Dear Sir:
The Endovascular Treatment of Acute Basilar-Artery Occlusion (ATTENTION) and Thrombectomy 6 to 24 Hours after Stroke Due to Basilar-Artery Occlusion (BAOCHE) trials demonstrated the superiority of endovascular treatment (EVT) over the best medical management (BMM) in patients with basilar artery occlusion (BAO) [
1,
2]. The time from stroke onset to treatment decreased the degree of benefit conferred by EVT in patients with anterior circulation [
3-
5]. However, it remains unclear whether the time to treatment modifies the treatment effect size of EVT in patients with BAO.
We sought to examine the effect of the time from stroke onset to hospital arrival (both as categorical [<6 h vs. ≥6-12 h vs. ≥12-24 h] and continuous variables) on the effectiveness and safety of EVT in this pre-specified secondary analysis of the ATTENTION registry.
The primary outcome measure was the distribution of the modified Rankin Scale (mRS) score at 90 days, which was assessed by board-certified vascular neurologists as part of usual care for all patients with stroke in all participating centers. The secondary clinical outcomes were as follows: comparisons of mRS scores (0 or 1 vs. 2 to 6; 0 to 2 vs. 3 to 6; 0 to 3 vs. 4 to 6) at 90 days, the National Institutes of Health Stroke Scale (NIHSS) score at 24 hours and at 5 to 7 days (or at the time of hospital discharge), and successful reperfusion according to the post-intervention modified Thrombolysis in Cerebral Infarction score. Safety outcomes included symptomatic intracranial hemorrhage (sICH) and mortality at 90 days. Additional statistical methods are represented in
Supplementary Methods.
A total of 2,134 patients were enrolled in the ATTENTION registry from March 2017 to February 2021. Of these, 1,672 received EVT, and 462 received BMM. The baseline characteristics of the patients in different time windows are summarized in
Supplementary Table 1. The median onset-to-hospital time was 333 minutes (interquartile range [IQR]: 219-584 min) for the EVT group and 335 minutes (IQR: 207-613 min) for the BMM group. Patients with a longer onset-to-hospital time had higher posterior circulation Alberta Stroke Program Early Computed Tomography Score (pc-ASPECTS) scores, higher rates of hyperlipidemia, and a lower incidence of intravenous thrombolysis. The causative mechanisms of stroke differed significantly according to the time from onset to hospital arrival.
The 90-day mRS score distribution according to treatment allocation for each onset-to-door time subgroup is shown in
Supplementary Figure 1. No significant interaction was observed between the treatment and trichotomized onset-to-door time for ordinal mRS scores (adjusted
P for interaction=0.92). The interaction was not significant when analyzed as a continuous variable (adjusted
P for interaction=0.66). Similarly, no significant interactions were observed for any secondary endpoints (
Table 1).
In the adjusted model, the trichotomized onset-to-door time was not associated with the 90-day ordinal mRS scores or 90-day mortality rates (
Table 2). In addition, there were no significant associations between onset-to-door time as a continuous variable and the predicted probabilities of achieving mRS scores of 0-3, 0-2, 0-1, death at 90 days, sICH at 24 hours, or NIHSS at 24 hours and 5-7 days (
Supplementary Figure 2). We analyzed the correlation between onset-to-door time and endpoints across intervals but found no significant associations (
Supplementary Table 2).
This pre-specified analysis of the ATTENTION registry indicates that the EVT treatment effect compared to medical management is not modified by onset-to-door time intervals. Additionally, time to hospital arrival was not a predictor of prognosis.
Several studies have shown a direct link between shorter time-to-treatment and improved functional outcomes in patients undergoing EVT [
4,
5]. Certain analyses have shown a more nuanced relationship between time to treatment and functional outcomes [
6,
7]. The BEST (Endovascular Treatment Versus Standard Medical Treatment for Vertebrobasilar Artery Occlusion) trial showed an unexpected link between EVT efficacy and time from onset to randomization. In patients randomized within 260 minutes, EVT was not superior to medical management (odds ratio [OR] 0.86, 95% confidence interval [CI] 0.31-2.38). However, EVT significantly improved functional outcomes for those randomized after 260 minutes compared to standard care (OR 2.86, 95% CI 1.02-7.97) [
8]. This may be due to a higher rate of intravenous thrombolysis in control patients during the earlier window, leading to better outcomes compared to the later window. In a prospective study of 184 patients with BAO, most of whom were treated with intravenous thrombolysis and recanalization without extensive baseline ischemia (pc-ASPECTS ≥8) up to 48 hours from onset, good outcomes were observed in half of the patients, independent of time to treatment [
9].
In line with our findings, the BEST trial reported that the time from symptom onset to randomization was not associated with the proportion of mRS scores 0-3 at 90 days (OR 1.00, 95% CI 1.00-1.00, P=0.67) [
8]. Additionally, in the BAOCHE trial, the proportion of patients with mRS scores of 0-3 was similar between those randomized within 6-12 hours (45.3%) and 12-24 hours (47.8%) [
2]. The lack of an association between the time from stroke onset and treatment in our study may be related to several factors. The most likely explanation might be related to differences in stroke burden at presentation across different time periods in different studies. Therefore, our findings are in alignment with an analysis of the REVASCAT (Randomized Trial of Revascularization With Solitaire FR Device Versus Best Medical Therapy in the Treatment of Acute Stroke due to Anterior Circulation Large Vessel Occlusion Presenting Within Eight Hours of Symptom Onset) trial, which demonstrated that the time from symptom onset to reperfusion was strongly associated with outcomes in patients with low ASPECTS scores but not in patients with high ASPECTS scores [
10]. The similar impact of EVT across the three time thresholds could be linked to the fact that infarct growth may be slower in patients with BAO than in those with anterior circulation occlusions. Because large-artery atherosclerosis was the mechanism of stroke in approximately 40% of our cohort, the development of collaterals may be more robust, thereby sustaining tolerance to ischemia over a longer period.
The main limitation of this analysis was the small number of patients in the onset-to-door time >12-24 hours category, which may have resulted in an underpowered test for the interaction between onset-to-door time and treatment allocation. Second, despite adjustments for patient- and hospital-level factors, selection bias and residual confounding factors could have affected the study findings. Third, most patients in the cohort had high pc-ASPECTS, indicating a small infarct burden; therefore, it is unclear whether the observed lack of time sensitivity to EVT treatment applies to patients with more extensive basilar artery infarctions.
Supplementary materials
Supplementary Table 2.
Association of onset-to-arrival time as continuous variables and each outcome for treatment across three time windows in patients received EVT
jos-2024-03874-Supplementary-Table-2.pdf
Supplementary Figure 1.
Modified Rankin Scale (mRS) score distribution at 90 days according to treatment arms and onset-to-door time. EVT, endovascular treatment; BMM, best medical management.
jos-2024-03874-Supplementary-Fig-1.pdf
Supplementary Figure 2.
Predicted probability of outcomes in relation to continuous variation in estimated BAO to hospital arrival time, adjusted for covariates. The estimated time of BAO was defined as the time of sudden onset of basilar-artery stroke symptoms, with no consideration of any preceding minor prodromal symptoms. For patients whose stroke was evident on awakening or who had an unwitnessed time of stroke onset because of unconsciousness, the time was calculated from the time at which the patient was last seen to be well. Predicted probabilities (solid lines) and 95% confidence intervals (dotted lines) were controlled for covariates listed in the main text. Curves show the adjusted predicted outcome rate for a hypothetical patient with mean values for baseline characteristics across the range of estimated BAO to hospital arrival time, for outcomes of (A) mRS 0-3 at 90 days, (B) mRS 0-2 at 90 days, (C) mRS 0-1 at 90 days, (D) mTICI 2b/3, (E) sICH, (F) death at 90 days, (G) NIHSS at 24 hours, (H) NIHSS at 5-7 days or at discharge. BAO, basilar artery occlusion; mRS, modified Rankin Scale; mTICI, modified Thrombolysis in Cerebral Infarction; sICH, symptomatic intracranial hemorrhage; NIHSS, National Institutes of Health Stroke Scale.
jos-2024-03874-Supplementary-Fig-2.pdf
Acknowledgments
We thank staff and participants in the ATTENTION Registry for their contribution to the collection of data.
Table 1.
Endovascular thrombectomy effect by onset-to-door time subgroups
|
<6 hours (n=1,129) |
≥6-12 hours (n=733) |
≥12-24 hours (n=272) |
P for interaction |
Clinical outcomes |
|
|
|
|
mRS at 90 days*
|
1.60 (1.22, 2.11) |
1.38 (0.96, 1.97) |
1.63 (0.91, 2.94) |
0.92 |
mRS 0-3 at 90 days†
|
1.51 (1.24, 1.83) |
1.20 (0.90, 1.61) |
1.21 (0.80, 1.82) |
0.51 |
mRS 0-2 at 90 days†
|
1.55 (1.23, 1.96) |
1.14 (0.83, 1.57) |
1.39 (0.74, 2.59) |
0.28 |
mRS 0-1 at 90 days†
|
1.31 (0.97, 1.76) |
0.91 (0.65, 1.28) |
1.38 (0.65, 2.96) |
0.36 |
NIHSS score at 24 hours‡
|
-0.03 (-2.00, 1.93) |
-0.89 (-3.41, 1.64) |
0.19 (-3.94, 4.31) |
0.54 |
NIHSS score at 5-7 days or discharge‡
|
-2.40 (-4.50, -0.3) |
-0.15 (-2.66, 2.35) |
-4.68 (-8.65, -0.71) |
0.55 |
Safety outcomes |
|
|
|
|
Mortality at 90 days†
|
0.61 (0.44, 0.84) |
0.66 (0.44, 1.00) |
0.59 (0.31, 1.13) |
0.87 |
sICH at 3 days†
|
12.74 (1.73, 93.84) |
2.68 (0.76, 9.50) |
NA |
0.74 |
Table 2.
Association of onset-to-arrival time and each outcome for treatment in patients who received EVT
|
<6 hours (n=1,129) |
≥6-12 hours (n=733) |
≥12-24 hours (n=272) |
P for trend |
Clinical outcomes |
|
|
|
|
mRS at 90 days*
|
Ref |
0.93 (0.73, 1.19) |
0.87 (0.68, 1.10) |
0.18 |
mRS 0-3 at 90 days†
|
Ref |
0.98 (0.85, 1.12) |
0.96 (0.79, 1.17) |
0.68 |
mRS 0-2 at 90 days†
|
Ref |
0.93 (0.79, 1.08) |
0.92 (0.72, 1.17) |
0.38 |
mRS 0-1 at 90 days†
|
Ref |
0.88 (0.72, 1.07) |
0.93 (0.68, 1.27) |
0.43 |
NIHSS score at 24 hours‡
|
Ref |
0.05 (-1.53, 1.62) |
0.52 (-1.60, 2.65) |
0.68 |
NIHSS score at 5-7 days or discharge‡
|
Ref |
0.56 (-1.05, 2.18) |
-0.36 (-2.64, 1.91) |
0.36 |
mTICI 2b-3†
|
Ref |
0.99 (0.95, 1.03) |
1.01 (0.94, 1.08) |
0.98 |
Safety outcomes |
|
|
|
|
Mortality at 90 days†
|
Ref |
1.03 (0.88, 1.20) |
1.02 (0.83, 1.25) |
0.81 |
sICH at 3 days†
|
Ref |
0.88 (0.57, 1.35) |
1.28 (0.77, 2.13) |
0.58 |
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