Abstract
Background:
The role of intravenous thrombolysis (IVT) as bridging treatment prior to endovascular thrombectomy (EVT) is under debate and better patient selection is needed.
Objectives:
As the efficacy and safety of IVT diminish with time, we aimed to examine the impact of bridging treatment within different time frames from symptom onset.
Design:
A retrospective registry study.
Methods:
Data were extracted from ongoing prospective EVT registries in two large tertiary centers. The current study included IVT-eligible patients with onset to door (OTD) < 4 h. We examined the efficacy and safety of bridging treatment through a comparison of the IVT + EVT group with the direct-EVT group by different time frames.
Results:
In all, 408 patients (age 71.1 ± 14.6, 50.6% males) were included, among them 195 received IVT + EVT and 213 underwent direct EVT. Both groups had similar characteristics. In the IVT + EVT group only, longer OTD was associated with lower rates of favorable outcome (p = 0.021) and higher rates of hemorrhagic transformation (HT; p = 0.001). In patients with OTD ⩽ 2 h, IVT + EVT compared to direct EVT had higher rates of TICI 2b-3 (86.2% versus 80.7%, p = 0.038). In patients with OTD > 2 h, IVT + EVT had lower rates of favorable outcome (33.3% versus 56.9%, p = 0.021), worse discharge National Institutes of Health Stroke Scale [7 (2–13) versus 3 (1–8), p = 0.024], and higher rates of HT (34.0% versus 8.5%, p < 0.001).
Discussion:
In this study, we found OTD times to have a significant effect on the impact of IVT bridging treatment. Our study shows that among patients with OTD < 2 h bridging treatment may be associated with higher rates of successful recanalization. By contrast, in patients with OTD > 2 h, bridging treatment was associated with worse outcomes. Further time-sensitive randomized trials are needed.
Keywords: bridging treatment, endovascular thrombectomy, thrombolysis
Introduction
Endovascular thrombectomy (EVT) is considered the most beneficial reperfusion therapy for acute ischemic stroke (AIS) due to large vessel occlusion (LVO) in the anterior circulation. 1 The role of intravenous thrombolysis (IVT) as a bridging treatment prior to EVT is still debatable. Although current guidelines advocate for IVT treatment in all eligible LVO cases, 1 studies examining bridging treatment, including six randomized control trials and several meta-analyses,2–4 have demonstrated inconclusive results. Finding subpopulations that may benefit or conversely be harmed by the IVT + EVT approach may allow better patient selection that could potentially lead to improved outcomes.
The efficacy of IVT is time dependent on diminishing effects depending on the time from symptoms onset. 5 Moreover, the longer the brain parenchyma is subjected to ischemia, it is more susceptible to hemorrhagic transformation (HT) in the setting of LVO. 6 Therefore, our primary goal was to examine the impact of bridging-IVT treatment within different time frames from symptom onset.
Methods
Study population
This observational study was conducted in two large academic centers. Both centers prospectively enroll all patients with LVO who underwent EVT. The study was approved by the institutional review boards of the participating centers with a waiver of informed consent.
In the current study, we analyzed data from patients that presented within 4 h of symptoms onset, in the years 2017–2021 (Supplemental Figure 1). We compared clinical and radiological outcomes, between the IVT + EVT group (all patients were treated with alteplase) and the direct-EVT group. We examined the impact of both treatment strategies in accordance with symptoms onset to door times (OTD). Further analysis compared bridging treatment to direct EVT in patients with OTD below 2 h and in those with OTD between 2 and 4 h (As arrival after 4 h precludes thrombolysis administration within 4.5 h). The institutional protocols of our two academic centers allow patients presenting in the early stage of AIS who have an Alberta Stroke Program Early CT Score (ASPECTS) 7 ⩾6 to undergo direct-EVT without bridging-IVT treatment if the neuroendovascular team is present at the hospital.
To minimize potential bias, we excluded from our study patients who were not eligible to receive IVT, including patients treated with oral anticoagulants. In addition, patients who showed major improvement with a resolution of their main deficits following IVT and were not taken to digital subtraction angiography if repeat CTA showed resolution of the previously seen vessel occlusion were excluded from the primary analysis. Data from the two centers for patients treated between 01 January 2016 and 31 December 2021 who met the inclusion criteria were pooled for retrospective analysis.
EVT treatment algorithm
All included patients underwent EVT using any approved device or approach at the discretion of the treating endovascular team. Data on procedural variables, including modified thrombolysis in cerebral infarction (mTICI) score 8 at the end of the procedure and the number of passes needed to achieve the best possible recanalization, were also studied. mTICI2b-3 was considered a successful target vessel recanalization. All patients were admitted to intensive care stroke units and treated with similar institutional protocols. Treatment protocols included intensive care unit admissions post-procedure maintaining a fixed systolic blood pressure below 140 mmHg for all patients who achieved target recanalization and below 180 mmHg for those who received IVT and did not achieve successful recanalization.
Data collection
Neurological deficits were measured using the National Institutes of Health Stroke Scale (NIHSS) 9 at admission and discharge. Time metrics were routinely measured at predefined definitions. Stroke etiology was classified with the Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification. 10 All patients underwent CT angiography (CTA) upon admission and a repeat non-contrast head CT (NCCT) 24 h post-procedure. Imaging variables, including admission CTA and repeated NCCT, were routinely assessed by vascular neurologists and neuroradiologists blinded to the clinical scenario. Collateral status was assessed on admission CTA according to the Alberta stroke programme early CT score (ASPECT) collateral grading scale, 11 with a score of 4−5 defined as good collaterals. HT was assessed both radiologically and clinically according to the European Cooperative Acute Stroke Study 2 (ECASS-2) criteria. 12 We used post-EVT NCCT data to classify HT into petechial hemorrhagic infarction and parenchymal hematoma type 1 or 2, defined as confluent hemorrhage covering less or more than 1/3 of the infarct volume, respectively. 13 A dual-energy CT protocol was used to enable distinction between HT and contrast extravasation due to blood–brain barrier damage. Further clinical division was made into asymptomatic and symptomatic ICH (sICH). sICH was defined as any apparent extravascular blood in the brain or within the cranium that was associated with clinical deterioration (defined as an increase of 4 points or more in the score on the NIHSS), or led to death, and was identified as the predominant cause of the neurologic deterioration. 14
Functional outcome was assessed with the modified Rankin Score (mRS) 15 prior to stroke, upon discharge, and 90 days after stroke. A favorable functional outcome was defined based on mRS-90 as either mRS ⩽ 2 for patients with baseline mRS ⩽ 2 or mRS 3 in patients who had baseline mRS 3 prior to admission.
Statistical analysis
Statistical analysis was performed using the SPSS software (version 27.0, IBM, Chicago, IL, USA). p < 0.05 was considered significant. Continuous variables were reported as a mean value (±SD), ordinal variables as median and interquartile range (IQR), and dichotomous variables as a percentage of the total. Comparisons or distributions between categories were assessed using Student’s t-test for continuous variables, the chi-square test for qualitative variables, and the Mann–Whitney or to compare differences between two independent groups when the dependent variable is either ordinal or continuous, but not normally distributed. Multivariate regression models that included age, sex, and predictors who were found significant in the univariate analysis were used to outline modifiers of outcome.
Results
In all, 408 patients (age: 71.1 ± 14.6, 50.6% males) were included in the study, among them 299 patients had symptoms to door time (OTD) of less than 2 h (average 56 ± 28 min) and 109 had OTD between 2 and 4 h (173 ± 37 min). No significant between groups differences were found in baseline characteristics, percent of bridging therapy, and outcome measures (Table 1).
Table 1.
Patients’ characteristics by symptoms to door.
| Characteristics | OTD < 2 h N = 299 | OTD > 2 h N = 109 | p Value |
|---|---|---|---|
| Age (SD) | 69.3 (14.9) | 71.1 (14.6) | 0.273 |
| Sex: male (%) | 152 (50.8) | 55 (50.5) | 0.946 |
| Hypertension (%) | 194 (64.9) | 81 (74.3) | 0.072 |
| Diabetes (%) | 91 (30.4) | 37 (33.9) | 0.499 |
| Hyperlipidemia (%) | 147 (49.2) | 51 (46.8) | 0.671 |
| Smoking (%) | 82 (27.4) | 31 (28.4) | 0.839 |
| Atrial fibrillation (%) | 103 (34.4) | 35 (32.1) | 0.659 |
| Ischemic heart disease (%) | 97 (32.4) | 34 (31.2) | 0.811 |
| Valvular disease (%) | 15 (5.0) | 7 (6.4) | 0.578 |
| Congestive heart failure (%) | 32 (10.7) | 9 (8.3) | 0.280 |
| Chronic renal failure (%) | 17 (5.7) | 11 (10.2) | 0.115 |
| Prior stroke (%) | 47 (15.7) | 14 (12.8) | 0.471 |
| Malignancy (%) | 32 (11.6) | 14 (13.5) | 0.610 |
| Statins (%) | 82 (29.3) | 29 (27.6) | 0.748 |
| Antiplatelets (%) | 86 (29.0) | 28 (26.2) | 0.583 |
| Vessel lesion (%) | 0.145 | ||
| ICA | 64 (21.4) | 26 (25.2) | |
| M1 MCA | 160 (53.5) | 52 (47.7) | |
| M2 MCA | 44 (14.7) | 21 (19.3) | |
| Basilar | 16 (5.4) | 3 (2.8) | |
| ACA | 3 (1.0) | 1 (0.9) | |
| PCA | 1 (0.3) | 0 (0) | |
| Tandem lesion | 43 (14.4) | 22 (20.1) | 0.168 |
| Side, right (%) | 141 (47.2) | 50 (45.9) | 0.567 |
| TOAST (%) | 0.961 | ||
| Cardioembolism | 163 (54.5) | 57 (52.3) | |
| Large artery atherosclerosis | 59 (19.7) | 29 (26.6) | |
| Other determined etiology | 18 (6.0) | 4 (3.7) | |
| Undetermined | 44 (14.7) | 12 (11.0) | |
| Collaterals, good (%) | 121 (40.5) | 50 (45.9) | 0.296 |
| Symptom to door (SD) | 56.4 (27.7) | 173.6 (36.7) | <0.001 |
| Door to groin puncture (SD) | 155.4 (157.0) | 166.6 (187.0) | 0.552 |
| tPA (%) | 145 (48.5) | 50 (45.9) | 0.463 |
| Number of passes (IQR) | 1 (1–3) | 1 (1–3) | 0.878 |
| TICI 2b-3 (%) | 242 (85.5) | 89 (88.1) | 0.514 |
| First pass (%) | 114 (38.1) | 45 (41.3) | 0.407 |
| Stent (%) | 46 (15.4) | 15 (13.8) | 0.766 |
| HT (%) | 52 (17.4) | 22 (20.2) | 0.460 |
| HT PH (%) | 23 (7.7) | 16 (14.7) | 0.031 |
| HT PH2 (%) | 14 (4.7) | 4 (3.7) | 0.678 |
| Symptomatic HT (%) | 7 (2.3) | 1 (0.9) | 0.368 |
| NIHSS on admission (IQR) | 16 (11–20) | 14 (10–19) | 0.662 |
| NIHSS on discharge (IQR) | 4 (1–9) | 4 (1–9) | 0.887 |
| NIHSS, delta (IQR) | 9 (2–14) | 6 (2–11) | 0.204 |
| mRS baseline (IQR) | 0 (0–1) | 0 (0–2) | 0.835 |
| mRS discharge (IQR) | 3 (2–5) | 3 (2–5) | 0.124 |
| mRS 90 (IQR) | 3 (1–5) | 3 (1–4) | 0.625 |
| Mortality (%) | 41 (13.7) | 10 (9.2) | 0.220 |
| Outcome, favorable (%) | 138 (49.6) | 44 (45.8) | 0.520 |
ACA, anterior cerebral artery; HT, hemorrhagic transformation; ICA, internal carotid artery; MCA, middle cerebral artery; mRS, modified Rankin scale; NIHSS, National Institute of Health Stroke Scale; PCA, posterior cerebral artery; PH, parenchymal hemorrhagic transformation.
p value < 0.05 was marked as bold.
The IVT + EVT cohort (n = 195, age: 71.1 ± 13.7, 53.8% male) and the direct-EVT group (n = 213, age: 68.6 ± 15.6, 47.9% male) had similar stroke etiology and comparable OTD and symptoms onset to EVT (OTE) times (Supplemental Table 1). Direct-EVT patients had higher rates of statins and antiplatelet treatment (32.4% versus 21.5%, p = 0.041, 34.1% versus 21.5%, p = 0.006, respectively), tandem lesions (18.8% versus 12.8%, p = 0.024), and carotid stent deployment during EVT procedure (23.0% versus 6.2%, p < 0.001). No differences were observed in outcome, mortality, HT, and discharge NIHSS. We further performed a sub-analysis including four patients in whom EVT was aborted due to significant clinical improvement after IVT administration. This analysis demonstrated similar results.
Bridging treatment outcome by OTD
Among patients treated with IVT + EVT, longer OTD was associated with lower rates of favorable outcome (p = 0.021), worse mRS-90 (p = 0.013), higher rates of HT (p = 0.004), and higher rates of parenchymal hemorrhagic transformation (p < 0.001). Figure 1 illustrates the changes in rates of favorable outcome, HT, and TICI-2b3 according to OTD by hours. Moreover, when comparing patients admitted in the very early time frame (OTD < 90 min) with those arriving in the delayed time frame (OTD 180–240 min), patients who arrived at the emergency department within 90 min were more likely to have favorable outcome [OR 2.81 (CI: 1.05–7.56), p = 0.024], and less likely to develop HT [OR 0.35 (CI: 0.14–0.9), p = 0.029].
Figure 1.
Changes in rates of favorable outcome, HT, parenchymal hemorrhagic transformation, and TICI-2b3 according to OTD by hours.
HT, hemorrhagic transformation; OTD, onset to door; TICI, thrombolysis in cerebral infarction.
On the contrary, among direct-EVT patients with OTD < 4 h, no significant association was found between OTD and favorable outcome, mRS-90, HT, or TICI 2b-3 rates (Figure 1).
Bridging treatment versus direct-EVT in OTD < 2 h
In all, 299 patients had arrived at the emergency department within 120 min of symptoms onset or last well time. Direct-EVT (n = 154, age 68.3 ± 15.2, 47.4% males) and IVT + EVT patients (n = 145, age: 70.4 ± 14.5, 54.5% males) had similar thrombus location, stroke etiology, OTD, or OTE time frames (Table 2). Direct-EVT patients had higher rates of hypertension (70.1% versus 59.3%, p = 0.05), statins and antiplatelet treatment (35.7% versus 18.6%, p = 0.004, 34.6% versus 22.9%, p = 0.026, respectively), and carotid stent deployment during EVT procedure (22.7% versus 7.6%, p < 0.001) compared with IVT + EVT patients.
Table 2.
Direct-EVT versus IVT + EVT in patients with symptoms to door <2 h.
| Characteristics | Direct-EVT N = 154 | IVT + EVT N = 145 | p Value |
|---|---|---|---|
| Age (SD) | 68.3 (15.2) | 70.4 (14.5) | 0.212 |
| Sex: male (%) | 73 (47.4) | 79 (54.5) | 0.221 |
| Hypertension (%) | 108 (70.1) | 86 (59.3) | 0.05 |
| Diabetes (%) | 49 (31.8) | 42 (29.0) | 0.592 |
| Hyperlipidemia (%) | 79 (51.3) | 68 (46.9) | 0.447 |
| Smoking (%) | 44 (28.6) | 38 (26.2) | 0.647 |
| Atrial fibrillation (%) | 53 (34.4) | 50 (34.5) | 0.614 |
| Ischemic heart disease (%) | 52 (33.8) | 45 (31.0) | 0.811 |
| Valvular disease (%) | 6 (3.9) | 7 (6.4) | 0.360 |
| Congestive heart failure (%) | 15 (9.7) | 17 (11.7) | 0.897 |
| Chronic renal failure (%) | 10 (6.5) | 7 (4.8) | 0.525 |
| Prior stroke (%) | 27 (17.5) | 20 (13.8) | 0.375 |
| Malignancy (%) | 20 (12.9) | 12 (8.3) | 0.081 |
| Statins (%) | 55 (35.7) | 27 (18.6) | 0.004 |
| Antiplatelets (%) | 53 (34.6) | 33 (22.9) | 0.026 |
| Vessel lesion (%) | 0.159 | ||
| ICA | 37 (24.0) | 27 (18.6) | |
| M1 MCA | 81 (52.6) | 79 (54.5) | |
| M2 MCA | 20 (13.0) | 24 (16.6) | |
| Basilar | 7 (4.5) | 9 (6.2) | |
| ACA | 2 (1.3) | 1 (0.7) | |
| PCA | 0 (0) | 1 (0.7) | |
| Tandem lesion | 26 (16.8) | 17 (11.7) | 0.074 |
| Side, right (%) | 75 (48.7) | 66 (45.5) | 0.384 |
| TOAST (%) | 0.748 | ||
| Cardioembolism | 83 (53.9) | 80 (55.2) | |
| Large artery atherosclerosis | 34 (22.1) | 25 (17.2) | |
| Other determined etiology | 7 (4.5) | 11 (7.6) | |
| Undetermined | 24 (15.6) | 20 (13.8) | |
| Collaterals, good (%) | 61 (45.2) | 59 (56.2) | 0.177 |
| Symptom to door (SD) | 54.6 (31.7) | 58.4 (22.5) | 0.246 |
| Door to groin puncture (SD) | 149.2 (189.4) | 161.7 (115.1) | 0.501 |
| Number of passes (IQR) | 1 (1–3) | 1 (13) | 0.691 |
| TICI 2b-3 (%) | 117 (80.7) | 125 (86.2) | 0.038 |
| PH (%) | 15 (9.7) | 8 (5.5) | 0.161 |
| First pass (%) | 65 (42.2) | 49 (33.8) | 0.855 |
| Stent (%) | 35 (22.7) | 11 (7.6) | <0.001 |
| HT (%) | 29 (18.8) | 23 (15.8) | 0.553 |
| HT PH (%) | 15 (10) | 8 (5.6) | 0.161 |
| HT PH2 (%) | 9 (5.9) | 5 (3.5) | 0.328 |
| Symptomatic HT (%) | 5 (3.2) | 2 (1.4) | 0.295 |
| NIHSS on admission (IQR) | 16 (11–20) | 15 (10–20) | 0.197 |
| NIHSS on discharge (IQR) | 4 (1–11) | 4 (1–7) | 0.122 |
| NIHSS, delta (IQR) | 9 (3–14) | 8 (2–13) | 0.218 |
| mRS baseline (IQR) | 0 (0–2) | 0 (0–1) | 0.568 |
| mRS discharge (IQR) | 3 (2–5) | 3 (2–5) | 0.845 |
| mRS 90 (IQR) | 3 (1–5) | 3 (2–4) | 0.886 |
| Mortality (%) | 19 (12.3) | 22 (15.2) | 0.476 |
| Outcome, favorable (%) | 71 (50.7) | 67 (48.6) | 0.718 |
ACA, anterior cerebral artery; HT, hemorrhagic transformation; ICA, internal carotid artery; MCA, middle cerebral artery; mRS, modified Rankin scale; NIHSS, National Institute of Health Stroke Scale; PCA, posterior cerebral artery; PH, parenchymal hemorrhagic transformation.
p value < 0.05 was marked as bold.
IVT + EVT patients had higher rates of TICI 2b-3 compared to direct-EVT (86.2% versus 80.2%, p = 0.038). In a multivariate analysis, bridging treatment remained the only significant predictor for achieving TICI-2b3 [OR 2.89 (1.24–6.78), p = 0.014] (Supplemental Table 2). No differences were found in the rates of favorable outcome, mortality, and HT.
Bridging treatment versus direct-EVT in OTD of 2–4 h
In all, 109 patients had arrived at the emergency department 2–4 h of symptoms onset or last well time. Direct-EVT (n = 59, age: 69.5 ± 16.9, 49.2 males) and IVT + EVT patients (n = 50, age: 72.4 ± 11.3, 52% males) had similar baseline characteristics, thrombus location, stroke etiology, OTD, or STE time frames (Table 3). Direct-EVT patients had lower rates of previous stroke (6.8% versus 20%, p = 0.04) and higher rates of carotid stent deployment during EVT procedure (23.7% versus 2.0%, p < 0.001) compared with IVT + EVT patients.
Table 3.
Direct-EVT versus IVT + EVT in patients with symptoms to door time of 2–4 h.
| Characteristics | Direct-EVT N = 59 | IVT + EVT N = 50 | p Value |
|---|---|---|---|
| Age (SD) | 69.5 (16.9) | 72.4 (11.3) | 0.319 |
| Sex: male (%) | 29 (49.2) | 26 (52.0) | 0.767 |
| Hypertension (%) | 41 (69.5) | 40 (80.0) | 0.211 |
| Diabetes (%) | 19 (32.2) | 18 (36.0) | 0.677 |
| Hyperlipidemia (%) | 27 (45.8) | 24 (48.0) | 0.816 |
| Smoking (%) | 18 (30.5) | 13 (26.0) | 0.603 |
| Atrial fibrillation (%) | 20 (33.9) | 15 (30.0) | 0.664 |
| Ischemic heart disease (%) | 18 (30.5) | 16 (32.0) | 0.867 |
| Valvular disease (%) | 3 (5.1) | 4 (8.0) | 0.536 |
| Congestive heart failure (%) | 5 (8.5) | 4 (8.0) | 0.752 |
| Chronic renal failure (%) | 5 (8.5) | 6 (12.0) | 0.563 |
| Prior stroke (%) | 4 (6.8) | 10 (20.0) | 0.04 |
| Malignancy (%) | 6 (10.2) | 8 (16.0) | 0.465 |
| Statins (%) | 14 (23.7) | 15 (30.0) | 0.375 |
| Antiplatelets (%) | 19 (32.2) | 9 (18.0) | 0.092 |
| Vessel lesion (%) | 0.744 | ||
| ICA | 15 (25.4) | 11 (22.0) | |
| M1 MCA | 26 (44.1) | 26 (52.0) | |
| M2 MCA | 10 (16.9) | 11 (22.0) | |
| Basilar | 2 (3.4) | 1 (2.0) | |
| ACA | 1 (1.7) | 0 (0) | |
| PCA | 0 (0) | 0 (0) | |
| Tandem lesion | 14 (23.7) | 8 (16.0) | 0.179 |
| Side, right (%) | 29 (49.2) | 21 (42.0) | 0.702 |
| TOAST (%) | 0.767 | ||
| Cardioembolism | 30 (50.8) | 27 (54.0) | |
| Large artery atherosclerosis | 19 (32.2) | 10 (20.) | |
| Other determined etiology | 3 (5.1) | 1 (2.0) | |
| Undetermined | 3 (5.1) | 9 (18.0) | |
| Collaterals, good (%) | 30 (50.8) | 20 (40.0) | 0.501 |
| Symptom to door (SD) | 168.8 (36.9) | 178.9 (36.1) | 0.160 |
| Door to groin puncture (SD) | 172.8 (220.7) | 161.9 (143.1) | 0.773 |
| tPA (%) | 144 (48.5) | 47 (44.3) | 0.463 |
| Number of passes (IQR) | 1 (1–3) | 1 (1–3) | 0.659 |
| TICI 2b-3 (%) | 50 (84.7) | 39 (78.0) | 0.136 |
| First pass (%) | 28 (47.4) | 17 (34.0) | 0.437 |
| Stent (%) | 14 (23.7) | 1 (2.0) | <0.001 |
| HT (%) | 5 (8.5) | 17 (34.0) | <0.001 |
| HT PH (%) | 3 (5.2) | 13 (27.1) | 0.002 |
| HT PH2 (%) | 1 (1.7) | 3 (6.0) | 0.224 |
| Symptomatic HT (%) | 0 (0) | 1 (2.0) | 0.259 |
| NIHSS on admission (IQR) | 12 (7–19) | 14 (11–19) | 0.168 |
| NIHSS on discharge (IQR) | 3 (1–8) | 7 (2–13) | 0.024 |
| NIHSS, delta (IQR) | 6 (2–11) | 5 (2–11) | 0.586 |
| MRS baseline (IQR) | 0 (0–1) | 0 (0–2) | 0.205 |
| MRS discharge (IQR) | 3 (1–4) | 4 (3–5) | 0.007 |
| MRS 90 (IQR) | 2 (1–4) | 3 (2–4) | 0.423 |
| Mortality (%) | 7 (11.9) | 3 (6.0) | 0.291 |
| Outcome, favorable (%) | 29 (56.9) | 15 (33.3) | 0.021 |
ACA, anterior cerebral artery; HT, hemorrhagic transformation; ICA, internal carotid artery; IQR, Interquartile range; MCA, middle cerebral artery; mRS, modified Rankin scale; NIHSS, National Institute of Health Stroke Scale; PCA, posterior cerebral artery; PH, parenchymal hemorrhagic transformation; tPA, tissue plasminogen activator.p value < 0.05 was marked as bold.
In patients with OTD of 2–4 h, patients receiving bridging treatment in comparison to direct-EVT patients had lower rates of favorable outcome (33.3% versus 56.9%, p = 0.021), higher rates of HT (34.0% versus 8.5%, p < 0.001), higher rates of parenchymal hemorrhagic transformation (27.1% versus 5.2%, p = 0.002), worse NIHSS on discharge [7 (2–13) versus 3 (1–8), p = 0.024], and worse mRS on discharge [4 (3–5) versus 3 (1–4), p = 0.007). In a multivariate analysis, bridging therapy remained significantly associated with HT [OR 6.25 (1.61–24.24), p = 0.008), parenchymal hemorrhagic transformation [OR 7.32 (1.26–42.51), p = 0.027], and had a nearly significant trend for unfavorable outcome [OR = 2.37 (0.95–5.93), p = 0.064, Supplemental Table 3).
Discussion
In this observational study, we demonstrated the pivotal impact of timing of bridging-IVT on the clinical, radiological, and EVT procedural outcomes. OTD times were associated with the rates of favorable outcome, mRS-90, and HT among patients receiving IVT + EVT but not in those treated with direct-EVT. We found that for patients presenting 0–2 h from onset, bridging-IVT was associated with a beneficial effect on procedural outcomes manifested by achieving higher rates of target recanalization. This finding is in agreement with the previously published meta-analyses showing the overall positive effect of bridging-IVT on successful recanalization rates.2,4 By contrast, in the 2–4 h OTD patients, IVT was not associated with higher rates of target recanalization and was associated with higher rates of HT and poor outcomes. We further demonstrated that the beneficial effect of thrombolysis is higher among patients with OTD below 90 min, and lowest among patients with OTD above 180 min. Our results are supported by the results of a recent study, which demonstrated that bridging-IVT efficacy was associated with IVT timing. However, that trial used door-to-needle times and not OTD and did not examine IVT timing impact on safety and HT. 16
The beneficial effect of thrombolysis is known to decrease with the time passed since symptoms onset. 5 Previous studies have demonstrated that the help-to-harm ratio of thrombolysis is 18.1 for patients treated within 90 min versus 5.0 for patients treated 180–270 min from onset. 17 In a recent propensity score matching study compared with the non-IVT group, thrombolysis performed within 2 h significantly reduced the risk of 3-month mortality by 37%, whereas thrombolysis performed between 2 and 4.5 h significantly reduced the risk of 3-month mortality by only 26%. 18 It should also be noted that the beneficial effect of thrombolysis is lower in patients with LVO compared with more distal occlusions. 19 Moreover, the safety of IV tissue plasminogen acctivator (tPA) diminishes with time from symptom onset in the setting of large territory ischemic strokes that are more prone to undergo HT. 19 Indeed, in the current study, in patients presenting within the 2- to 4-h OTD timeframe, bridging-IVT was associated with higher rates of HT and ultimately worse functional outcomes. Furthermore, among direct-EVT patients, longer OTD times were not associated with worse outcomes or higher rates of HT. As most patients are being selected for EVT based on imaging findings, prolongation of times does not significantly impact EVT results. This was previously found in various studies including the randomized trials which demonstrated EVT to be beneficial in patients in the delayed time frame for intervention.20,21 Therefore, the association found here between OTD and the impact of bridging treatment cannot be solely explained by the effect of time lapsed, rather it probably derives from IVT-related complications or toxicity. 6 Possibly, as previously suggested, 22 the worse outcome in the IVT + EVT group may be partially attributed to asymptomatic forms of HT. This may be supported by the higher rates of any parenchymal hemorrhagic transformation associated with bridging treatment in the current study.
Our study illuminates OTD as a possible simple parameter for patient selection for bridging-IVT treatment. We believe that our findings may also explain the conflicting results of previous trials. To date, six randomized control trials have been conducted to examine IVT bridging treatment, of those four reported beneficial effect23–26 while two found non-inferiority of direct-EVT approach.27,28 When examining these RCTs, a suggested association between time to randomization and IVT impact arises – IVT + EVT demonstrated favorable outcome in all trials with a median time to randomization of 151 min or less, while in trials supporting direct-EVT, the median time to randomization was 168 min and above. A similar trend is found when looking at the results of large registries. In the Italian registry, which reported bridging treatment has a beneficial effect, the median OTD was 95 min. 29 Whereas, in two other register cohorts that reported no benefit of thrombolysis, the median OTD values were 110 and 171 min.30,31
These findings support the results of our study and point out that OTD has a major role in patient selection for bridging treatment. Moreover, our study possibly suggests the superiority of direct-EVT among patients with OTD of 2–4 h and may suggest avoiding IVT among such patients, as it was associated with worse outcomes and higher rates of HT. However, these results should be interpreted with caution. Further studies are needed to better determine the selection for bridging treatment, including studies focusing on the inter-relation between bridging treatment and OTD in other large cohorts, as well as examining other factors such as imaging parameters. Only a few studies to date have focused on patient selection parameters for bridging therapy. These studies reported no association with the occlusion site, age, or the presence of atrial fibrillation.32–34 A post hoc analysis of the MR-CLEAN-NO-IV trial has demonstrated an association with the first-line thrombectomy technique used. 35 Other parameters may include pre-treatment with antiplatelets or statins. 36 Pre-treatment with statins was previously reported to be associated with better outcomes among LVO patients.37,38 However, in our cohort, higher rates of statins pre-treatment were found among direct-EVT patients and were not associated with outcome or recanalization rates after multi-variant analysis.
Study limitations include the observational nature of our study and the relatively small number of posterior circulation LVO cases. Second, as direct-EVT was allowed if the neuroendovascular team was present in the hospital and according to the discretion of the senior stroke neurologists, a potential selection bias cannot be excluded. However, it should be noted that no significant differences were found between groups. Third, we could not compare patients with witnessed onset to those with wake-up stroke due to insufficient data and small numbers. Finally, we did not include in our study time frames of achieving successful recanalization.
Conclusion
In this study, we found OTD times to have a significant effect on the impact of IVT bridging treatment. Our study shows that among patients in the earlier time frame of 0–120 min from symptom onset, bridging treatment may be associated with favorable effects. By contrast, in patients with OTD above 2 h, IVT was associated with poor outcomes, a finding that could suggest refraining from IVT in such patients. However, our findings should be viewed as hypothesis-generating and need corroboration in larger time-sensitive randomized clinical trials.
Supplemental Material
Supplemental material, sj-docx-1-tan-10.1177_17562864231216637 for The pivotal role of timing of intravenous thrombolysis bridging treatment prior to endovascular thrombectomy by Jeremy Molad, Hen Hallevi, Estelle Seyman, Einor Ben-Assayag, Tali Jonas-Kimchi, Udi Sadeh, Ofer Rotschild, Naaem Simaan, Anat Horev, Jose Cohen, Ronen R. Leker and Asaf Honig in Therapeutic Advances in Neurological Disorders
Acknowledgments
None.
Footnotes
ORCID iDs: Jeremy Molad 
https://orcid.org/0000-0001-6868-4849
Asaf Honig
https://orcid.org/0000-0002-9489-0133
Supplemental material: Supplemental material for this article is available online.
Contributor Information
Jeremy Molad, Department of Stroke and Neurology, Tel-Aviv Sourasky Medical Center, 6 Weizmann Street, Tel-Aviv 64239, Israel.
Hen Hallevi, Department of Stroke and Neurology, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel; Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
Estelle Seyman, Department of Stroke and Neurology, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel.
Einor Ben-Assayag, Department of Stroke and Neurology, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel; Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
Tali Jonas-Kimchi, Department of Radiology, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel.
Udi Sadeh, Department of Radiology, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel.
Ofer Rotschild, Department of Stroke and Neurology, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel.
Naaem Simaan, Department of Neurology, Ziv Medical Center, Safed, Israel.
Anat Horev, Department of Neurology, Soroka Medical Center, Beer-Sheva, Israel.
Jose Cohen, Department of Neurosurgery, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Ronen R. Leker, Department of Neurology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
Asaf Honig, Department of Neurology, Soroka Medical Center, Beer-Sheva, Israel.
Declarations
Ethics approval and consent to participate: The study was approved by the Institutional Review Boards of the Hadassah-Hebrew University Medical Center (HMO 18-0378) and the Tel-Aviv Sourasky Medical Center (18-0535). The need for patient consent was waived due to the retrospective design of this study.
Consent for publication: Not applicable.
Author contributions: Jeremy Molad: Conceptualization; Data curation; Formal analysis; Methodology; Project administration; Writing – original draft.
Hen Hallevi: Conceptualization; Supervision; Writing – review & editing.
Estelle Seyman: Data curation; Writing – review & editing.
Einor Ben-Assayag: Formal analysis; Writing – review & editing.
Tali Jonas-Kimchi: Data curation; Investigation; Writing – review & editing.
Udi Sadeh: Data curation; Writing – review & editing.
Ofer Rotschild: Data curation; Investigation; Writing – review & editing.
Naaem Simaan: Data curation; Investigation; Writing – review & editing.
Anat Horev: Data curation; Writing – review & editing.
Jose Cohen: Data curation; Writing – review & editing.
Ronen R. Leker: Methodology; Supervision; Writing – review & editing.
Asaf Honig: Conceptualization; Data curation; Methodology; Project administration; Writing – original draft.
Funding: The authors received no financial support for the research, authorship, and/or publication of this article.
The authors declare that there is no conflict of interest.
Availability of data and materials: Full data is available following a formal reasonable request and in compliance with state and participating centers’ regulations.
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Associated Data
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Supplementary Materials
Supplemental material, sj-docx-1-tan-10.1177_17562864231216637 for The pivotal role of timing of intravenous thrombolysis bridging treatment prior to endovascular thrombectomy by Jeremy Molad, Hen Hallevi, Estelle Seyman, Einor Ben-Assayag, Tali Jonas-Kimchi, Udi Sadeh, Ofer Rotschild, Naaem Simaan, Anat Horev, Jose Cohen, Ronen R. Leker and Asaf Honig in Therapeutic Advances in Neurological Disorders