The effect of intravenous thrombolysis on patients with successful thrombectomy depends on final reperfusion grade: A retrospective study

Abstract Aims Although intravenous thrombolysis (IVT) has not shown confirmative effects on the outcomes of patients receiving successful thrombectomy, it might influence the outcomes of a subset of these patients. This study aims to evaluate whether the effects of IVT depend on final reperfusion grade in patients with successful thrombectomy. Methods This is a single‐center, retrospective analysis of patients with an acute anterior circulation large‐vessel occlusion and a successful thrombectomy between January 2020 and June 2022. Final reperfusion grade was evaluated by the modified Thrombolysis in Cerebral Infarction (mTICI) score, which was dichotomized into incomplete (mTICI 2b) and complete (mTICI 3) reperfusion. The primary outcome was functional independence (90‐day modified Rankin Scale score 0–2). Safety outcomes were 24‐h symptomatic intracranial hemorrhage and 90‐day all‐cause mortality. Multivariable logistic regression analyses were used to assess the interactions between IVT treatment and final reperfusion grade on outcomes. Results When comparing all 167 patients enrolled in the study, IVT did not influence the extent of functional independence (adjusted OR: 1.38; 95% CI: 0.65–2.95; p = 0.397). The effect of IVT on functional independence depended on final reperfusion grade (p = 0.016). IVT benefited patients with incomplete reperfusion (adjusted OR: 3.70; 95% CI 1.21–11.30; p = 0.022), but not those with complete reperfusion (adjusted OR: 0.48, 95% CI: 0.14–1.59; p = 0.229). IVT was not associated with 24‐h symptomatic intracerebral hemorrhage (p = 0.190) or 90‐day all‐cause mortality (p = 0.545). Conclusions The effect of IVT on functional independence depended on final reperfusion grade in patients with successful thrombectomy. IVT appeared to benefit patients with incomplete reperfusion, but not those with complete reperfusion. Because reperfusion grade cannot be determined prior to endovascular treatment, this study argues against withholding IVT in IVT‐eligible patients.


| INTRODUC TI ON
With the steady advancement of mechanical thrombectomy (MT), the necessity of intravenous thrombolysis (IVT) before MT has been questioned, 1 especially when the risk for hemorrhage is considered. 2 A recent meta-analysis of randomized clinical trials revealed comparable functional and safety outcomes in IVT-eligible patients that received bridging therapy or direct MT. 3 Therefore, personalized reperfusion strategies concerning IVT administration before MT might be a better option. 4 Therefore, it is imperative to determine which candidate patients may benefit from IVT prior to MT.
Recent studies have evaluated the interactions between IVT and baseline variables on MT outcomes such as occlusion site, 5 collateral status, 6 Alberta Stroke Program Early CT Score (ASPECTS), 7 in-hospital treatment delay, 8 and initial MT techniques. 9 Meanwhile, final reperfusion grade, commonly evaluated by the modified Thrombolysis in Cerebral Infarction (mTICI) score, 10 might be another potentially relevant factor. IVT was found to be associated with improved functional outcome amongst patients with unsuccessful MT (mTICI 0-2a), 11 yet in a recent real-world, observational study, this benefit was not observed in patients with anterior circulation largevessel occlusion following successful reperfusion (mTICI 2b-3). 12 Still, it is worth noting that the final reperfusion status varies substantially amongst patients with successful reperfusion. 13 While a status of mTICI 3 indicates 100% reperfusion of the target territory, mTICI 2b indicates 50%-99% reperfusion. 10 In addition, it is proposed that mTICI 2b is typically caused by procedure-related distal vessel occlusions, 4 which might respond to pre-MT IVT. Thus, it is important to investigate whether the treatment effect of IVT depends on final reperfusion grade in patients with successful reperfusion.

| Study design and patient selection
Between January 2020 and June 2022, consecutive patients who underwent MT at Dalian Municipal Central Hospital for an acute ischemic stroke with large-vessel occlusion were recruited into this retrospective study. Patients were included if they (1) had a proximal anterior circulation occlusion (intracranial internal carotid artery or middle cerebral artery (M1 or M2 segment) occlusions, or both), (2) were treated with MT within 6 hours from stroke onset, (3) were older than 18 years, (4) had a National Institutes of Health Stroke Scale (NIHSS) score ≥ 6, an ASPECTS ≥ 6, and a pre-stroke modified Rankin Scale (mRS) ≤ 2, (5) had a successful reperfusion defined by a final mTICI score of 2b or 3, and (6) had a functional outcome assessment using mRS at 90 days. IVT with 0.9 mg/kg of alteplase was administered to eligible patients with written informed consent obtained according to current management guidelines. 14 These patients were assigned into the incomplete reperfusion group (mTICI Hospital without re-informing the patients because of the retrospective approach. Only anonymized data was used, and the patient privacy was not violated. The study was conducted according to the principles expressed in the Declaration of Helsinki.

| Data collection
The following variables were collected: age, sex, medical history in- in Acute Stroke Treatment classification (TOAST). 15 The pre-stroke mRS was assessed by reception neurologists during medical history collection and during the physical examination. The pre-MT collateral status was dichotomized into good (grade 3-4) and poor (grade 0-2) collaterals according to the American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology collateral flow grading system. 16 Imaging variables were assessed by two experienced neurointerventionalists blinded to patient information, with a consensus reading in the case of discrepancies.

| Outcome evaluation
The primary outcome was functional independence (mRS ≤ 2) at 90 days after stroke, assessed by stroke neurologists during the clinical follow-up visit (28/167) or via a standardized telephone interview with the patients or their caregivers (139/167). Safety outcomes were the incidence of 24-h symptomatic intracranial hemorrhage (SICH) and 90-day all-cause mortality rate. SICH was defined as evidence of intracranial hemorrhage associated with an increase of 4 or more points on the NIHSS scores. 17

| Statistical analysis
The Shapiro-Wilk test was used to test data distribution.
Categorical variables were expressed as frequencies and percentages. Continuous variables were expressed as mean (SD) or median [interquartile range (IQR)] in the case of non-normal distribution.
Baseline characteristics were compared using the Student t test/ Mann-Whitney U test, or χ 2 test/Fisher's exact test, as appropriate, in complete and incomplete refusion groups.
We assessed whether the effects of pre-MT IVT on primary and safety outcomes depended on final reperfusion grade (mTICI 2b versus mTICI 3) using multivariable binary logistic regression analysis. To select the variables included in the multivariable logistic regression, we first compared the baseline variables with outcomes using univariable analysis. Then, a backward stepwise multivariable binary logistic regression analysis was performed to identify variables that affected the outcomes. Variables with p < 0.10 in the univariate analysis were added to the multivariable analysis. p ≥ 0.10 of the likelihood ratio test was used as exclusion criteria from the final backward stepwise analysis. Finally, an interaction term (IVT × final reperfusion grade) was added into the final multivariable analysis to determine whether IVT's effects depended on final reperfusion grade. We reported unadjusted odds ratios (OR) for univariate analyses and adjusted OR for multivariable analyses with a 95% confidence interval (CI). All tests were 2-tailed with a significance level of 0.05. All analyses were performed with the STATA software (version 17.0, StataMP, StataCorp).  Table 1, which were balanced in both groups.

| Baseline characteristics
F I G U R E 1 Flowchart illustrating the study inclusion/exclusion and grouping processes. ICA, internal carotid artery; MCA, middle cerebral artery. 2380 | TANG et al.  Figure 2).

| Primary outcome
There was significant interaction between IVT and final reperfusion grade on functional independence (p = 0.016;   Figure 2).

Interactions between IVT and final reperfusion grade on SICH
incidence or on all-cause mortality rate were not observed (

| DISCUSS ION
This study showed that the effect of IVT on functional independence depended on final reperfusion grade in patients with acute anterior circulation large-vessel occlusion and successful thrombectomy.
Amongst patients with incomplete reperfusion, IVT was significantly associated with functional independence without increasing SICH or mortality. In contrast, IVT did not have an effect on functional independence in patients with complete reperfusion.
Final reperfusion status is a key factor influencing clinical outcomes of patients that have a large-vessel occlusion treated with MT. 4 Thus, successful reperfusion is the goal of MT. 18 Complete reperfusion increases the likelihood of functional independence at 90 days by 15%-20% over incomplete reperfusion. 13  Although reperfusion of injured brain tissue provides an impetus for the development of post thrombolysis hemorrhagic transformation, 24 pre-MT IVT may also help to resolve embolisms of distal vessels, improve perfusion, and reduce the final volume of injured brain tissue. 13 These benefits may balance the potentially increased bleeding risk, 24 and result in a net benefit for patients with incomplete reperfusion.
This study has several limitations. First, it is a single-center, retrospective study with a relatively small sample size, which could inevitably cause selection bias. However, the results obtained are both pathophysiologically plausible and clinically relevant. The sharpness of the outcome might be partially explained by the low data heterogeneity benefited from a single center study design. As such, a prospective study specifically designed to confirm the results obtained in this study is warranted. Second, the stroke neurologists assessing outcomes in this study were not blinded to patient information. To mitigate this limitation, the final reperfusion grade was evaluated by experienced neurointerventionalists blinded to patient information.
Third, without advanced neuroimaging results, we can only suggest a hypothesis rather than a more concrete explanation of our findings. Perioperative dynamic perfusion imaging in future research may further elucidate potential mechanisms, such as improving microvascular compromise in no-reflow phenomenon. 25

| CON CLUS IONS
The treatment effect of IVT on functional outcome depended on final reperfusion grade in patients with successful thrombectomy.
IVT appeared to benefit patients with incomplete reperfusion, but not those with complete reperfusion. Because reperfusion grade cannot be determined prior to endovascular treatment, this study argues against withholding IVT in IVT-eligible patients.

CO N FLI C T O F I NTER E S T S TATEM ENT
The authors declare no conflict of interest.

DATA AVA I L A B I L I T Y S TAT E M E N T
The data that support the findings of this study are available from the corresponding author upon reasonable request.