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J Stroke > Volume 27(1); 2025 > Article
Siddiqi, Ignacio, Kaveeta, Bala, Ademola, Tkach, Buck, Catanese, Hunter, Dowlatshahi, Shamy, Zafar, Field, Appireddy, Wadhwa, Sajobi, Swartz, Almekhlafi, Demchuk, Menon, and Singh: Thrombolysis in Patients With Versus Without Visible Occlusion: A Secondary Analysis From the AcT Trial
Dear Sir:
Approximately 70% of patients who present with symptoms of acute ischemic stroke (AIS) have no visible occlusion (NVO) on intracranial computed tomography angiography (CTA) [1]. These patients may either have lacunar stroke, intracranial pial arterial occlusions that are not visible on CTA, vascular stenosis resulting in hypoperfusion, spontaneous recanalization, or conditions that are stroke mimics. Owing to these different mechanisms, current data on the safety and efficacy of intravenous thrombolysis in patients with NVO is conflicting [2,3]. The aim of the current study, from the phase 3 Alteplase Compared to Tenecteplase in Patients With Acute Ischemic Stroke (AcT) randomized controlled trial, is to report on safety and efficacy outcomes in patients with NVO versus those with visible occlusion (VO) on baseline CTA who received thrombolysis.
This sub-study is an exploratory analysis of the AcT trial, which randomized adult patients with stroke symptoms, eligible for intravenous thrombolysis as per guidelines, to either alteplase or tenecteplase [4,5]. The trial was regulated by Health Canada and approved by research ethics boards at all participating sites. The trial used deferred consent procedures wherever approved by local research ethics boards. The current analysis included patients with interpretable baseline CT angiogram who received intravenous thrombolysis. An independent blinded imaging core lab with 4-20 years of experience read all imaging data. VO was defined as any occluded artery visualized on baseline CTA. NVO were those patients who did not have any intracranial occlusion on baseline CTA. Safety outcomes included symptomatic intracerebral hemorrhage (sICH) within 24 hours, mortality, and evidence of bleeding on follow-up imaging as per the Heidelberg Bleeding Classification described in the trial protocol [5] (Supplementary Methods). Functional outcomes included modified Rankin Scale (mRS) [6] 0-1, mRS 0-2, ordinal mRS at 90-120 days, return to pre-stroke function, length of stay in hospital, and EuroQol 5-Dimension 5-Level (EQ-5D-5L).
Baseline characteristics and imaging variables were described in patients with NVO as compared to VO using descriptive statistics. Categorical variables were expressed as frequencies with percentages and quantitative variables as medians with interquartile ranges or means with standard deviations as appropriate per distribution of data. Fisher’s exact test and Wilcoxon rank sum test or t-test were used for categorical and continuous variables, respectively, as appropriate. Adjusted analyses were performed using mixed-effects models adjusted for age, sex, baseline stroke severity (National Institutes of Health Stroke Scale [NIHSS] score), thrombolytic type, and stroke onset-to-needle time as fixed effect variables, and participating site as random effect variable. All analyses were considered exploratory. Statistical significance was defined as 2-tailed P value ≤0.05. Analyses was performed using Stata/MP version 16.0 (StataCorp., College Station, TX, USA).
Of 1,577 patients randomized in the AcT trial, 1,470 (93.2%) patients received thrombolysis within 4.5 hours, had baseline CTA available, and were included in the study (Supplementary Figure 1). Of 1,470 patients, 479 (32.6%; 247 receiving tenecteplase and 232 receiving alteplase) were in NVO group and 991 (67.4%; 509 receiving tenecteplase and 482 receiving alteplase) were in VO group. Patients in NVO group were younger (median 71 yr vs. 75 yr, P<0.001), presented with less severe strokes (median NIHSS 6 vs. 12, P<0.001), and had longer onset to needle time (median 141 min vs. 119 min, P<0.001) (Table 1). In VO group, 493 (49.7%) patients received endovascular treatment.
Comparing safety outcomes, rates of any intracranial hemorrhage and type II hemorrhagic infarction were significantly lower in NVO group (8.2% vs. 26.0%, adjusted relative risk [RR] 0.38, 95% confidence interval [CI], 0.26-0.55 and 2.5% vs. 11.2% adjusted RR 0.23, 95% CI, 0.12-0.42; respectively). There was no difference between groups for other hemorrhage subtypes, sICH rates, and other safety outcomes (Table 2 and Figure 1A). Patients in NVO group had significantly lower mortality (8.1% vs. 19.1%, adjusted RR 0.67, 95% CI, 0.46-0.98). Comparing efficacy outcomes, patients in NVO group had significantly shorter hospital stay (4 vs. 6 days; adjusted RR 0.70, 95% CI, 0.67-0.73). Rates of excellent functional outcome (mRS 0-1), functional independence (mRS 0-2), and return to baseline function at 90 days were similar between two groups in unadjusted and adjusted analyses (Table 2 and Figure 1B). Baseline characteristics, safety outcomes, and efficacy outcomes of tenecteplase and alteplase groups are provided in the Supplementary Tables 1-3 and Supplementary Figures 2 and 3. There were no differences in any outcomes between alteplase and tenecteplase arms in the NVO group.
In this exploratory analysis from the AcT trial, patients in the NVO group, compared to those in the VO group, had lower mortality rates. The group also had numerically lower rates of sICH and higher rates of excellent functional outcomes, although this did not reach significance. These results are also similar when compared to overall trial results [7]. Consistent with previous studies [3,8], the current study shows that thrombolysis, either with alteplase or tenecteplase, is safe in patients with AIS symptoms with NVO compared to those with VO. This can be due to several reasons. First, some of the patients may have had lacunar strokes, which potentially have better outcomes [9]. Second, a minority of patients in the NVO group may have recanalized prior to any imaging. Lastly, some of the patients in the NVO group may have been stroke mimics who have better outcomes and lower rates of ICH compared to those with AIS [10].
Patients in the NVO group had longer onset-to-needle and even door-to-needle times as compared to the VO group. This may be due to the challenge that accompanies clinical decision-making for these AIS patients for different reasons. Firstly, patients in the NVO group might have presented with less severe symptoms, which could lead to a delayed recognition of stroke or a lower urgency to initiate treatment. Additionally, the diagnostic processes for no vessel occlusion strokes may require more comprehensive evaluation, potentially extending the time to thrombolysis.
The fact that patients with NVO have good safety outcomes with thrombolysis is especially relevant for clinical decision-making regarding whether a patient presenting with stroke-like symptoms and NVO should receive thrombolysis. While thrombolysis is well-established to be effective for AIS, fewer patients receive thrombolysis than are eligible. The results from the present study are encouraging in that they propose that it is safe to do so and may help with rapid decision-making in the future.
One limitation of our study is that we did not analyze the number of patients that had an infarct on follow-up imaging. AcT was a pragmatic trial with most enrolled patients having a follow-up CT (51.4%), instead of magnetic resonance imaging, which may not be sensitive enough to detect small strokes and differentiate mimics. Second, we cannot comment on the efficacy of thrombolysis versus no thrombolysis with this data. Third, we do not have data on stroke etiology, which can potentially affect outcomes due to varying recurrent stroke risk. Lastly, this is an exploratory analysis, thus limiting the conclusions.
This post hoc subgroup analysis of the AcT trial suggests that intravenous thrombolysis is safe in patients with suspected ischemic stroke presenting within 4.5 hours from symptom onset with NVO on baseline imaging.

Supplementary materials

Supplementary materials related to this article can be found online at https://doi.org/10.5853/jos.2024.03062.
Supplementary Table 1.
Baseline characteristics of population with no visible occlusion that received tenecteplase versus alteplase
jos-2024-03062-Supplementary-Table-1,2.pdf
Supplementary Table 2.
Safety outcomes in patients who received tenecteplase vs. alteplase in no visible occlusion subgroup
jos-2024-03062-Supplementary-Table-1,2.pdf
Supplementary Table 3.
Efficacy outcomes in patients who received tenecteplase vs. alteplase in no visible occlusion subgroup
jos-2024-03062-Supplementary-Table-3.pdf
Supplementary Figure 1.
Flowchart of participants included in analysis. CTA, computed tomography angiography.
jos-2024-03062-Supplementary-Fig-1,2.pdf
Supplementary Figure 2.
Hemorrhage rates as per Heidelberg Bleeding Classification in patients with no visible occlusion by thrombolytic type (alteplase vs. tenecteplase). ICH, any intracranial hemorrhage; sICH, symptomatic intracerebral hemorrhage; HI1, hemorrhagic infarction type 1; HI2, hemorrhagic infarction type 2; PH1, parenchymal hematoma type 1; PH2, parenchymal hematoma type 2; rPH1, remote parenchymal hematoma type 1; rPH2, remote parenchymal hematoma type 2; SDH, subdural hemorrhage; SAH, subarachnoid hemorrhage; IVH, intraventricular hemorrhage.
jos-2024-03062-Supplementary-Fig-1,2.pdf
Supplementary Figure 3.
Outcome by visible occlusion status and thrombolytic type. Horizontal stacked bar graphs show the outcome distribution for modified Rankin Scale (mRS) at 90-120 days by visible occlusion and thrombolytic type. Bars are labeled with proportions.
jos-2024-03062-Supplementary-Fig-3.pdf

Notes

Funding statement
None
Conflicts of interest
The authors have no financial conflicts of interest.
Author contribution
Conceptualization: NS, AZS. Study design: NS. Methodology: NS, BM. Data collection: NS, AZS. Investigation: NS, BM, KI, CK, FB, AA, AT, BHB, LC, GH,DD, MS, AZ, TSF, RA, AW, TS, RS, MA, AD. Statistical analysis: NS, TS, AZS. Writing—original draft: AZS. Writing—review & editing: all authors. Funding acquisition: NS, BM. Approval of final manuscript: all authors.

Acknowledgments

We would like to acknowledge all the patients who took part in the AcT Trial.

Figure 1.
Hemorrhage rates and functional outcomes in patients with no visible occlusion versus those with visible occlusion. (A) Hemorrhage rates as per Heidelberg classification by visible occlusion status (yes/no). (B) Outcome by visible occlusion status (yes/no). ICH, intracranial hemorrhage; sICH, symptomatic intracerebral hemorrhage; HI1, hemorrhagic Infarction type 1; HI2, hemorrhagic Infarction type 2; PH1, parenchymal hematoma type 1; PH2, parenchymal hematoma type 2; rPH1, remote parenchymal hematoma type 1; rPH2, remote parenchymal hematoma type 2; SDH, subdural hemorrhage; SAH, subarachnoid hemorrhage; IVH, intraventricular hemorrhage; mRS, modified Rankin Scale.
jos-2024-03062f1.jpg
Table 1.
Baseline characteristics of population with no visible occlusion versus with visible occlusion
Characteristic No visible occlusion (n=479) Visible occlusion (n=991) P
Age (yr) 71 (59-81) 75 (65-84) <0.001
Female sex 213 (44.5) 492 (49.7) 0.066
Baseline NIHSS 6 (5-10) 12 (7-19) <0.001
Baseline NIHSS score categories <0.001
 <8 289 (60.3) 287 (29.0)
 8-15 163 (34.0) 312 (31.5)
 ≥16 27 (5.6) 392 (39.6)
Type of enrolling center 0.060
 Primary stroke center 37 (7.7) 51 (5.2)
 Comprehensive stroke center 442 (92.3) 940 (94.9)
Thrombolytic type 0.956
 Alteplase 232 (48.4) 482 (48.6)
 Tenecteplase 247 (51.6) 509 (51.4)
Workflow times (min)
 Stroke symptom onset to hospital arrival 94 (60-147) 77 (52-123) <0.001
 Stroke symptom onset to randomisation 133 (96-190) 112 (83-168) <0.001
 Stroke symptom onset to needle 141 (104-200) 119 (90-175) <0.001
 Door (hospital arrival) to needle (thrombolysis start) 133 (96-190) 112 (83-168) <0.001
Site of occlusion NA
 Intracranial ICA NA 129 (8.8)
 M1-MCA 223 (15.2)
 M2-MCA 299 (20.3)
 Vertebrobasilar 61 (4.2)
 Distal 254 (17.3)
 Cervical ICA 25 (1.7)
Values are presented as median (interquartile range) or n (%).
NIHSS, National Institutes of Health Stroke Scale; ICA, internal carotid artery; MCA, middle cerebral artery; NA, not applicable.
Table 2.
Safety and efficacy outcomes in patients with no visible occlusion versus those with visible occlusion
Outcome No visible occlusion (n=479) Visible occlusion (n=991) Risk difference (95% CI) Adjusted RR (95% CI)§
Safety outcomes
 Death within 90 days of randomization 38 (8.1) 189 (19.1) -0.11 (-0.14 to -0.08) 0.67 (0.46 to 0.98)
 24-h sICH* 11 (2.3) 36 (3.6) -0.01 (-0.03 to 0.00) 1.00 (0.47 to 2.12)
 Any ICH on imaging 39 (8.2) 255 (26.0) -0.18 (-0.22 to -0.14) 0.38 (0.26 to 0.55)
 Subarachnoid hemorrhage 13 (2.7) 86 (8.8) -0.02 (-0.04 to 0.01) 0.54 (0.29 to 1.01)
 Subdural hemorrhage 3 (0.6) 4 (0.4) 0.00 (-0.01 to 0.01) 3.53 (0.59 to 20.9)
 Intraventricular hemorrhage 9 (1.9) 31 (3.2) -0.01 (-0.03 to 0.01) 0.81 (0.36 to 1.82)
 HI1 (scattered small petechia) 6 (1.3) 35 (3.6) -0.02 (-0.04 to -0.01) 0.44 (0.17 to 1.11)
 HI2 (confluent petechiae) 12 (2.5) 110 (11.2) -0.09 (-0.11 to -0.06) 0.23 (0.12 to 0.42)
 PH1 (hematoma occupying <30% of infarct with no substantive mass effect) 11 (2.3) 34 (3.5) -0.01 (-0.03 to -0.01) 0.75 (0.35 to 1.57)
 PH 2 (hematoma occupying ≥30% of infarct with obvious mass effect) 4 (0.8) 33 (3.4) -0.03 (-0.04 to -0.01) 0.58 (0.19 to 1.78)
 Remote PH1 (hematoma outside infarcted tissue without mass effect) 3 (0.6) 11 (1.1) 0.00 (-0.01 to 0.00) 0.55 (0.14 to 2.11)
 Remote PH2 (hematoma outside infarcted tissue with obvious mass effect) 1 (0.2) 4 (0.4) 0.00 (-0.01 to 0.00) 0.52 (0.05 to 5.54)
 Extracranial bleeding requiring blood transfusions 0 (0.0) 12 (1.2) -0.01 (-0.02 to -0.01) -
 Orolingual angioedema 6 (1.3) 10 (1.0) 0.00 (-0.01 to 0.01) 1.22 (0.41 to 3.67)
Efficacy outcomes
 mRS score 0-1 at 90-120 days 204 (43.3) 316 (31.9) NA 1.0 (0.8 to 1.1)
 mRS score 0-2 at 90-120 days 308 (65.4) 509 (51.4) NA 1.0 (0.9 to 1.1)
 Actual mRS score at 90-120 days 2 (1-3) 2 (1-5) NA 0.88 (0.7 to 1.1)
 Return to baseline function 157 (34.3) 220 (24.5) NA 1.1 (0.9 to 1.2)
 Length of hospital stay 4 (2-8) 6 (3-13) NA 0.70 (0.67 to 0.73)
 EQ-5D index 0.61 (0.37-0.76) 0.61 (0.35-0.74) 0.90 (0.73 to 1.11) 1.13 (0.90 to 1.42)
 EQ-5D-VAS 75 (60-90) 75 (55-87) 0.82 (0.67 to 1.03) 0.96 (0.77 to 1.20)
Values are presented as n (%) or median (interquartile range), unless otherwise indicated.
sICH, symptomatic intracerebral hemorrhage; ICH, intracranial hemorrhage; HI1, hemorrhagic infarction type 1; HI2, hemorrhagic infarction type 2; PH1, parenchymal hematoma type 1; PH2, parenchymal hematoma type 2; mRS, modified Rankin Scale; EQ-5D Index, EuroQol-5 Dimensions Index; EQ-5D-VAS, EuroQol-5 Dimensions Visual Analog Scale; CI, confidence interval; RR, relative risk; -, not computable; NA, not applicable; NIHSS, National Institutes of Health Stroke Scale.
* Defined as any intracerebral hemorrhage that was temporally related to or directly responsible for decline in patient’s clinical status;
Subclassification based on Heidelberg Bleeding Classification;
Common odds ratio;
§ Mixed effects Poisson regression model adjusting for age, sex, stroke severity (NIHSS), thrombolytic type and onset to needle time as fixed effects and participating site as random effects.

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