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. 2025 May 27;104(10):e213641.
doi: 10.1212/WNL.0000000000213641. Epub 2025 Apr 28.

Effect of Thrombolytics on Delayed Reperfusion After Incomplete Thrombectomy: Target Trial Emulation

Adnan Mujanovic  1 , Vignan Yogendrakumar  2   3 , Felix C Ng  2   4 , Thomas Gattringer  5   6 , Bettina Lara Serrallach  1 , Thomas R Meinel  7 , Leonid Churilov  8 , Oliver Nistl  5 , Shaokai Zheng  1   9 , Peter J Mitchell  10 , Nawaf Yassi  2   11 , Mark W Parsons  12 , Gagan Jyoti Sharma  2 , Hannes A Deutschmann  5 , Geoffrey Alan Donnan  2 , Marcel Arnold  7 , Fabiano Cavalcante  13 , Eike I Piechowiak  1 , Timothy John Kleinig  14 , David Julian Seiffge  7 , Stephen M Davis  2 , Tomas Dobrocky  1 , Jan Gralla  1 , Markus Kneihsl  5   6 , Urs Fischer  7 , Bruce C V Campbell  2 , Johannes Kaesmacher  1   15   16
Affiliations

Effect of Thrombolytics on Delayed Reperfusion After Incomplete Thrombectomy: Target Trial Emulation

Adnan Mujanovic et al. Neurology. .

Abstract

Background and objectives: More than half of the endovascularly treated ischemic stroke patients with incomplete reperfusion (expanded Thrombolysis in Cerebral Infarction [eTICI] <3) show delayed reperfusion (DR) on 24-hour perfusion imaging, which is associated with favorable clinical outcome. The effect of intravenous thrombolysis (IVT) on the rates of DR remains unclear. This study aimed to assess the treatment effect of IVT on the occurrence of DR.

Methods: Pooled data from 3 randomized controlled trials (EXTEND-IA and EXTEND-IA TNK parts 1 and 2) and 2 comprehensive stroke centers (University Hospitals Graz and Bern) were analyzed. Only patients with a final reperfusion score of eTICI 2a-2c and available perfusion imaging at follow-up of 24 ± 12 hours were included. The primary outcome was the presence of DR on 24-hour follow-up CT/MRI perfusion imaging, defined as the absence of any focal perfusion deficit on perfusion imaging, despite incomplete reperfusion on the final angiography series during thrombectomy. For the secondary analysis, we explored the association between the primary outcome (DR) and the time elapsed between start of IVT and the end of an intervention. To address confounding in observational data, we performed a target trial emulation.

Results: Of 832 included patients with eTICI 2a-2c (median age 74 years, 49% female), 511 (61%) had DR. There was an independent treatment effect of IVT on DR (standardized risk ratio [sRR] 1.1, 95% CI 1.0-1.3; standardized risk difference [sRD] 8.2%, 95% CI 0.2%-16.1%), after adjusting for age, sex, atrial fibrillation, number of device passes, collateral score, and eTICI. Among those patients who have received IVT (n = 524/832, 63%), when adjusting for the aforementioned covariates, there was a causal effect of shorter time between administration of thrombolytics and end of the intervention on DR (sRR 0.93%, 95% CI 0.87-0.98; sRD -5.2%; 95% CI -9.1% to -1.3%, per hour increase).

Discussion: Exposure to thrombolytics showed independent treatment effect on the occurrence of DR among patients with incomplete reperfusion after thrombectomy who undergo perfusion imaging at the 24-hour follow-up. The effect of thrombolytics on DR was observed if there was a high chance of therapeutic concentrations of thrombolytics at the time point when the proximal vessel was recanalized, but distal occlusions persisted and/or occurred.

Classification of evidence: This study is rated Class III because it is a nonrandomized study and there are substantial differences in baseline characteristics of the treatment groups.

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Conflict of interest statement

A. Mujanovic reports financial support from the Swiss National Science Foundation (fees paid to institution). V. Yogendrakumar reports no disclosures relevant to the manuscript. F.C. Ng reports support by the Australian National Health Medical Research Council and National Heart Foundation in research fellowships. T. Gattringer reports research grant from the Austrian Science Foundation and also reports the following: BMS Pfizer: speakers' honoraria, travel support; Bayer: speakers' honoraria, travel support; Boehringer Ingelheim: speakers' honoraria, travel support, advisory board; Novartis: speakers' honoraria, advisory board; Astra Zeneca: speakers' honoraria, advisory board. B.L. Serrrallach, T.R. Meinel, L. Churilov, O. Nistl, S. Zheng, P.J. Mitchell, N. Yassi, M.W. Parsons, G.J. Sharma, H.A. Deutschmann, G.A. Donnan, M. Arnold, F. Cavalcante, E.I. Piechowiak, T.J. Kleining, D.J. Seiffge, and S.M. Davis report no disclosures relevant to the manuscript. T. Dobrocky reports Microvention consultancy. J. Gralla and M. Kneihsl report no disclosures relevant to the manuscript. U. Fischer is a PI of ELAN, is co-PI of DISTAL, TECNO, SWIFT DIRECT trials; has research grants from Medtronic, Stryker, Rapid Medical, Penumbra, and Phenox; has consultancies for Medtronic, Stryker, and CSL Behring; is part of advisory boards for Alexion/Portola, Boehringer Ingelheim, Biogen, and Acthera; is part of clinical event committees for the COATING trial and the DSMBs of the TITAN, LATE_MT, and IN EXTREMIS trials; and is president of the Swiss Neurologic Society. All fees are paid to the institutions. B.C.V. Campbell reports no disclosures relevant to the manuscript. J. Kaesmacher reports Microvention consultancy within the framework of a corelab; financial support from Medtronic for the BEYOND SWIFT registry and SWIFT DIRECT trial; medication supply support from Boheringer-Ingelheim for the TECNO trial; a research agreement with Siemens Healthineers regarding flat panel perfusion imaging; and research grants from the Swiss National Science Foundation supporting the TECNO trial, Swiss Academy of Medical Sciences supporting MRI research, and Swiss Heart Foundation supporting cardiac MRI in the aetiological work-up of stroke patients. All fees are paid to the institutions. Go to Neurology.org/N for full disclosures.

Figures

Figure 1
Figure 1. Delayed Reperfusion and Persistent Perfusion Deficit on Follow-Up Perfusion Imaging
Runs from final digital subtraction angiography (DSA) images are displayed with high contrast levels to emphasize the capillary phase deficits. Time-to-peak (TTP) perfusion maps were used for these example cases. (A) Admission perfusion imaging shows a left-side M2 occlusion (left panel). DSA at the end of an intervention shows incomplete reperfusion (eTICI 2b67, middle panel). Follow-up perfusion imaging shows complete delayed reperfusion without residual perfusion deficits (right panel). (B) Admission perfusion imaging shows a right-side M1 occlusion (left panel). DSA at the end of an intervention shows incomplete reperfusion (eTICI 2c, middle panel). Follow-up perfusion imaging shows complete delayed reperfusion without residual perfusion deficits (right panel). (C) Admission perfusion imaging shows a left-side M2 occlusion (left panel). DSA at the end of an intervention shows incomplete reperfusion (eTICI 2b67, middle panel). Follow-up perfusion imaging shows persisting perfusion deficit that directly corresponds to the area of incomplete reperfusion from the DSA (right panel). (D) Admission perfusion imaging shows a left-side M1 occlusion (left panel). DSA at the end of an intervention shows incomplete reperfusion (eTICI 2b50, middle panel). Follow-up perfusion imaging shows persisting perfusion deficit that directly corresponds to the area of incomplete reperfusion from the DSA (right panel).
Figure 2
Figure 2. Causal Diagram
(A) In a standard patient, IVT is given before the start of EVT. IVT could influence the technical result of EVT including eTICI score, number of passes, and collaterals. After incomplete reperfusion is observed at the end of the EVT, we were interested in whether there was treatment effect of exposure to IVT on DR, given similar age, sex, presence of AFib, eTICI score, number of passes, and collaterals. The research question of this article is related to the remaining thrombolytic treatment effect of already given IVT (dashed square). The primary study hypothesis was that exposure to IVT may increase the chances of having DR at the 24-hour follow-up imaging. (B) The association between IVT and DR is presented through a causal diagram. There are several confounders that may mediate the association of IVT with DR. For example, both eTICI and number of passes are associated with DR and may also be influenced by IVT. On purpose, we closed all causal pathways of IVT by which the occurrence of delayed reperfusion could be influenced indirectly and partially before incomplete reperfusion occurs (eTICI, number of passes, and collaterals). This direct pathway (green line) refers to the effects of IVT that occur after reopening of all the vessels and after EVT has been concluded. In addition, we closed pathways of important confounders that could influence DR but also influence the likelihood of getting IVT (age, sex, AFib). All confounders and mediators are highlighted in red lines. The target trial emulation design allows us to estimate the direct effect of IVT on DR (green line) once a patient experiences incomplete reperfusion, that is, in a given patient with a specific reperfusion score, number of passes, collaterals, etc, does IVT promote DR? AFib = atrial fibrillation; DR = delayed reperfusion; eTICI = expanded Treatment in Cerebral Infarction; EVT = endovascular therapy; IVT = IV thrombolysis; PPD = persistent perfusion deficit.
Figure 3
Figure 3. Effect of Intravenous Thrombolytics and Delayed Reperfusion Stratified by the Final Reperfusion Score
Bar plots stratified by the incomplete reperfusion score. Percentages refer to the number of patients in each stratum who have either developed persistent perfusion deficit (darker colors) nor delayed reperfusion (brighter colors) at the 24-hour follow-up. Treatment effect of IV thrombolytics on delayed reperfusion was preserved independent of the final reperfusion score (sRR 1.1, 95% CI 1.0–1.3, sRD 8.2%, 95% CI 0.2%–16.1%). eTICI = expanded Treatment in Cerebral Infarction; sRR = standardized risk ratio.
See this image and copyright information in PMC

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