ASK the EXPERT(s): What can we do after failed, unsuccessful, or incomplete Mechanical Thrombectomy in Anterior Circulation Large-Vessel Occlusion Stroke?

In our first ASK the EXPERT(S) of the year, we interviewed Dr Johannes Kaesmacher and Professor Urs Fischer from University Hospital Bern, Inselspital, Switzerland about their recent publication in JAMA Neurology.

Kaesmacher J, Bellwald S, Dobrocky T, et al. Safety and Efficacy of Intra-arterial Urokinase After Failed, Unsuccessful, or Incomplete Mechanical Thrombectomy in Anterior Circulation Large-Vessel Occlusion Stroke. JAMA Neurol. Published online December 09, 2019. doi:

How common is failed/unsuccessful/incomplete MT in anterior circulation large vessel occlusion stroke?

Johannes: According to recent real-world registry data from Europe and the US, approximately 10% of patients fail to reperfuse by endovascular means (Thrombolysis in Cerebral Infarction, TICI 0/1) and 12-20% of patients do not reach a successful reperfusion, accordingly (TICI 0-2a).

What are the possible reasons?

Johannes: Reasons for failed reperfusion (TICI0/1) consist of failure to establish intracranial access (e.g. owning to vessel tortuosity/elongation or due to an inability to pass an accompanying cervical occlusion), failure to pass the thrombus with a microwire or microcatheter or failure to remove the thrombus despite multiple attempts. In TICI2a or incomplete TICI2b reperfusions, distal thrombi occluding distal branches are usually causal. Although some patients present with multi-vessel occlusions on admission, the large majority of distal branch occlusions after thrombectomy are caused by the mechanical intervention itself.

What are the current treatment options/approaches in these scenarios?

Johannes: For access and thrombus pass difficulties, alternative access routes including radial or carotid punctures may be beneficial. Moreover, improvements in device stability and navigability will further reduce the rates of intracranial access failure.

In cases where the thrombus may be passed with the microwire but several stent-retrievers fail to remove the clot or early reocclusion is observed (e.g. due to an underlying atherosclerosis), permanent intracranial rescue may be performed.

For TICI2a or incomplete TICI2b occlusions there are large efforts being made to reduce periinterventional fragmentation in the first place, e.g. by refined flow-arrest techniques, new stent-retriever designs or new large-bore catheters. Likely, thrombus fragmentation will not become completely avoidable and additional treatment considerations are distal stent-retriever thrombectomy, distal intermediate or microcatheter aspirations and/or intra-arterial thrombolysis. This may be realized as stand-alone injection in proximity to the thrombus or as combined approach using intra-arterial injection, together with repeated retrieval maneuvers.

Can you briefly summarise the design, patient selection, intervention and main outcomes of the study?

Johannes: We included consecutive patients, who underwent stent-retriever thrombectomy at a single center. We presented our data with strata of additional administration of intra-arterial Urokinase or standard of care. In both groups, some patients were also treated with intravenous thrombolysis. The decision to additionally administer intra-arterial Urokinase was not standardized and was made in consensus by the treating neurologist and neuroradiologist. Main outcome of the study was the rate of symptomatic intracranial hemorrhage. Secondary outcomes were good functional (mRS 0-2) and all-cause mortality at day 90.

What are the key findings?

Johannes: Most importantly, the rate of symptomatic intracranial hemorrhage was not different between the groups. Interestingly, some patients showed improved reperfusion after intra-arterial administration of Urokinase and there was some evidence for improved outcomes in fully adjusted models, accordingly. It has to be kept in mind though that there was evidence for selection bias, as patients treated with intra-arterial Urokinase had more favorable baseline characteristics. While we have tried to account for these imbalances, there is a chance of residual confounding.

How should we take the results forward both clinically and research-wise?

Johannes: From a clinical perspective, the presented results may serve as a rational to administer intra-arterial thrombolytics as an adjunct after MT. Especially, when the likelihood of already occurred infarction in the hypoperfused area is small, however, the likelihood of the hypoperfused area to undergo infarction in the future is high. In addition, the risk of intracranial hemorrhage according to baseline factors should be taken into account. As stated in the manuscript, however, the results should not be interpreted as proof of intra-arterial thrombolytics being a generally safe treatment options in all patients who fail to reperfuse by mechanical means. Future research has to put more focus on the distinct outcome and stratification of TICI2a/TICI2b reperfusions. It is obvious that some patients will benefit from additional, more aggressive treatments, but others will certainly not: Patient selection will be key.

In the era of MT, what do you think will be role of intra-arterial therapy in the future of EVT?

Urs: The main aim of all revascularisation therapies in patients with an acute ischaemic stroke is to achieve complete reperfusion in the territory of the occluded vessels as soon as possible. In previous studies, successful reperfusion was defined as “TICI 2b” or “TICI 3” reperfusion, but we have recently shown that “TICI 3” reperfusions are associated with superior outcome and better safety profiles than “TICI 2b” reperfusions and that this effect was independent of time and collaterals (Kaesmacher J, et al. J Neurol Neurosurg Psychiatry 2018;89:910–917). Therefore, further efforts and risks have to be taken to achieve full, i.e. “TICI 3” reperfusion.

Distal access catheters and intra-arterial lytics have the potential, to improve “TICI 2b” to “TICI 3” reperfusion; however, both strategies have not yet been tested in randomised controlled trials. In the absence of randomised controlled trials, we were able to show that in selected patients, adjunctive treatment with intra-arterial urokinase during or after mechanical thrombectomy was safe and improved angiographic reperfusion. Further randomised trials are therefore necessary to investigate, whether intra-arterial therapies with various intra-arterial lytics can further improve the outcome of patients with large vessel occlusion and incomplete (i.e. < TICI 3) reperfusion.

Is there any other potential role of intra-arterial therapy for acute stroke treatment? e.g. reducing distal embolization during the procedure? Tackling very distal occlusion?

Urs: There are several potential roles for intra-arterial therapy for acute stroke treatment. Embolisation of clot fragments into distal arteries or into previously unaffected territories are frequently observed, and during the intervention, undetected distal vessel occlusions may be seen. In these situations, intra-arterial lytics as well as distal access catheters may help to completely restore reperfusion, when intravenous thrombolysis is no longer possible. Furthermore, in patients with in situ thrombosis from intracranial atherosclerotic disease, intra-arterial therapy may help to prevent further thrombus formation and thus improve reperfusion. However, these interventions have to be carefully tested in randomised controlled trials before being used in clinical routine.

Interviewed by Dr Linxin Li, Centre for Prevention of Stroke and Dementia, University of Oxford, UK