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Research

Intra-arterial tenecteplase after successful endovascular recanalisation in patients with acute posterior circulation arterial occlusion (ATTENTION-IA): multicentre randomised controlled trial

BMJ 2025; 388 doi: https://doi.org/10.1136/bmj-2024-080489 (Published 14 January 2025) Cite this as: BMJ 2025;388:e080489
  1. Wei Hu, neurologist1,
  2. Chunrong Tao, neurologist1,
  3. Li Wang, neurointerventionist1,
  4. Zhongjun Chen, neurointerventionist2,
  5. Di Li, professor2,
  6. Wenhuo Chen, professor3,
  7. Tingyu Yi, professor3,
  8. Lihua Xu, professor4,
  9. Chuanqing Yu, professor5,
  10. Tao Wang, neurointerventionist5,
  11. Xiaoxi Yao, professor6,
  12. Tao Cui, professor7,
  13. Guangxiong Yuan, professor8,
  14. Junfeng Su, professor9,
  15. Li Chen, neurointerventionist9,
  16. Zhiming Zhou, professor10,
  17. Zhengfei Ma, professor11,
  18. Junjun Wang, professor12,
  19. Benxiao Wang, neurointerventionist12,
  20. Hongxing Han, professor13,
  21. Hao Wang, professor13,
  22. Jie Chen, professor14,
  23. Peiyang Zhou, professor15,
  24. Zhihua Cao, neurointerventionist15,
  25. Youquan Ren, professor16,
  26. Xueli Cai, professor17,
  27. Huaizhang Shi, professor18,
  28. Guang Zhang, neurointerventionist18,
  29. Liping Yu, professor19,
  30. Xingyun Yuan, professor19,
  31. Jinglun Li, professor20,
  32. Guoyong Zeng, professor21,
  33. Chuyuan Ni, neurointerventionist22,
  34. Tong Li, professor23,
  35. Yingchun Wu, professor24,
  36. Yuwen Li, professor25,
  37. Kai Li, neurointerventionist25,
  38. Yong Liu, neurointerventionist26,
  39. Yao Wang, professor27,
  40. Yu Jin, professor28,
  41. Hanwen Liu, professor29,
  42. Jianshang Wen, professor30,
  43. Jun Sun, research assistant1,
  44. Yuyou Zhu, professor1,
  45. Rui Li, neurologist1,
  46. Chao Zhang, neurointerventionist1,
  47. Tianlong Liu, neurointerventionist1,
  48. Jianlong Song, neurointerventionist1,
  49. Li Wang, neurointerventionist1,
  50. Juan Cheng, neurologist1,
  51. Adnan I Qureshi, professor31,
  52. Thanh N Nguyen, professor3233,
  53. Jeffrey L Saver, medical doctor34,
  54. Raul G Nogueira, professor35,
  55. Xinfeng Liu, professor1
  1. 1Department of Neurology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
  2. 2Department of Neurological Intervention and Neurological Intensive Care, Central Hospital of Dalian University of Technology (Dalian Municipal Central Hospital), Dalian, China
  3. 3Department of Neurology, Zhangzhou Affiliated Hospital of Fujian medical University, Zhangzhou, China
  4. 4Department of Neurology, Jiamusi Central Hospital, Jiamusi, China
  5. 5Department of Neurology, First Affiliated Hospital of Anhui University of Science and Technology, First People’s Hospital of Huainan, Huainan, China
  6. 6Department of Neurology, The First People’s Hospital of Chenzhou, Chenzhou, China
  7. 7Department of Neurology, Taihe County People’s Hospital, Tiahe, China
  8. 8Department of Emergency, Xiangtan Central Hospital, Xiangtan, China
  9. 9Department of Neurology, Jingzhou Hospital Affiliated to Yangtze University, Jingzhou, China
  10. 10Department of Neurology, Yijishan Hospital of Wannan Medical College, Wuhu, China
  11. 11Department of Neurology, Suzhou Hospital of Anhui Medical University, Suzhou, China
  12. 12Department of Neurology, Wan Bei General Hospital of Wanbei Coal power Group, Suzhou, China
  13. 13Department of Neurology, Linyi People’s Hospital, Linyi, China
  14. 14Department of Neurosurgery, Tongling People’s Hospital, Tongling, China
  15. 15Department of neurology, Xiangyang No.1 People’s Hospital, Hubei University of Medicine, Xiangyang, China
  16. 16Department of Neurology, Linquan Country People’s Hospital, Linquan, China
  17. 17Department of Neurology, Lishui Municipal Central Hospital, Lishui, China
  18. 18Department of Neurology, The First Affiliated Hospital of Harbin Medical University, Harbin, China
  19. 19Department of Neurology, The First People’s Hospital of Xianyang, Xianyang, China
  20. 20Department of Neurology, The Affiliated Hospital of South West Medical University, Luzhou, China
  21. 21Department of Neurology, Ganzhou people’s Hospital, Ganzhou, Jiangxi, China
  22. 22Department of Neurology, Huangshan City people’s Hospital, Huangshan, China
  23. 23Department of Neurology, Nanning Second People’s Hospital, Nanning, China
  24. 24Department of Neurology, Ordos Central Hospital, Ordos, China
  25. 25Department of Neurology, Heze Municipal Hospital, Heze, Shandong, China
  26. 26Department of Neurology, Lu’an Hospital of Anhui Medical University, Lu’an, China
  27. 27Department of Neurology, Sixian People’s Hospital, Sixian, China
  28. 28Department of Neurology, Bozhou People’s Hospital, Bozhou, China
  29. 29Department of Neurology, Guangdong Provincial People’s Hospital Ganzhou Hospital, Ganzhou Municipal Hospital, Ganzhou, China
  30. 30Department of Neurology, Shucheng People’s Hospital, Shucheng, China
  31. 31the Zeenat Qureshi Stroke Institute and Department of Neurology, University of Missouri, Columbia, USA
  32. 32Department of Radiology, Boston Medical Center, Boston University School of Medicine, Boston, MA, USA
  33. 33Department of Neurology, Boston Medical Center, Boston University School of Medicine, Boston, MA, USA
  34. 34Department of Neurology and Comprehensive Stroke Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
  35. 35the UPMC Stroke Institute, Department of Neurology and Neurosurgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
  1. Correspondence to: X Liu Department of Neurology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China xfliu2{at}ustc.edu.cn
  • Accepted 11 November 2024

Abstract

Objective To assess whether intra-arterial tenecteplase administered after successful endovascular recanalisation improves outcomes in patients with acute arterial occlusion of the posterior circulation.

Design Multicentre randomised controlled trial.

Setting 31 hospitals in China, 24 January 2023 to 24 August 2023.

Participants 208 patients with successful recanalisation (grade 2b50-3 on the extended thrombolysis in cerebral infarction scale) of an occlusion in the V4 segment of the vertebral artery; proximal, middle, or distal segment of the basilar artery; or P1 segment of the posterior cerebral artery: 104 were randomly allocated to receive tenecteplase and 104 to receive standard care.

Interventions Intra-arterial tenecteplase (0.0625 mg/kg, maximum dose 6.25 mg) administered proximal to the residual thrombus (if still present) or distal to the origin of the main pontine perforator branches over 15 seconds, or endovascular treatment only (control group).

Main outcome measures The primary outcome was freedom from disability (modified Rankin scale score 0 or 1) at 90 days after randomisation. Primary safety outcomes included symptomatic intracranial haemorrhage within 36 hours and all cause mortality at 90 days. All efficacy and safety analyses were conducted by intention to treat and adjusted for age, pre-stroke modified Rankin scale score, time from onset of moderate to severe stroke (National Institutes of Health stroke scale score ≥6) to randomisation, hypertension, and baseline stroke severity.

Results At 90 days, 36 patients (34.6%) in the tenecteplase group and 27 (26.0%) in the control group had a modified Rankin scale score of 0 or 1 (adjusted risk ratio 1.36, 95% confidence interval 0.92 to 2.02; P=0.12). Mortality at 90 days was similar between the tenecteplase and control groups: 29 (27.9%) v 28 (26.9%), adjusted risk ratio 1.13, 0.73 to 1.74. Symptomatic intracranial haemorrhage within 36 hours occurred in eight patients (8.3%) in the tenecteplase group and three (3.1%) in the control group (adjusted risk ratio 3.09, 0.78 to 12.20).

Conclusions In patients with acute ischaemic stroke due to acute posterior large or proximal vessel occlusion, intra-arterial tenecteplase administered after successful recanalisation was not associated with a statistically significant reduction in combined disability and mortality at 90 days.

Trial registration ClinicalTrials.gov NCT05684172.

Introduction

Acute posterior circulation ischaemic stroke affects about 20% of patients with stroke.12 Compared to patients with anterior circulation stroke, those with occlusions of the posterior circulation—particularly of the basilar artery—have higher rates of death or disability.34 Endovascular thrombectomy is an established treatment for patients with moderate or severe acute ischaemic stroke due to basilar artery occlusion,567 with high rates of recanalisation and improved functional outcome. Despite receiving endovascular thrombectomy, more than three quarters of patients in randomised trials showing the superiority of endovascular treatment over best medical management in patients with basilar artery occlusion were disabled or dead at three months, making further advances in treatment desirable.89

The low rates of positive outcomes despite successful endovascular thrombectomy in part may be due to incomplete reperfusion at the level of both macro-circulation (eg, distal occlusions) and micro-circulation (no-reflow).1011 Adjunctive intra-arterial infusion of thrombolytic agents after successful endovascular recanalisation has the potential to further improve outcomes by lysing persisting thrombi in distal arteries and the microcirculation.12 Adjunctive intra-arterial infusion of thrombolytic agents appeared promising for large vessel occlusions of the anterior circulation in the phase 2b chemical optimization of cerebral embolectomy (CHOICE) randomised trial (121 participants).13 The proportion of patients achieving an excellent outcome (modified Rankin scale score of 0 or 1) at 90 days increased from 40.4% to 59.0%, 36.4%; P=0.047). However, it remains uncertain whether this treatment approach could benefit patients with acute occlusions of the posterior circulation.

The intra-arterial tenecteplase after successful endovascular recanalisation in patients with acute posterior circulation arterial occlusion (ATTENTION-IA) trial aimed to assess the efficacy of administering intra-arterial tenecteplase after successful recanalisation in improving clinical outcomes in patients with intracranial occlusions of the V4 segment of the vertebral artery; proximal, middle, or distal segment of the basilar artery; or P1 segment of the posterior cerebral artery.

Methods

Trial design

The ATTENTION-IA trial was a multicentre, randomised, open label, blinded endpoint clinical trial conducted at 31 centres across China (see supplementary figures S1 and S2). The protocol in the supplementary file provides details of the trial rationale, design, and methods. Protocol violations occurred in two patients (one in each of the study arms), leaving 206 patients (81%) in the per protocol analyses.

The steering committee designed and oversaw the conduct and analysis of the trial. An independent data and safety monitoring board was responsible for safety, ethics, and conduct oversight. An independent clinical research organisation (Hope Medical Technology) was involved in monitoring the progress of the trial to ensure adherence to the protocol. An independent clinical event adjudication committee whose members were unaware of the trial group assignments, adjudicated the primary and secondary efficacy outcomes. An independent clinical events committee assessed adverse events, procedural related complications, and serious adverse events. An independent statistician was responsible for statistical analysis. Complete methods of this trial have been published previously.14

Patient selection

Adults (≥18 years) presenting with moderate to severe stroke (National Institutes of Health stroke scale (NIHSS) score ≥6) due to occlusions in the basilar artery, vertebral artery (in isolation or with concomitant basilar occlusion), or P1 segment of the posterior cerebral artery within 24 hours from onset were eligible for recruitment. Time of onset was defined as last known time free of major deficits and not considering preceding minor prodromal symptoms. Patients who had received intravenous thrombolysis could also be enrolled in this trial. Patients were excluded if they had a pre-stroke disability score of >1 on the modified Rankin scale, intracranial haemorrhage on neuroimaging, or a posterior circulation-acute stroke prognosis early CT score (pc-ASPECTS) of <6 on non-contrast computed tomography (CT), CT angiography source images, or magnetic resonance imaging (MRI) diffusion weighted imaging. The protocol in the supplementary file lists the full inclusion and exclusion criteria.

Randomisation and masking

Once written informed consent had been obtained and successful endovascular recanalisation (extended thrombolysis in cerebral infarction (eTICI) grade 2b50-3 defined as ≥50% reperfusion of the involved territory) of the target occlusion performed, patients were randomised to receive either intra-arterial tenecteplase or standard care using endovascular treatment only (control group) in a 1:1 ratio. A simple randomisation process was conducted through a web based system (IRLite), accessible on mobile devices or web page platforms, utilising a central, web based, computer generated randomisation schedule. The trial was open label and therefore the team performing the endovascular thrombectomy and patients or their legal representatives were aware of the treatment allocation. all research staff conducting telephone interviews and members of the independent endpoint adjudication committee were, however, masked to the treatment assignment. The trial steering committee and the investigators not involved in the endovascular thrombectomy procedure were masked throughout the entire conduct of the trial. The imaging committee was masked to clinical data, except for the date and time of image acquisition.

Interventions

Both treatment arms received endovascular thrombectomy, using stent retrievers, thromboaspiration, balloon angioplasty, stent deployment, or a combination of these approaches. The treatment modality for each patient was at the discretion of the treating team. Centres and interventionalists were highly experienced. In the ATTENTION (1672/2134) and (BASILAR) (647/829; assessment of endovascular treatment for acute basilar artery occlusion via a nationwide prospective registry) registries in China,415 about 80% of participants with acute basilar artery occlusion underwent thrombectomy, with a mortality rate of 42% and morbidity rate (modified Rankin scale score 4-6 at 90 days) of 65%. To participate in the ATTENTION-IA trial, the neurointerventionists had to be specially qualified to perform such treatments, including having more than five years’ experience in cerebrovascular interventions and a minimum of 80 independently completed thrombectomies.

Patients randomised to the tenecteplase group received an intra-arterial infusion of tenecteplase (0.0625 mg/kg, maximum dose 6.25 mg) through a distal access catheter or microcatheter located proximal to the residual thrombus (if still present) or distal to the origin of the main pontine perforator branches over 15 seconds. The dose was chosen proportional to the intra-arterial alteplase dose used in the CHOICE trial.13 Patients randomised to the control group received standard care without intra-arterial adjunctive treatment.

Radiological follow-up using CT plus CT angiography, MRI, or magnetic resonance angiography was conducted within 36 hours after randomisation, and at any other time when neurological symptoms worsened. Local trained investigators assessed outcomes on the modified Rankin scale, EuroQol-5 dimensions-5 level, and Barthel index at 90 days based on a standardised telephone interview.

Outcomes

The primary efficacy outcome was the proportion of participants with a modified Rankin scale score of 0 or 1 at three months (0 or 1 indicating freedom from disability, and 2-6 indicating disability or death).

The primary safety outcomes were symptomatic intracranial haemorrhage within 36 hours and all cause mortality within 90 days. Current guidelines recommend CT about 24 (±12) hours after endovascular thrombectomy. The timeframe for assessing intracranial haemorrhage was initially set at 72 hours but was later adjusted to 36 hours. We defined symptomatic intracranial haemorrhage according to the modified Heidelberg definition (local or remote parenchymal haemorrhage type 2, subarachnoid haemorrhage and/or intraventricular haemorrhage on the post-treatment imaging scan, combined with a neurological deterioration of ≥4 points on the NIHSS score from baseline, or from the lowest NIHSS score between baseline and 36 hours, or leading to death that the clinical events committee judged to be responsible for the deterioration).16

Secondary clinical efficacy outcomes were functional independence (modified Rankin scale score 0-2) at 90 days, level of disability (shift analysis of the distribution of modified Rankin scale scores) at 90 days, neurological deficit (NIHSS score) at 24 hours and at 5-7 days or discharge, health related quality of life (EQ5D-5L) at 90 days, and activities of daily living (Barthel index) at 90 days. Secondary imaging efficacy outcomes included successful recanalisation at 24-72 hours determined by a modified arterial occlusive lesion scale score of 2 or 3 using magnetic resonance angiography or CT angiography at 24-72 hours and any intracranial haemorrhage according to the Heidelberg classification.1617

Sample size calculation

The sample size was based on estimations of treatment effect magnitude from the results of the recent ATTENTION and CHOICE trials.813 We assumed that the proportion of participants with modified Rankin scale scores of 0-1 at the 90 day follow-up visit would be 20% in the control group and 38% in the tenecteplase group, yielding an absolute risk reduction of 18% with intervention. Based on a two sided, normal approximation test, α of 0.05, and a 1:1 randomisation, 99 patients in the treatment group and 99 in the control group would provide 80% power for comparison of the proportion of patients who achieved the primary endpoint. To account for up to 5% attrition, we adjusted the sample size to 104 patients in the tenecteplase group and 104 in the control group.

Statistical analysis

The primary analysis was performed in the intention-to-treat population, which consisted of all patients who provided consent, or with consent provided by an authorised representative, before randomisation. We prespecified calculation of effect estimates with multivariable analysis adjusting for age, pre-stroke modified Rankin scale, time from onset to randomisation and baseline stroke severity (NIHSS score), and factors showing imbalance between the two treatment groups. A robust sandwich variance model was used to compare dichotomous outcomes: relative risk was estimated using the Poisson distribution with a log link function. After verification of the proportional odds assumption using the Brant test, we used an ordinal logistic regression model to estimate the shift of modified Rankin scale scores towards a better functional outcome. For the comparison of the two treatment groups for the secondary outcomes of the NIHSS score and the EQ-5D at 90 days (modelled as continuous variables), we used linear regression to estimate the mean difference between study arms.

Subgroup analyses were prespecified for the primary outcome according to age, stroke severity (baseline NIHSS score), cause of stroke (intracranial atherosclerotic disease, cardioembolic, other), early versus late onset time window (0 to <6 v 6 to 24 hours), site of arterial occlusion, baseline pc-ASPECTS (6-8 v 9-10), use of intravenous thrombolysis, initial treatment strategy for recanalisation, and degree of reperfusion (eTICI grade before study drug was administered (2b50/67 v 2c/3)).14

Because the statistical plan did not include a provision for correcting the widths of confidence intervals for multiple comparisons, we considered secondary outcomes or subgroup analyses as exploratory. No imputation for missing data was performed as no patients were lost to follow-up or had data missing for the main baseline covariates and primary outcome. All analyses were performed using STATA software, version 17.0.

Patient and public involvement

No patients or members of the public were involved in the design or implementation of the trial. In addition, to keep the confidentiality of clinical data, no patients were involved in data analysis, interpretation, or writing up of the results. The study protocol and manuscript have been widely discussed among doctors and neurologists, who will be involved in disseminating the study findings to healthcare professionals, patients, and members of the public.

Results

Patients

From 24 January 2023 to 24 August 2023, 208 participants were enrolled and randomised to either the intra-arterial tenecteplase group (n=104) or control group (n=104). All were included in the main analysis. The per protocol sensitivity analysis included 206 patients after excluding two with protocol violations (eTICI grade ≥2b50 reperfusion was not achieved in one patient, and treatment for a basilar artery occlusion was ≥24 hours from onset in one patient). No patients were lost to follow-up or had data missing for the main baseline covariates. Figure 1 shows the flow of patients through the study, along with reasons for exclusion.

Fig 1
Fig 1

Trial profile of patients randomly assigned in a 1:1 ratio to receive either endovascular treatment plus intra-arterial tenecteplase (tenecteplase group) or endovascular treatment only (control group)

Baseline characteristics

Table 1 and supplementary table S1 show the baseline personal, clinical, and imaging characteristics of the patients. The mean age was 66.0 (standard deviation 11.1) years, and 24.5% (n=51) were women. The median NIHSS score before endovascular thrombectomy was 20.0 (interquartile range (IQR) 12.5-35.0). Overall, 28 patients (26.9%) in the tenecteplase group and 25 (24.0%) in the control group received intravenous thrombolysis before endovascular thrombectomy, with alteplase in 41 (19.7%) patients, tenecteplase in six (2.9%), and urokinase in six (2.9%). The median time from onset to endovascular recanalisation was 6.7 hours (IQR 4.2-8.9 hours), and median time from symptom onset to randomisation was 7.0 (4.6-9.4) hours. The site of arterial occlusion was the basilar artery in 144 (69%) patients, vertebral artery in 54 (26%), and posterior cerebral artery in 10 (5%). Intracranial stent or angioplasty was performed in 45 (43.3%) participants in the tenecteplase group and 36 (34.6%) in the control group. General anaesthesia was used in 47 patients (45.2%) in the tenecteplase group and 43 (41.4%) in the control group. Baseline characteristics were similar between the groups except for an imbalance in the rate of hypertension: 73 (70.2%) in the tenecteplase group and 88 (84.6%) in the control group (table 1).

Table 1

Baseline characteristics of patients randomised to receive intra-arterial tenecteplase or no adjunctive treatment after successful endovascular recanalisation. Values are number (percentage) unless stated otherwise

View this table:

Primary efficacy outcome

After adjusting for age, pre-stroke modified Rankin scale score, time from symptom onset to randomisation, hypertension, and baseline NIHSS score, the overall proportion of patients with a 90 day modified Rankin scale score of 0 or 1 was not significantly different between the tenecteplase group and control group (34.6% and 26.0%, respectively; adjusted risk ratio 1.36, 95% confidence interval (CI) 0.92 to 2.02; P=0.12; adjusted absolute difference 8.3 percentage points, 95% CI −3.8 to 20.4) (table 2).

Table 2

Outcomes in patients randomised to receive intra-arterial tenecteplase or no adjunctive treatment after successful endovascular recanalisation. Values are number (percentage) unless stated otherwise

View this table:

Primary safety outcomes

For the analysis of safety outcomes, adjustments were made for age, pre-stroke modified Rankin scale, time from onset to randomisation, hypertension, and baseline NIHSS score. The incidence of symptomatic intracranial haemorrhage was 8.3% in the tenecteplase group and 3.1% in the control group (adjusted risk ratio 3.09, 95% CI 0.78 to 12.20; adjusted absolute difference 5.7%, 95% CI −1.0% to 12.4%). The 90 day mortality was similar between the tenecteplase and control groups (27.9% v 26.9%; adjusted risk ratio 1.13, 95% CI 0.73 to 1.74; adjusted absolute difference 2.5%, 95% CI −9.6% to 14.6%; table 2).

Secondary outcomes

Figure 2 shows the distribution of the modified Rankin scale scores at 90 days in the two groups. The ordinal logistic regression model suggested that the adjusted common odds ratio for a favourable shift in modified Rankin scale score was 1.00 (95% CI 0.61 to 1.62). A total of 40 patients (38.5%) in the tenecteplase group and 42 (40.4%) in the control group scored 0-2 on the modified Rankin scale at 90 days (adjusted risk ratio 0.93, 95% CI 0.67 to 1.28) (table 2). Patency of the index artery assessed by CT angiography or magnetic resonance angiography at 24-72 hours was achieved in 63 patients (90.0%) in the tenecteplase group and 64 (91.4%) in the control group (table 2). Barthel index and EQ-5D-5L scores were similar between the groups. Table 2 shows the other secondary clinical and imaging outcomes.

Fig 2
Fig 2

Distribution of modified Rankin scale scores (functional outcomes) at 90 days in intention-to-treat population (no patients lost to follow-up). Scores range from 0 to 6: 0=no symptoms; 1=no clinically important disability; 2=slight disability (patients can look after themselves without assistance but are not able to carry out previous activities); 3=moderate disability (patients require some help but are able to walk unassisted); 4=moderately severe disability (patients are unable to attend to bodily needs without assistance and are unable to walk unassisted); 5=severe disability (patients require constant nursing care and attention); and 6=death

Subgroup and per protocol analyses

Figure 3 and supplementary figure S4 show the results of the prespecified subgroup analyses for the primary outcome. When patients in the tenecteplase group were compared with those in the control group, the adjusted relative risk of achieving a modified Rankin scale score of 0 to 1 was 1.64 (95% CI 1.02 to 2.62) for those with baseline NIHSS scores of 6-19, compared with 0.93 (0.45 to 1.94) for those with baseline NIHSS scores ≥20 (P for heterogeneity=0.16). An additional exploratory subgroup analysis indicated that the adjusted risk ratio was 1.89 (95% CI 0.96 to 3.70) among patients who underwent immediate stenting and 1.10 (0.66 to 1.84) among those who did not undergo immediate stenting (P for interaction=0.23). The results of the analyses in the per protocol population were generally similar to those of the main analyses for the primary, secondary, and safety outcomes (see supplementary table S4 and figures S3 and S4).

Fig 3
Fig 3

Subgroup analyses of modified Rankin scale scores of 0 or 1 at 90 days (primary outcome). The trial had no prespecified correction for multiple comparisons for a definitive analysis of subgroups. CI=confidence interval; CT=computed tomography; eTICI=extended thrombolysis in cerebral infarction; NIHSS=National Institutes of Health stroke scale; pc-ASPECTS=posterior circulation-acute stroke prognosis early CT score

Discussion

The results of this multicentre randomised trial suggested that intra-arterial tenecteplase use after successful endovascular treatment resulted in similar functional outcomes and mortality at 90 days to endovascular treatment alone in patients presenting with acute intracranial occlusions of the posterior circulation in the vertebral artery, basilar artery, or P1 segment of the posterior cerebral artery. The rates of the primary endpoint of excellent outcome (modified Rankin scale score 0 or 1) at 90 days were not statistically significantly different between the two groups. The risk of symptomatic intracranial haemorrhage was numerically higher in patients who received intra-arterial tenecteplase.

The results for the secondary outcomes and subgroup and sensitivity analyses were consistent with the result for the primary outcome. All multivariable analyses were adjusted for age, pre-stroke modified Rankin scale score, time from onset to randomisation, hypertension, and baseline NIHSS score. Subgroup analyses did not suggest a statistically significant difference between study arms by time to endovascular treatment, stroke subtype, or whether intravenous thrombolysis was or was not administered before endovascular treatment.

Comparison with other studies

We chose tenecteplase over alteplase as the thrombolytic agent to administer after thrombectomy. Its enhanced fibrin specificity and prolonged half life make tenecteplase a more suitable single bolus option than alteplase after endovascular thrombectomy. The tenecteplase versus alteplase before thrombectomy for ischemic stroke (EXTEND-IA TNK) trial showed the superiority of tenecteplase over alteplase in recanalisation of acute large vessel occlusion before thrombectomy.18 A retrospective analysis comparing 33 patients who received intra-arterial tenecteplase with 48 patients who received intra-arterial alteplase suggested a trend towards better clinical outcomes with tenecteplase, with no discernible difference in haemorrhage rates between the two thrombolytic agents.19 The phase IIb adjunctive intra-arterial tenecteplase following mechanical thrombectomy pilot trial (ALLY) of 20 patients who underwent endovascular thrombectomy for large vessel occlusion and had a final eTICI grade of 2b or 2c not amenable to further mechanical retrieval showed intra-arterial tenecteplase (1.5-4.5 mg) to be a safe adjunct to thrombectomy, with one (5%) symptomatic intracranial haemorrhage event.20 Moreover, a series of acute stroke trials have shown non-inferior or even superior angiographic and clinical outcomes from intravenous tenecteplase use compared with intravenous alteplase.21222324

We observed a nominally more favourable overall prognosis compared to the ATTENTION trial.8 Among patients who underwent endovascular thrombectomy, the proportion with a modified Rankin scale score of 0 or 1 in the ATTENTION trial was 16%, whereas in the ATTENTION-IA trial this proportion increased to 25% at 90 days. Additionally, the mortality rate decreased from 40% in the ATTENTION trial to 25% in the ATTENTION-IA trial. This might be because ATTENTION-IA included patients with NIHSS scores of 6-9 as well as those with occlusion of the P1 segment of the proximal posterior cerebral artery (comprising 15.0% and 4.8% of the total participants, respectively). Another factor was that nearly all patients achieved successful recanalisation in the ATTENTION-IA trial compared with 93% in the ATTENTION trial. However, given the neutral results in our trial compared with the statistically significant findings observed in the CHOICE trial, future trials might also consider utilising alteplase as the intra-arterial thrombolytic agent.

Unlike the CHOICE trial, which restricted stenting due to the requirement for dual antiplatelet treatment, the ATTENTION-IA trial permitted stent placement. This decision was made because of the high prevalence of intracranial atherosclerosis as the underlying mechanism for posterior circulation large vessel occlusion in China.25 Consequently, stent placement was deemed necessary in many patients to maintain flow of the occluded arteries.26 Despite the inclusion of stenting in our trial, we found that the results were not significantly altered. Subgroup analysis, comparing patients who underwent stenting with those who did not, revealed similar proportions of patients with modified Rankin scale scores of 0 or 1 at 90 days (P=0.56).

Consistent with the CHOICE trial, our study did not exclude patients who had received intravenous thrombolysis before endovascular treatment. Our analysis revealed no evidence indicating an increased risk of intracranial haemorrhage associated with intra-arterial tenecteplase use after endovascular treatment in patients who had previously received intravenous thrombolysis.

Patients with lower baseline NIHSS scores (6-19) seemed to benefit more from intra-arterial tenecteplase than those with higher scores. Although a pc-ASPECTS score of >6 was necessary for study inclusion, CT imaging lacks precision in assessing brainstem damage. Only a few patients (12.5-19.9%) received baseline MRI, which is more reliable. Given the higher baseline NIHSS scores, some patients with more severe symptoms might not benefit from intra-arterial tenecteplase.

In this trial, tenecteplase was infused distal to the pontine perforators in 56% of patients in the tenecteplase group because of concerns about safety. However, about 70% of patients had distal vertebral artery or proximal/mid-basilar artery occlusions, potentially resulting in reduced flow into brainstem perforators. Future trials might consider altering the infusion site to the proximal basilar artery, which may enhance the efficacy of tenecteplase infusion. The time between recanalisation after endovascular thrombectomy and randomisation was about 15 minutes. Given that the cause of stroke in China predominantly results from intracranial atherosclerotic disease, typically at least 10 minutes were needed to observe adequate blood flow to ensure sustained stability.

In contrast with the findings of the CHOICE trial, we identified a higher occurrence of any intracranial haemorrhage in the tenecteplase group compared with control group. Additionally, although not statistically significant, the risk of symptomatic intracranial haemorrhage was numerically higher in the tenecteplase group. The trial was under-powered and had no prespecified correction for multiple comparisons for a definitive analysis of safety outcomes. The increased risk of intracranial haemorrhage in patients receiving intra-arterial tenecteplase should be interpreted with caution as the effect relies on a relatively small number of patients. Furthermore, the requirement for periprocedural antithrombotic agents in patients who have received a stent could have contributed to this numerically higher rate of symptomatic intracranial haemorrhage observed in the tenecteplase group. Notably, the rate of symptomatic intracranial haemorrhage in the tenecteplase group was still within the range of 4.5-9% reported in other trials investigating the efficacy of endovascular thrombectomy in patients with basilar artery occlusion.89172728

Limitations of this study

This study had several limitations. Firstly, as only patients from China were enrolled into the study, our results may not be generalisable to patients in western countries. A previous trial suggested that the proportion of patients with large artery atherosclerosis was significantly higher among Chinese patients, whereas the proportion with cardioembolism was lower.29 This discrepancy in stroke pathophysiology could limit the generalisability of our findings to other populations. Secondly, owing to the study design it was not possible for practical reasons to blind the clinicians performing the intervention or the patients or their legal representatives. Therefore, bias related to the open label design cannot be excluded. Thirdly, it is possible that inclusion of patients who underwent acute balloon angioplasty or stenting and received acute antiplatelet therapy (eg, tirofiban) might have attenuated the treatment effect with intra-arterial tenecteplase or increased the bleeding risk. These patients were, however, included to improve the generalisability of the results given the high frequency of intracranial atherosclerosis in posterior circulation occlusions in both Asian and non-Asian populations. The inclusion of patients with a low NIHSS score (6-9) and isolated posterior circulation acute occlusions may have influenced our results owing to the uncertainty about the efficacy of endovascular thrombectomy in these settings. The two treatment groups were imbalanced for the number of patients with hypertension, but adjustment for this discrepancy did not alter the effect size between groups. Another weakness of the study was the lack of perfusion imaging assessment after endovascular thrombectomy, which limits our ability to detect potential changes in reperfusion with intra-arterial thrombolytic treatment. The composition of clots in people with stroke substantially influences the response to thrombolysis and is highly heterogeneous, varying with different causes.30 Our study lacked the power to explore specific subgroups of patients, so a potential benefit for people with particular clot or stroke types cannot be ruled out. The variation in patient recruitment across centres might have been due to experience of the centres and patient volume. Finally, as there was a non-significant adjusted absolute difference in the rates of 90 day modified Rankin scale score of 0 or 1 of 7.6% favouring the intra-arterial tenecteplase group and the study was powered to show an absolute risk reduction of 18%, it is possible that the study was underpowered to find a smaller but still clinically meaningful difference. However, none of the secondary functional outcomes (ie, 90 day change in modified Rankin scale score and modified Rankin scale score of 0-2) achieved statistical significance.

Conclusions

Among patients presenting with acute posterior circulation ischaemic stroke and arterial occlusion within 24 hours of symptom onset, intra-arterial tenecteplase after successful endovascular recanalisation did not improve 90 day excellent functional outcomes compared with successful endovascular recanalisation alone. Symptomatic intracranial haemorrhage was numerically higher in patients receiving intra-arterial tenecteplase. Additionally, 90 day mortality did not differ between the groups.

What is already known on this topic

  • The prognosis for patients with acute posterior arterial occlusion is unsatisfactory, and a need for optimisation of adjuvant treatment remains

  • Adjunct intra-arterial thrombolysis after thrombectomy to improve functional outcomes in acute posterior arterial occlusion remains underexplored

What this study adds

  • Among patients with successful recanalisation of the vertebral artery, basilar artery, or the P1 segment of the posterior cerebral artery, adjunct intra-arterial tenecteplase was not associated with a higher likelihood of an excellent outcome at three months

  • The risk of symptomatic intracranial haemorrhage was numerically higher in patients who received intra-arterial tenecteplase, although not statistically significant

Ethics statements

Ethical approval

Approved by the medical ethics committee of the First Affiliated Hospital of the University of Science and Technology of China and all relevant local ethics committees. The trial was conducted in accordance to Good Clinical Practice and the Declaration of Helsinki.

Data availability statement

Data collected for the study, including deidentified individual participant data and a data dictionary defining each field in the set, can be made available to researchers on reasonable request and after signing appropriate data sharing agreements. Data access requests should be sent to the corresponding author. Such requests must be approved by the respective ethics boards and appropriate data custodians.

Acknowledgments

Recomgen Pharmaceutical in Shijiazhuang, China, supplied the tenecteplase used in this trial.

Footnotes

  • Contributors: A full list of the ATTENTION-IA investigators is provided in the appendix. WH, CT, and XL prepared the first draft of the report. WH, CT, LW, TNN, JLS, RGN, and XL conceptualised the study design and provided critical comments for the manuscript. SJ and TL managed the data. WH and CT calculated the sample size and developed the statistical plan. CT and RL did the statistical analyses, with supervision by WH and XL. All other authors were local investigators or co-investigators and recruited participants, collected data, revised the final version of the manuscript, and critically reviewed the report and approved the final version before submission. The steering committee was responsible for the overall design, protocol development, interpretation, and supervision of the trial. The trial executive committee implemented the study. All authors vouch for the completeness and accuracy of the data, data analyses, and reporting of adverse events, and for the fidelity to the trial protocol. XL acts as guarantor. He had full access to all the data in the study and took final responsibility for the decision to submit for publication. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.

  • Funding: This study was funded by the Fundamental Research Funds for the Central Universities (YD9110002014). The First Affiliated Hospital of University of Science and Technology of China sponsored the trial. The funders had no role in considering the study design; the collection, analysis, or interpretation of data; the writing of the report; or the decision to submit the article for publication.

  • Competing interests: All authors have completed the ICMJE uniform disclosure form at https://www.icmje.org/disclosure-of-interest/ and declare: funding from the Fundamental Research Funds for the Central Universities; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

  • Transparency: The corresponding author (XL) affirms that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.

  • Dissemination to participants and related patient and public communities: The media and clinical sites will report the findings of ATTENTION-IA and provide a text link to the audience and patients. Potential public channels for sharing this research include X, LinkedIn, Research Gate, and WeChat.

  • Provenance and peer review: Not commissioned; externally peer reviewed.

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