BACKGROUND: For patients with large vessel occlusion and carotid tandem lesions, the best treatment approach is not clear. Intravenous thrombolysis in addition to endovascular treatment might increase the risk of intracranial haemorrhage and decrease effectiveness in this cohort, particularly for patients receiving acute carotid stenting. In an individual participant data meta-analysis of six randomised controlled trials (RCTs), no clear benefit was seen of intravenous thrombolysis in patients with large-vessel occlusion stroke who were eligible for direct endovascular treatment. We aimed to assess whether the presence of carotid tandem lesions would modify the safety and efficacy of intravenous thrombolysis in patients who could directly undergo endovascular treatment, in a prespecified secondary subgroup analysis of this individual participant data meta-analysis.
METHODS: We previously did a systematic review and individual participant data meta-analysis of six RCTs comparing intravenous thrombolysis plus endovascular treatment with endovascular treatment alone in patients with anterior circulation stroke presenting directly at centres capable of endovascular treatment. The principal investigators of the six identified trials provided individual participant data for 2313 patients, which we pooled. The primary outcome was functional outcome, as measured by 90-day modified Rankin Scale score. Heterogeneity of treatment effect was assessed in the intention-to-treat population using ordinal regression models, with interaction terms for treatment and carotid tandem lesions, followed by a mixed-effects meta-analysis. A sensitivity analysis included only patients who received acute carotid stenting. The study is registered with PROSPERO, CRD42023411986.
FINDINGS: Of the 2313 patients who were included in the individual patient data meta-analysis, 2267 (98%) had data for carotid tandem lesions, of whom 1136 were assigned intravenous thrombolysis plus endovascular treatment and 1131 were assigned endovascular treatment alone. 340 patients had carotid tandem lesions (161 intravenous thrombolysis plus endovascular treatment, 179 endovascular treatment alone) and 1927 did not have tandem lesions (975 intravenous thrombolysis plus endovascular treatment, 952 endovascular treatment alone). The median age of patients was 71 years (IQR 62-78); 1003 (44·2%) patients were female and 1264 (55·8%) were male. Compared with endovascular treatment alone, the addition of intravenous thrombolysis did not improve functional outcome in patients with tandem lesions (adjusted common odds ratio [acOR] 1·00, 95% CI 0·62-1·62) or in those without tandem lesions (1·17, 0·99-1·37). No significant heterogeneity of treatment effect was observed between patients with tandem lesions and those without (ratio of odds ratios 0·81, 95% CI 0·48-1·37; pinteraction=0·44). Intracranial haemorrhage rates in patients with tandem lesions were similar for those receiving intravenous thrombolysis plus endovascular treatment (58 [37%] of 155) and for those receiving endovascular treatment alone (65 [38%] of 172; acOR 0·95, 95% CI 0·59-1·54). Rates of symptomatic haemorrhage in patients with tandem lesions were also similar (six [4%] of 159 for those receiving intravenous thrombolysis plus endovascular treatment vs ten [6%] of 179 for those receiving endovascular treatment alone; 0·81, 0·28-2·30). The sensitivity analysis including only patients who received acute carotid stenting showed similar results to the primary analysis.
INTERPRETATION: The findings of this prespecified secondary analysis of an individual patient data meta-analysis show that, in patients with carotid tandem lesions, the addition of intravenous thrombolysis to endovascular treatment was not associated with an increase in the risk of bleeding or with modification of functional outcome. These data suggest that the presence of tandem lesions should not solely influence the decision to administer intravenous thrombolysis to patients who can directly undergo endovascular treatment.
FUNDING: Stryker, Boehringer Ingelheim, and Amsterdam University Medical Centers, University of Amsterdam.
| Discipline Area | Score |
|---|---|
| Emergency Medicine |  |
| Neurology | |
This systematic review and individual participant data meta-analysis evaluated IV thrombolysis plus EVT with EVT alone in patients with anterior circulation stroke. The primary outcome was neurological functional outcome based on 90-day mRS. The authors pooled data for 2313 patients and found adding IV thrombolysis to EVT did not improve functional outcomes in patients with or without carotid tandem lesions. The rates of ICH were similar. There are several limitations including no rescoring of imaging data and differences in individual study definitions and scoring criteria. Interventionists were not blinded to thrombolysis and the results are not applicable to TNK.
The ACEP Clinical Policy on acute ischemic stroke (https://www.acep.org/patient-care/clinical-policies/thrombolytics-for-the-management-of-acute-ischemic-stroke) provides a rare Level B recommendation in favor of thrombolytics with thrombectomy for LVO. This individual patient data meta-analysis demonstrating a lack of benefit of thrombolytic + EVT vs EVT alone could push the needle of that ACEP Clinical Policy recommendation away from thrombolytics in favor of EVT alone.
The parent SR/MA of RCTs (PMID 37640037), published in 2023, was inconclusive as to whether we should be adding thrombolytics in addition to EVT rather than performing EVT alone. The addition of thrombolytics resulted in more hemorrhage, but also a statistically non-significant trend toward better functional outcomes. Designed as a non-inferiority trial, it did not show non-inferiority of EVT alone, but did not establish superiority with the addition of thrombolytics. Using the same data set, this time the authors sought to determine whether the presence of a carotid tandem lesion could help determine a subgroup of patients in whom the addition of thrombolytics to EVT was beneficial (or harmful). It did not. Carotid tandem lesions were not associated with either increased benefit nor increased risk for hemorrhage compared with patients without tandem lesions. The search to define which EVT eligible patients should (or should not) receive thrombolytics will continue.
Intravenous thrombolysis in tandem occlusions does not appear to improve prognosis, nor does it increase the risk for bleeding in the presence of tandem occlusion. In view of the variable diagnostic modalities, it would seem appropriate to always perform thrombolysis followed by thrombectomy, considering that this does not cause harm.