for patients receiving intra-arterial therapy (adjusted odds ratio 1.67, 95% Confidence Interval 1.21-2.30). This benefit was conferred to all prespecified dichotomisations of the mRS except death 12. The incidence of functional independence, defined as mRS 0-2, was also greater in this population by 13.5% (32.6% vs. 19.1%) 12. Secondary outcomes including clinical (NIHSS score after 5-7 days), radiological (TICI 2b or 3), and safety (adverse events) all favoured the intervention group.

Compared to the previous three negative randomized control trials examining the efficacy of IA therapy, MR CLEAN had several advantages. It benefitted from the increased availability of CTA to confirm the presence of proximal anterior circulation occlusion, allowing its use in the inclusion criteria. 82% of all patients in the intervention group also were subject to intervention using stent retrievers, which have been demonstrated to be superior to first generation devices. Limitations include a broad inclusion criteria, including patients with characteristics that would confer poor baseline prognosis. This included those who had contraindications or non responders to IV tPA. Nonetheless, the trial was the first to offer compelling evidence for intra-arterial therapy to be used as a first line standard of care when patients with anterior circulation strokes present within 6 hours. Numerous subsequent trials were terminated prematurely for this reason. Please refer to Table 2 for summary of randomized control trials.

The EXTEND-IA (Extending the Time for Thrombolysis in Emergency Neurological Deficits - Intra-Arterial) randomized control trial confirmed the positive findings from MR CLEAN, and underlined the importance of prudent imaging based selection to maximise the efficacy of endovascular stroke therapy.13 Patients with ICA or MCA occlusions within 4.5 hours of onset, CT evidence of perfusion mismatch and core infarct volume of less than 70 mL were randomized to receive mechanical thrombectomy with the Solitaire device after IV tPA vs tPA alone. Endovascular therapy had to be commenced within 6 hours of stroke onset.

The trial had to be stopped after randomisation of 70 patients in a 1:1 manner. Endovascular therapy demonstrated significantly superior rates of early neurological improvement at 3 days (80% vs. 37%), and functional independence at 90 days (mRS 0-2 71% vs. 40%).13 The safety profile of patients in the endovascular treatment was also validated, with no significant differences in the rates of death or symptomatic ICH.

The imaging guided approach to identifying patients who would benefit from reperfusion therapy allowed more expedient randomisation and thus time to intervention. The high rates of revascularisation (TIMI 2-3 86%) compared to previous trials could be attributed to the sole use of the Solitaire FR stent retriever, previously shown to have superior outcomes compared to first generation devices used in initial trials.9,13 Limitations include the small population number. This may have therapeutic implications given the strict inclusion criteria- more than 7,798 patients were screened- and possibly overestimate treatment effect.

Concurrently released and published with EXTEND-IA, the ESCAPE (Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion With Emphasis on Minimizing CT to Recanalization Times) trial also highlighted the efficacy of endovascular therapy in patients using CT guided patient selection within 12 hours of stroke onset.14 Three hundred Sixteen patients with CT Angiography evidence of proximal artery occlusion with good collateralisation and small infarct core using an ASPECTS (Alberta Stroke Program Early Computed Tomography Score) of 6 to 10, were randomized to receive medical management versus rapid endovascular treatment predominantly using stent retrievers, within 60 minutes.14,39 Both arms received IV tPA if patients presented within 4.5 hours.

One hundred Sixty-five patients were randomized to the intervention arm and were noted to have a superior primary outcome of functional independence (90 day mRS score of 0-2 53.0% vs. 29.3% in the control group), with an associated reduction in mortality (10.4% vs. 19.0%) and no significant difference in adverse events.14

Given analysis of previous trials illustrating the importance of time to reperfusion, there was a strong emphasis on delivering rapid endovascular therapy, with a median time of 84 minutes from noncontrast CT to first reperfusion. The superior rates of recanalization compared to MR CLEAN (TICI 2b to 3 72.4%) could be attributed to this.12,14 These patients were predominantly treated at centers with significant experience in endovascular management and sophisticated imaging, allowing expedient treatment from stroke onset. This may impact the generalizability of results.

Presented at the 2015 International Stroke Conference with EXTEND-IA and ESCAPE, the SWIFT PRIME ("Solitaire™ FR as Primary Treatment for Acute Ischemic Stroke") study's results also demonstrated the efficacy of endovascular therapy using the Solitaire device.15 196 patients with evidence of a small-moderate core infarct, defined as an ASPECTS score of >6, were randomised to either receive combined IV tPA and endovascular therapy with the Solitaire device within 6 hours of anterior circulation stroke onset vs IV tPA alone. Primary outcomes included 3 month neurological outcome and recanalization rates.40

Patients who received endovascular therapy with IV tPA were again found to have unequivocally higher rates of 90 day functional independence (mRS 0-2: 60% vs. 35%, P<0.001) compared to the control group, without any significant difference in mortality or adverse outcomes. Notably, 88% of patients had successful reperfusion (TICI 2b-3) immediately post intervention, which could be attributed to a high proportion of occlusions in the M1 segment (67%), and the sole use of the Solitaire device. This may impact generalizability of results, particularly with regards to M2 and ICA occlusions.

The REVASCAT (Endovascular Revascularization With Solitaire Device Versus Best Medical Therapy in Anterior Circulation Stroke Within 8 hours) trial was also published simultaneously with SWIFT PRIME, highlighting the efficacy using the Solitaire device for proximal anterior circulation stroke within 8 hours of onset.16 206 patients across 4 hospitals in were randomized in a 1:1 ratio between the treatment and control groups. Patients with a large infarct core, defined as ASPECT scores of <7 and <6 on non-contrast CT and MRI DWI respectively, were excluded from the study. Recanalization (TICI 2b-3) was achieved in 65.7% of patients. Treatment with thrombectomy was again found to be superior for restoring functional independence compared to standard medical therapy (90 day mRS 0-2: 43.7% vs. 28.2% in the control group), with a similar safety profile.

The inferior rates of functional independence compared to EXTEND IA, ESCAPE, and SWIFT PRIME may be in part due to the use of ASPECTS scoring criteria, which is less accurate than diffusion imaging for the estimation of infarct core volume, and longer times from stroke onset to reperfusion. Two further studies- THERAPY and THRACE- were concurrently presented with REVASCAT at the 2015 European Stroke Organisation conference.17,18 THRACE randomised 414 patients across 26 centres in France, who presented within 5 hours of symptom onset with either anterior or posterior large artery occlusions, to receive mechanical thrombectomy after. IV tPA vs IV tPA alone. Preliminary results suggested a significant benefit in 90 day functional independence (mRS 0-2) in patients undergoing endovascular therapy.17 THERAPY (The Randomized, Concurrent Controlled Trial to Assess the Penumbra System's Safety and Effectiveness in the Treatment of Acute Stroke) enrolled only 102 patients before recruitment was halted prematurely because of the positive results of its predecessors.18 Patients with large artery anterior circulation strokes due to a clot length >8mm, who presented within 4.5 hours, were assigned to either IV tPA alone or IV tPA with adjunctive therapy using the Penumbra aspiration device. Preliminary results revealed that more patients were functionally independent (mRS 0-2) at 90 days, though this difference was not statistically significant likely due to inadequate patient numbers. THERAPY differed from other trials due to the sole use of the Penumbra aspiration device, and the inclusion of only patients with a large clot burden. We await the formal publication of results from these trials.

After illustrating the safety and recanalization efficacy of thrombectomy in the subgroup of patients with late presentation (>8 hours) strokes and CT or MR evidence of proximal anterior vessel occlusions with viable penumbra, the investigators of the DAWN (DWI/PWI and CTP assessment in the triage of wake-up and late presenting strokes undergoing neurointervention) trial are furthering this hypothesis with a multicenter study aiming to demonstrate improved clinical outcomes at 90 days using the Trevo Retriever with medical management compared to medical management alone.41,42 An estimated 500 patients will be randomized, with primary outcomes based on 90 day mRS scores and mortality.

The PISTE (Pragmatic Ischaemic Stroke Thrombectomy Evaluation) trial aims to randomise 800 patients across multiple centers in the UK, who present within 4.5 hours of symptom onset with a clinically significant neurological deficit (NIHSS ≥6) and imaging (CT/MRA/DSA) evidence of a large vessel occlusion, to IV thrombolysis alone versus additional mechanical thrombectomy using a variety of devices.43 IA therapy is commenced within 6 hours of presentation using an approved device as per the discretion of the neurointerventionalist. The primary outcome measured is again mRS 0-2 at 3 months. Secondary outcomes include full recovery (mRS 0-1), recanalization, safety (ie rates of ICH) and mortality.

Given the success of the Solitaire device in mechanical embolectomy, it currently remains the most popular device used for the treatment of acute ischemic stroke.13 However, there are several new devices currently being developed with the aim of offering improved recanalization and safety profiles, with a particular emphasis on minimising distal clot embolization.

Endovascular intra-arterial therapy improves recanalization rates compared to intravenous thrombolysis. Initial approaches and randomized controlled trials could not demonstrate a corresponding association with improved neurological outcome. However, the development of superior intra-arterial devices, rapid treatment times and increasing availability of sophisticated imaging techniques has resulted in the establishment of intra-arterial therapy as a front line therapy for acute ischaemic stroke.