Intravenous thrombolysis (IVT) and endovascular treatment (ET) are the standard therapies for patients with acute ischemic stroke (AIS) due to a large vessel occlusion (LVO). If patients are eligible for both treatments, current guidelines recommend IVT prior to ET (bridging therapy) (1–3). Both treatments are time-sensitive and rapid initiation after symptom onset (SO) is recommended, as delayed flow restoration (FLR) clearly correlates with poor functional outcome (4). However, little is known about the impact of the timing of IVT at specific time points relative to ET on functional and angiographic outcome. The CHOICE trial demonstrated an improved clinical outcome in AIS patients receiving adjunct intra-arterial thrombolysis (IAT) after successful FLR (5). Possible explanations for the observed results included improved microcirculation and thrombolysis of more distal vessel occlusions, emphasizing a synergistic effect of IVT when applied at FLR. Regarding the use of adjunct IVT at FLR, no randomized controlled trials are available. To investigate the issue, two studies were conducted using data from the German Stroke Registry-Endovascular Treatment (GSR-ET). The first study involved 1,303 patients and found that ongoing intravenous thrombolysis (IVT) upon FLR was associated with better functional outcomes after 90 days in patients with a Thrombolysis In Cerebral Infarction score 65 (TICI)-Score of 2b-3, compared to those who had finished IVT (6). This suggests that the results of the CHOICE trial can be applied in a real-world setting. The second study used a matched case–control analysis and found that simultaneous administration of IVT during ET (with a minimum overlap of 10 min) was beneficial for patients with large-vessel occlusion (LVO) stroke and a premodified Rankin Scale (pmRS) score of 0–3 (7).

For this analysis, we first aimed to validate those findings in a larger cohort from the GSR-ET, emphasizing a possible synergistic beneficial effect of IVT during ET on clinical outcome. Second, we aimed to expand the focus on the impact of simultaneous administration of IVT during ET to ET-related technical parameters, including ET duration, rates of first-pass thrombectomy, and peri-interventional complications.

In this article, we have presented the impact of ongoing IVT vs. completed IVT at the point of ET completion in a large real-life dataset consisting of anterior circulation LVO patients. Our main results were as follows.

First, ongoing IVT at ET completion was associated with good clinical outcome (mRS 0–2 or back to baseline after 90 days; OR 1.53; 95% CI 1.08–2.17; p < 0.05), and we observed increased odds of achieving a better functional outcome by ~30% in the mRS shift analysis (OR 0.70; 95% CI 0.55–0.89; p < 0.05), which is in line with previous analyses (6, 7).

Second, patients who received ongoing IVT at ET completion were more likely to achieve successful reperfusion (mTICI 2b-3) at final angiography (OR 1.37; 95% CI 1.03–1.83; p < 0.05). Recent data indicate that IVT prior to ET is associated with higher reperfusion rates. However, data on the influence of IVT timing relative to ET on reperfusion rates are sparse; this is a new consideration and needs to be further elaborated on (12–14).

Third, we observed a reduction of procedure duration by ~24 min in patients who underwent ongoing IVT at ET completion (ß = −24.35; 95% CI −32.92–[−15.79]; p < 0.05). This results in accelerated reperfusion of the ischemic tissue, aligning with the observed improvement in functional outcome.

Fourth, ongoing IVT until ET completion turned out to be an independent predictor of first-pass thrombectomy (OR 2.07; 95%CI 1.51–2.84; p < 0.05), which is known to function as a predictor of favorable clinical outcome; this is likely linked with the reduced procedure duration (15). Considering that IVT has been shown to enhance first-pass thrombectomy rates, it is reasonable to also incorporate the discussion of IVT timing, although less is known about this aspect (16).

Finally, ongoing IVT until ET completion was associated with fewer peri-interventional complications (OR 0.64; 95% CI 0.44–0.94; p < 0.05), including vasospasm, clot migration/embolization, vessel dissections/perforations, ICH after 24 h, and malignant middle cerebral artery infarction, which most likely contributes to the improved functional outcomes observed in these patients.

Together, our findings may have substantial clinical implications. Not only are IVT and ET essentially additive, but they work particularly well together if IVT is still ongoing at the time of ET completion; this finding is consistent with recent analyses (6, 7). This highlights the need for continuous optimization of in-hospital processes in order to reach FLR within 60 min after IVT. This includes the ongoing development and refinement of standardized operating procedures for workflow and treatment algorithms and minimization of transit time from the emergency department to the angiosuite, as well as the establishment of dedicated multidisciplinary stroke teams (17). Moreover, methods for establishment of ongoing IVT at ET completion, e.g., by means of dynamic adaption of IVT flow rate or IVT splitting, represent an interesting target for further research. Furthermore, patients treated with tenecteplase prior to ET are more likely to have significant serum concentration of IVT at the time point of ET completion, due to its longer serum half-life, which may be considered when evaluating outcomes in those patients. While our data indicated that ongoing IVT at the point of ET completion is advantageous, it is crucial not to misinterpret this as a reason to withhold or postpone IVT. Rapid administration of IVT following stroke onset remains strongly associated with favorable functional outcomes (18).

This analysis was conducted on a large sample of prospectively assessed multicenter real-life data, which is a clear strength. Our analysis yielded very homogeneous results with respect to the generally positive effect of ongoing thrombolysis. The overall rate of both good clinical outcome and good angiographic outcome was comparable to that observed in recent trials, considering our inclusion criteria, which resulted in a sample comprising anterior circulation LVO stroke patients admitted directly to the center and receiving both IVT and ET (19, 20).

Our study has several limitations. Due to its observational nature, we are not able to draw conclusions on causality based on our results. As our assumption of ongoing IVT was based on retrospectively assessed time intervals, we also cannot exclude a possible selection bias. Furthermore, we cannot eliminate the possibility of residual confounders that we did not account for in our analysis, including factors such as the longer time interval from admission to groin puncture in the completed-IVT group. While key baseline characteristics were evenly distributed between the two groups, it is essential to acknowledge that our available observational data may not fully capture intrahospital time delays in particular. Consequently, we cannot rule out the potential for bias in the outcomes. Based on our inclusion criteria, we excluded patients for whom data were missing on either the timepoint of IVT administration or the timepoint of flow restoration. Additionally, we excluded patients with missing data regarding the receipt of IVT or a combination of these variables. Therefore, we cannot completely rule out the possibility of bias due to these missing data. Moreover, while the rate of local IAT during ET was comparable between both groups, we cannot provide information about the specific time point at which IAT was applied. Therefore, based on our data, we cannot distinguish a masked effect of local IAT application at the time of FLR from the possible effect of systemic IVT that was observed. Furthermore, it is important to note that, given our inclusion criteria, our study results are specifically applicable to patients directly admitted to a stroke center (the “mothership” model). In fact, achieving flow restoration through endovascular treatment within 60 min after administration of IVT would not be feasible in the majority of the “drip and ship” patients (21). Moreover, it is widely accepted that withholding or delaying IVT is not recommended, and this would in particular contradict the main principle of “drip and ship,” which has been shown to be an efficient concept in stroke care, particularly in rural areas (22, 23).

We have demonstrated a beneficial impact of ongoing IVT until ET completion on both functional and angiographic outcomes in anterior circulation LVO patients admitted directly to a thrombectomy center. Ongoing IVT until ET completion may ease ET by means of facilitating first-pass thrombectomy and thus substantially reducing procedure times, as well as diminishing the rate of peri-interventional complications. This study highlights the need and potential for further research on the timing of IVT during ET.

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.

The studies involving human participants were reviewed and approved by Ethics Committee of the LMU Munich (protocol: 689-15). Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

JW and LKel conceptualized the study. JW, LKei, ST, and HZ collected the data. JW carried out the analysis and wrote the first draft of the manuscript. All authors commented on previous versions of the manuscript, read, and approved it in its final form.