Is there a value of intra-arterial thrombolysis in the era of modern stroke thrombectomy?

By Johannes Kaesmacher, MD, University Institute of Diagnostic and Interventional Neuroradiology, University Hospital Bern and Urs Fischer, MD MSc, Department of Neurology, University Hospital Bern

Intra-arterial prourokinase was one of the first endovascular stroke treatment regimens to be investigated in a systematic manner¹. Sixteen years later, multiple trials have shown an overwhelming benefit of endovascular stroke treatment with second generation mechanical devices². The success of these trials was thought to arise from two major contributing factors: (1) improved patient selection and (2) increased reperfusion efficacy of new thrombectomy devices, which were substantially higher than what had been reported for intra-arterial thrombolysis or first generation thrombectomy devices.

Why then reconsidering intra-arterial thrombolysis with recombinant (pro-)urokinase or low-dose rtPA in the setting of available devices, with superior efficacy and better safety profiles?

Currently, there is unequivocal observational evidence that complete reperfusion is superior to any other level of successful but incomplete reperfusion; hence, underlining the notion that incomplete but successful reperfusion is not merely a cosmetic problem^3,4. This appreciation was also evident when applying new multi-level grading scales of reperfusion success recently proposed by the HERMES collaborators⁵. While these data stress the need to reduce the incidence of periprocedural thrombus fragmentation, they also put into question if more aggressive treatment strategies in cases of >50% but <100% reperfusion are warranted and safe. While there is some preliminary evidence that such reperfusion improvement strategies can be successful in cases of residual occlusion reachable with stent-retrievers or small bore aspiration catheters, more distal occlusions are usually not reachable, but may harbor the risk of devastating sequelae.

In such scenarios intra-arterial thrombolysis may prove to be of added value in selected patients for the following reasons: (1) vascular and intracranial access is already established (2) small dosages of thrombolytics can be used (3) intra-arterial thrombolysis is effective in small occlusions (4) usually, the option of administering standard dose IV tPA is no longer available or its therapeutic effect has often already worn of.  Of course, intra-arterial administration in a partially reperfused but also ischemic territory is not without risks, as the main one being the risk of intracranial bleeding. By its very nature, such escalation strategies should therefore be based upon on a well-balanced consideration of risks and harms and a proper and timely reassessment of the current clinical and perfusion situation before its initiation. The eloquence of capillary blush deficits on 2D angiography images is not always easy to localize and most often lacks information associated with collateral flow from other (not injected) territories. Hence, clinical examination on the table or utilization of perfusion imaging using modern C-arm systems may help to estimate the clinical relevance of small persisting occlusions. In addition, such image-based reevaluation may help to predict the current risk of bleeding together with time-elapsed from symptom-onset.

Some patients included into the pivotal thrombectomy trials or published prospective multi-center registries were treated with second-generation devices and additionally received intra-arterial thrombolytics (with or without preceding IV thrombolysis). Pooling and analysis of such cases may help to estimate the value of intra-arterial thrombolytics and can help to counsel the design of potential trials. It remains difficult to foresee if intra-arterial thrombolytics should stay in the angio room during endovascular stroke treatment, but – despite being widely administered – there is room for improving the evidence regarding this issue. At the very least, there is no room for laziness.

References

1. Furlan A, Higashida R, Wechsler L, et al. Intra-arterial Prourokinase for Acute Ischemic Stroke. Jama. 1999;282(21):2003. doi:10.1001/jama.282.21.2003.
2. Goyal M, Menon BK, Van Zwam WH, et al. Endovascular thrombectomy after large-vessel ischaemic stroke: A meta-analysis of individual patient data from five randomised trials. Lancet. 2016;387(10029):1723-1731. doi:10.1016/S0140-6736(16)00163-X.
3. Rizvi A, Seyedsaadat SM, Murad MH, et al. Redefining “success”: a systematic review and meta-analysis comparing outcomes between incomplete and complete revascularization. J Neurointerv Surg. 2018. http://jnis.bmj.com/content/early/2018/05/25/neurintsurg-2018-013950.abstract.
4. Kaesmacher J, Dobrocky T, Heldner MR, et al. Systematic review and meta-analysis on outcome differences among patients with TICI2b versus TICI3 reperfusions: success revisited. J Neurol Neurosurg Psychiatry. 2018:jnnp-2017-317602. doi:10.1136/jnnp-2017-317602.
5. Liebeskind DS, Bracard S, Guillemin F, et al. eTICI reperfusion: defining success in endovascular stroke therapy. J Neurointerv Surg. 2018. http://jnis.bmj.com/content/early/2018/09/06/neurintsurg-2018-014127.abstract.