Introduction
Several clinical trials have demonstrated that mechanical thrombectomy (MT) is an effective therapy for acute ischemic stroke (AIS) compared to the use of intravenous thrombolysis (IVT) only [
1‐
5]. However, whether pre-treatment with intravenous thrombolytics (bridging-therapy) significantly affects MT success is a matter of debate. Earlier studies reported conflicting results [
1‐
8], even though more recent studies seem to conclude that MT alone may offer comparable safety and efficacy to bridging-therapy [
9‐
14]. Ongoing randomized trials are continuing to address this question.
We hypothesised that IVT may reduce retrieved clot area and may influence revascularisation outcome compared to MT alone. This multi-center international study investigated the influence of bridging-therapy compared to MT alone on the retrieved clot area and on revascularization outcome in a cohort of 550 AIS patients treated with aspiration, stentriever or rescue-therapy.
Discussion
In the treatment of AIS, time is brain. It is crucial to act as soon as possible in order to reduce the damage to the brain following a lack of blood supply. The impact of bridging-therapy on final revascularization outcome, and on the overall procedural outcome, is still a matter of debate. However, despite an increased risk of intracranial haemorrhage [
21], in the absence of contraindications to rtPA, the standard therapy for large vessel occlusion (LVO) above six NIHSS [
22] is a combination of MT and rtPA (the so-called “bridging-therapy”) for all eligible patients [
17‐
19,
21,
23,
24].
We hypothesised that prior IVT may be associated with smaller retrieved clots and may affect the rates of recanalization as measured by mTICI and affect the number of passes required to remove clot. Our results demonstrate that prior IVT did indeed reduce clot size, but did not influence pass number or recanalization outcome.
Tissue plasminogen activator promotes the breakdown of fibrin polymers; therefore, in theory, the reduced clot size in patients undergoing bridging-therapy should be expected, even though, to the best of our knowledge, this is the first study that shows the association of bridging-therapy to smaller retrieved clots. It must be acknowledged that we can only conclude on the effect of IVT in the cases where thrombectomy resulted in extraction of at least part of the clot. We do not have data in the cases of patients who did not undergo thrombectomy due to successful thrombolysis and or clinical improvement, or had unsuccessful thrombectomy, with no clot extracted. We also acknowledge that the two patient populations in this study, i.e. those undergoing respectively bridging-therapy or MT alone are different from each other. The population treated with MT alone included patients ineligible for rtPA for several reasons, from time window exclusion and ongoing anticoagulation for atrial fibrillation to other major contraindications [
17‐
19,
23,
24]. Moreover, the MT alone group also included some patients that did not receive rtPA because they had suffered a too severe stroke (NIHSS > 25). However, we can confirm that parameters such as NIHSS score on admission, suspected etiology and occlusion location were similar between the groups in this study. Therefore, it seems reasonable to attribute the smaller retrieved clot area of the bridging-therapy population to the effect of prior IVT treatment.
The number of passes to remove clot may depend on several factors such as clot burden, clot composition, stability, and porosity as well as operator experience [
25]. The impact of each of these factors has not been fully elucidated yet. However, it is clear that a lower number of procedural passes correlates with a better outcome [
25].
We found bridging-therapy and MT alone equivalent in terms of revascularization outcome, with similar number of passes and final mTICI scores for aspiration and stentriever procedures. As expected, rescue-therapy cases were associated with more passes and worse final recanalization, but bridging-therapy and MT alone were also equivalent in rescue-therapy cases. Our finding of the absence of any particular difference between bridging-therapy and MT alone on both number of passes and recanalization rates, is in line with several studies previously published [
26,
27]. As previously acknowledged, in this study we could not include the patients who recanalised with IVT only, without need for further endovascular treatment. Nonetheless, on the basis of our findings comparing MT alone to bridging-therapy, the results show that IVT makes the clot smaller, perhaps causing it to break into pieces, diminishing in this way its size, and perhaps increasing the risk of distal embolism to smaller arteries [
28]. IVT may soften the clot, however, since number of passes and final degree of recanalization were similar, rtPA does not seem to have a significant facilitating effect on detachment of clot during MT.
A main advantage of rtPA is that the treatment is readily available to centres that do not have the advanced technology needed or interventionalists with specialized skill sets or in remote areas that cannot provide an in-house stroke specialist 24/7 [
29]. It is still unclear if, for patients with suspected AIS whether rtPA versus immediate mechanical thrombectomy should be prioritized [
30] but the previous administration of rtPA may certainly be of help for patients living in areas where the primary referral hospital is a local stroke centre with no availability of mechanical thrombectomy option. We observed no significant difference in incidence of procedural related haemorrhage in the bridging-therapy and MT alone groups. Although bridging-therapy did not result in better revascularization outcome compared to MT alone, it is also true that it did not result in worse revascularization outcome than MT alone, at least considering the two groups compared in this study. Furthermore, a benefit of pre-treatment with IVT may be that rtPA still circulating may be helpful to dissolve the remnants of the thrombus. A clinical trial is currently investigating the possible benefits of local intra-arterial treatment post MT for this reason [
31]. It is possible that the lack of significant effect on number of passes to remove clot and final revascularisation outcome that we observed in this study reflects the fact that IVT may have both beneficial and detrimental effects due to its mechanism of action, but on balance does not adversely affect the outcome in MT procedures.
Study limitations and strengths
One of the limitations of this study is the lack of complete data about patients undergoing bridging-therapy. In particular, we have not probed information about the number of “drip and ship” patients or full details about IVT administration, timings, dosage and kind of drugs used, although this should be studied in the future. Inclusion of more extensive post procedural outcome data, such as lesion volume of infarct, mortality rate, 90 day mRS scores would also benefit future work. Another limitation is that we measured an area rather than a volume to give an indication of the size of the extracted clot, although we believe the area measurements are representative of the extracted clot burden.
However, a main strength of this study is the large patient population arising from four dedicated stroke centres in Europe, which reduces the effect of possible differences in clinical approach across the hospitals, giving robustness to our findings.
Conclusion
The present study highlighted that the administration of rtPA before mechanical thrombectomy, in patients who did not recanalise with IVT only and where thrombectomy resulted in extraction of at least a part of the clot, was associated with a significant reduction of retrieved clot area, although it did not impact the number of passes or final mTICI score. Future studies will be performed to investigate also other important parameters, like the sex and the age of the patients as well as the time from groin puncture to recanalization, which may differ between bridging-therapy and MT alone patients, influencing then the final outcome.
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