Excellent question Dr. Angermaier, and very interesting topic!

I am not an expert on this topic at all... But there are some issues I would like to comment regarding this question.

In a short retrospective study published on the International Journal of Stroke (Int J Stroke 2012; Sep 27. doi: 10.1111/j.1747-4949.00890.x) the conclusion from the review of 157 patients' angiographies, was that combined IV-IA therapy with full dose intravenous rtPA was safe and results in good recanalization rate without excess symptomatic intracranial haemorrhage. In this study only 104 patients received the combined therapy... So this was one of the studies that supported the IMS3 trial as a good option to assess this result.

The IMS3 (Lancet Neurol. 2014 Apr 25. pii: S1474-4422(14)70066-3. doi: 10.1016/S1474-4422(14)70066-3) was a randomized, open-label multicenter trial, in a phase-3 status, that compared IV-IA rtPA therapy with IV-rtPA alone (the window therapy was 3 hours)... But the trial was halted in April 2012, because there was no statistically significant difference in both groups on the primary endpoint (mRs 2 or less at 90 days) with 40,8% in the combined group and 38,7% in the IV alone group; death rates and bleeding were similar for both groups, and the benefit achieved for more sever strokes and those with more rapid treatment in the combined group, didn't reached significance.

In my center, as we are a reference center from the Social security system, we had only 3 cases in the last year of combined therapy. The decision was made by medical criteria of the treating physician, based on poor recovery at first hour of the IV rtpA. Our experience is short, but in two patients we achieved mRs less than 2, and in the other the stroke was very big and he was very impaired at the end (mRs 5). This is not part of our stroke protocol, and evidence-based guidelines don't recommend this approach, but as in many places, the fight to give patients our best effort seems rational for this type of interventions. More studies and better protocols are necessary to give a better answer to your interesting question.

Studies have shown that bridging therapy leads to no better outcomes than either IV tPA or endovascular therapy. The critical factor for the success of endovascular therapy is the time lag to therapy. Efforts should be made to focus on reducing this time lag. But, even so, given current data, there is no difference between IV tPA and IA tPA or EVT or EVT with prior bridging therapy. Thus, the standard of care is IV tPAa. If a need for EVT is anticipated (long segment thrombus/ T thrombus of the ICA terminus), bridging therapy maybe used in the interim, with the clear understanding that it does not provide additional leeway as far as time to EVT is concerned. This is what current data shows.

During and after recanalization of the occluded main arteries, prevention of the focal infarction is important. As we have described in the two previous papers (“Ito U, Hakamata Y, Kawakami E, Oyanagi K. Temporary [corrected] cerebral ischemia results in swollen astrocytic end-feet that compress microvessels and lead to delayed [corrected] focal cortical infarction. J Cereb Blood Flow Metab 2011; 31: 328–338” and “Umeo Ito, Yoji Hakamata, Kazuhiko Watabe and Kiyomitsu Oyanagi. Mannitol infusion immediately after reperfusion suppresses the development of focal cortical infarction after temporary cerebral ischemia in gerbils. Neuropathology 2014; ••, ••–••, doi:10.1111/neup.12113”), the microvasclogenic secondary focal cerebral ischemia induces focal cortical cerebral infarction after recanalization. We are now preparing the translational study for clinical application, combined with the findings during the vascular occlusion by “Little JR. Modification of acute focal ischemia by treatment with mannitol. Stroke 1978; 9: 4–9”.

We have never used thrombolysis during and after recanalisation in the present animal model. Target of our present study is prevention of the swelling and compression of the astrocytic end feet which compressed micro-vessels and resulted in the secondary focal micro-vasculogenic focal ischemia.

We have never used thrombolysis during and after recanalisation in the present animal model. Target of our present study is prevention of the swelling and compression of the astrocytic end feet which compressed micro-vessels and resulted in the secondary micro-vasculogenic focal ischemia.

During ischemia, and in early phase after re-canalisation as well, secondary micro-vasculogenic focal ischemia occurs compressed by remarkably swollen peri-microvascular astrocytic end-feet. We are preparing the translational study to prevent these secondary micro-vasculogenic focal ischemia.

Very interesting indeed Dr. Ito. Regarding your study, is inflammatory activity a remarkable target in peri-microvascular astrocytic end-feet and also in the near zone, in order to establish anti-inflammatory mechanisms to prevent further ischemia?

Thank you very much for your attention. l have no idea for the cause of the swelling of the peri-microvascular astrocytic end-feet. This is very active part where the astrocytes are contacting blood stream. So to speak a re-perfusion injury might be a cause. Anyway, this phenomenon might be the microvasculo-genic secondary focal ischemia to induce focal cortical infarction after recirculation by end-vascular repercussion therapy.

Dr. Angermaier, 

It is safe and this has been recently confirmed in recent endovascular treatment trials (for example the REVASCAT trial in which I was involved). Many patients received tPA before the endovascular procedure with no increase in complications. I think we should forget about comparing thrombectomy vs iv thrombolysis, we just need to give our patients everything that may improve their final  outcome.