4. The fourth INTEnsive ambulance-delivered BP Reduction in hyper-ACute stroke Trial Main results - European Stroke Organisation Conference - 15-17 May 2024 Gang Li MD PhD CTT 1) ET) a TN Pata delay eT Lee BIN Mees Reel) lO el A Jie Yang, Yapeng Lin, Chen Chen, Feifeng Liu, Xiaoying Chen, Craig Anderson for the INTERACTA Investigators /coordinators Collaborative institutional partnership By ONARLALH- OEAREE| seanieeiry cet» Scxanfoinaa Pes 4, The George institute ha ae aoeGrant funding Australia: National Health and Medical Research Council (NHMRC), The George Institute China ~ Shanghai: hanghai East Hospital of Tongji University, Shanghai Key Clinical Discipline, Shanghai Pudong Health Bureau, Shanghai Pudong New Area Health Committee, Shanghai Science and Technology Development Foundation China — Chengdu: Sichuan Science and Technology Program, Neurology Key Discipline of Sichuan, Chengdu Science and Technology Bureau, Sichuan Provincial People's Hospital, The First Affiliated Hospital of Chengdu Medical College, National Natural Science Foundation of China Takeda Pharmaceuticals China (no involvement in design, analysis or reporting)Acute ischemic stroke (AIS) — reperfusion treatment - time is critical C Intracerebral hemorrhage (ICH) — BP lowering treatment - likely also to be time-dependent > most hematoma growth <3 hr of onset (Lancet Neurol 2018;17:885) 0 No effects of pre-hospital initiated BP lowering treatment in 2 RCTs > nitroglycerin patch in RIGHT2 (UK) and MR ASAP (The Netherlands), and potential harms in ICH and lysis AIS > ?nitrates vs. other agents > ?differential effects by hemorrhage vs. ischemiaTo determine safety and efficacy of prehospital ambulance- initiated intravenous antihypertensive treatment - urapidil (rapid central and peripheral effects) - within 2 hours of onset of undifferentiated acute stroke Hypothesis — early intensive BP control = ICH —reduce hematoma growth + improve functional outcome = Cerebral ischemia — reduce time to reperfusion, reduce risk of reperfusion-ICH, and improve functional outcomeInclusion criteria: adults 218 years, FAST score >2 (with motor deficit), definite time of onset and ability to start treatment <2 hours, SBP 2150mmHg, no indication/contraindication to treatment Exclusion criteria: deep coma, severe co-morbid disease, epilepsy, recent head injury, or hypoglycemia Oe Intensive BP lowering gone eh Usual care Target SBP 130-140mmHg <30mins “ase No BP lowering treatment unless severe WV urapidil_ 25mg bolus (max. x2) hypertension (SBP >220mmHe) Handover from ambulance to hospital | ———~—E OOOO Intensive BP lowering Standard BP management SBP 130-140 mmHg - 7 days Guideline-recommended SBP v In-hospital CT/MRI, vital signs, NIHSS, GCS and BP over 7 days Independent 90-day outcome assessmentOutcomes: 1° - distribution of scores on mRS 2° -mRS (2-6/3-5); death; NIHSS; discharge; EQ-5D-3L; hematoma vol Safety - any serious adverse event (SAE) Sample size: 2320 pts, 90% power for 22% reduction in odds (common OR 0.78) of worse functional outcome, assuming 6% stroke mimics, 5% missing outcome Analysis: 1° - ITT - logistic regression + treatment, stratification, within-pt correlations Sensitivity: add premorbid mRS, sex, time to randomization, stroke type 2° - mITT- cerebral ischemia (AIS/TIA) or ICH, not mimics/structural ICH/SAH - PP-pts who received assigned treatment and no protocol deviations Subgroups: final diagnosis (ischemia vs. ICH vs. mimic) and age, sex, time, SBP, FAST, region, ambulance service, NIHSS scoreOutcomes: 1° - distribution of scores on mRS 2° -mRS (2-6/3-5); death; NIHSS; discharge; EQ-5D-3L; hematoma vol Safety - any serious adverse event (SAE) Sample size: 2320 pts, 90% power for 22% reduction in odds (common OR 0.78) of worse functional outcome, assuming 6% stroke mimics, 5% missing outcome Analysis: 1° - ITT - logistic regression + treatment, stratification, within-pt correlations Sensitivity: add premorbid mRS, sex, time to randomization, stroke type 2° - mITT- cerebral ischemia (AIS/TIA) or ICH, not mimics/structural ICH/SAH - PP - pts who received assigned treatment and no protocol deviations Subgroups: final diagnosis (ischemia vs. ICH vs. mimic) and age, sex, time, SBP, FAST, region, ambulance service, NIHSS score3+ years (March 20, 2020 to August 31, 2023) - 2425 patients for randomization + treatment 5488 patients screened 3063 excluded (49% SBP <1SOmmHg, 54% >2 hours) 2425 patients randomized CT 1215 to ambulance BP lowering 1210 to usual care 110 excluded Ti excluded + + 1205 in TT 1199 in TT 20 (2%) excluded 22 (2%) excluded (20 to tTFU) (21 to urFU) 1185 - analysis of primary outcome 1177 - analysis of primary outcomeOverall ASBP -7 (95%CI -8 to -6) mmHg me Ambulance | Hospital ASBP-15 mmHg 1 SBP -4 mmHg i“ (95%CI -17 to -13) | (95%CI -5 to -3) Fw ' i : im Fs 3 4 3 7 é i 10 7 0 \ = a Tiwsnangwmuwetiitgsawna 4 he 7 Number of patents: olAedian (iqr) time onset to randomization, mins 8P at randomization, mmHg Aedian (iqr) time onset to hospital, mins BP at hospital, mmHg ’emgraphic/medical history Mean (sd) age, yr Male History of hypertension History of stroke History of diabetes Premorbid symptom-free Nedian (iqr) NIHSS at hospital inal diagnosis Cerebral ischemia Hemorrhagic stroke mimic 63 (41-93) 178/98 80 (54-114) 159/89 70 (12) 60% 72% 19% 18% 67% 12 (6-18) 50% 43% 6% 59 (41-93) 178/98 75 (55-115) 170/94 70 (13) 64% 70% 20% 16% 69% 11 (6-17) 50% 43% 6%63 (41-93) 59 (41-93) ‘Median {igr) time onset to randomization, mins {8° at randomization, mmHg 178/98 178/98 Median (igr) time onset to hospital, mins 80(54-114) 175 (55-115) BP at hospital, mmHg. 159/89 170/94 Demgraphic/medical history Mean (sd) age, yr 70(12) 70 (13) Male 60% 64% History of hypertension 72% 70% History of stroke 19% 20% History of diabetes 18% 16% Premorbid symptom-free 67% 69% Median (igr) NIHSS at hospital 32 (6-18) 11(6-17) Final diagnosis Cerebral ischemia 50% 50% Hemorrhagic 43% 43% ‘Stroke mimic 0% oxbeat) oreta (eral es Common Odds Ratio (OR) 1.00 (95%CI 0.87-1.15) Modified Rankin Scale at 90 days Oo OF O02 O3 @4 Gs Bc Intervention (N=1208) (138 [190 [79 Control (N=1199) 16.1 16.3 30° 400 506070 8090S 100 Percentage of patients 10 20 mITT OR 0.99 (95%CI 0.85-1.15), PP - OR 0.96 (95%CI 0.82-1.12); consistent in sensitivity analysis nTACT a MMe eM OM Ieee Lista g [Variable Prehospital BP control Usual care BP control | or(95%ci) | MRS at 90 days ~ 3-6 vs. 0-2 MRS at 90 days — 3-5 vs. 0-2 Death Median NIHSS score at 24 hours Health utility EQ-SD-3L - mean (SD) Hospital discharge by Day 7 Living in an institution Serious adverse events (N=1205) (N=1199) 702/1185 (59.2) 721/1177 (61.3) 0.92 (0.78 to 1.09) 435/918 (47.4) 455/911 (49.9) 0.90 (0.74 to 1.08) 267/1185 (22.5) 266/178 (22.6) 1.00 (0.82 to 1.22) 11 (4 to 19) 10 (4 to18) os+0.41 o.s+0.42 33/1152 (29%) 354/1149 (31%) (0.92 (0.77 to 1.11) 112/918 (12%) 124/912 (14%) 0.87 (0.66 to 1.16) 28% 29%Functional outcome (mRS) 101 (to. 327) 029 @m2.138 130 (920.139 on ext.339 101 @77.130) tes oat.145) 053 x 115 092 (076.110 90 (ons. 140) 106 (028.130)Functional outcome (mRS) pei sanar_isa, Type of stroke 0.001 AISITIA 7 1.30 (1.06 , 1.60) Hemorthagic stroke + 0.75 (0.60 , 0.92) mimic SS 0.81 (0.43, 1.51) 1 2 Odds RatioFunctional outcome (mRS) Type of stroke AISITIA Hemorthagic stroke mimic Le 1.30 (1.06 , 1.60) a 0.75 (0.60, 0.92) Ss 0.81 (0.43, 1.51) 1 2 Odds Ratio 0.001merece ease ne eked tary Ca Kol} 00 Ambulance 200 Ambulance ASBP-14mmHg | ASBP-17 mmHg | 190 (95%CI -16 to -11) (95%Cl -19 to -14) ; cae HS & | TI i ' i 1 i t uo. TI | i z . ! 130. 4 fo 15 20 25 30 a5 Go tap 16 30 RE 9 15 20 25 50 A Ga hap ts 30 aS Time: RS 10 15 0:25 3 Sanaa’ Time: eon? Number of patients: Number of patients:— patients with cerebral ischemia (ischemic stroke and TIA) a 7 Common OR 1.30 (95%CI 1.06-1.60) “Modified Rankin Seale at 90 days Oo O O02 O3 @¢ Os me Intervention [786 | 196 [79 [EOE (599) Geen 218 bo (34 (as (600) a 10 20. 30 4 50 6 70 8 Percentage of patients 100 Sensitivity additional baseline co-variates OR 1.20 (9S%CI 0.98-1.47), mITT OR 1.23 (95%! 1.00-2.52), PP OR 1.24 (0.98, 1.56)IV thrombolysis 274/614 (45%) MRS at 90 days ~ 3-6 vs. 0-2 319/592 (54%) MRS at 90 days — 3-5 vs. 0-2 186/459 (41%) Death 133/592 (23%) Median NIHSS score at 24 hours 8 (3 to 16) Health utility EQ-5D-3L- mean (SD) 0.6+0.4 Hospital discharge by Day 7 171/581 (29%) Living at home 408/459 (89%) Serious adverse events 30% 256/612 (42%) 295/592 (50%) 194/491 (40%) 295/592 (17%) 7(2to14) 060.4 189/588 (32%) 440/492 (89%) 27% 1.23 (0.97 to 1.56) 1.06 (0.81 to 1.39) 11.48 (1.10 to 2.00) 0.86 (0.6 to 1.12) 1.12 (0.73 to 1.71)— patients with hemorrhagic stroke (primary and secondary ICH and SAH) Common OR 0.75 (95%CI 0.60-0.92) , P=0.007 Modified Rankin Scale at 90 days Oo O1 02 O3 O4 Gs geo Imogen) 2181 [83 [Te | ‘ontrol } i s- _ 7 on 33| 114 59/78 Eo eG 0 oO 10 20 30 40 50 60 70 80 90 100 Percentage of patients Sensitivity additional baseline co-variates OR 0.72 (95%CI 0.58-0.90), mITT OR 0.69 (95%C! 0.55-0.86), PP OR 0.65 (0.51-0.82)— Hemorrhagic stroke MRS at 90 days ~ 3-6 vs. 0-2 359/515 (70%) 401/507 (79%) 0.59 (0.44 to 0.79) MRS at 90 days ~3-5 vs. 0-2 234/390 (60%) 245/351 (70%) 0.64 (0.47 to 0.88) Death 125/515 (24%) 156/507 (31%) 0.71 (0.53 to. 0.94) Hematoma parameters Median Baseline volume, mL 17 (8-36) 20 (8-40) Relative hematoma growth at 24 hr 15% 21% 0.61 (0.41 to 0.90) Health utility EQ-50-3L ~ mean (SD) 0.40.39 0.36£0.38 0.07 (0.03, 0.12) Hospital discharge by Day 7 112/498 (23%) 120/487 (25%) 0.86 (0.64 to 1.17) Living at institution (%) 57/390 (15%) 65.351 (19%) 0.87 (0.66 to 1.16) Serious adverse events 27% 34%In patients with undifferentiated acute stroke in the ambulance, intensive BP lowering <2 hours of symptom onset: = All patients - no effect — not recommended in routine practice = Patients with hemorrhagic stroke - Major benefits first randomized evidence for effects on functional outcome effects on hematoma growth and reductions in complications Supports need for CODE ICH = Patients with acute ischemic cerebrovascular event — Harm reconsider optimal BP management strategy in hyperacute ischemic stroke _ wsSteering Committee: C Anderson (Chair, Pl), L Song (Co-PI), G Li (Co-Pl), J Yang (Co-Pl), Y Lin(Co-Pl), X Chen, C Chen, F Liu Advisory Committee: H Arima, P Bath, N Sprigg, G Ford, T Robinson, EC Sandset, J Saver, HB van der Worp Data Safety Monitoring Board J Dawson (Chair), L Wong, B Peng, Y Cao Statisticians L Billot, Q Li, X Liu, X Ren, H Song Medical Review Committee C Chen, Q Tang Imaging Adjudication Committee C Chen, F Liu, X Xiong, Q. Wang, R Liu, L Xiao, H Su Central Coordinating Center - The George Institute for Global Health China Y Wang (Project Manager}, X Chen, Z Yang, | Yu, B Wang, L Dong, Y Ning, B Regional Coordinating Center - Shanghai East Hospital, First Affiliated Hospital of Chengdu Medical College F Liu (Regional Project Manager), C Chen, X Wang, Z Zheng, X Chen, J Chen, Y Zheng, H Li, R Xu, H Li, Q Zhou, W Dai, S Yu, X Wang, J Qian; Y Guo (Regional Project Manager), R Hu, H Cheng, M Yang, F Mao, S He, Q Tan, K Liao, Y Chen, Y Tang, Q Zhong, Q You, T Guo, Y Su, R Liu, X Xu, Lg Zhu, C Chang, Q.Xu, Z Li, K Xie, H Su, L Xiao, G Qu, H Su, ¥ Tang, R Gang, S Dong, Y Luo, X Zeng, X Yu, Z Xu Ambulance and hospital Principal investigators and Coordinators Patients and families Funding bodies‘The NEW ENGLAND JOURNAL of MEDICINE ORIGINAL ARTICLE Intensive Ambulance-Delivered Blood- Pressure Reduction in Hyperacute Stroke G. Li, ¥. Lin, J. Yang, C.S. Anderson, C. Chen, F. Liu, L. Billot, Q. Li, X. Chen, X. Liu, X. Ren, C. Zhang, P. Xu, L. Wu, F. Wang, D. Qiu, M. Jiang, Y. Peng, C. Li, Y. Huang, X. Zhao, J. Liang, Y. Wang, X. Wu, Xiaoyun Xu, G. Chen, D. Huang, Y. Zhang, L. Zuo, G. Ma, Y. Yang, J. Hao, Xiahong Xu, X. Xiong, Y. Tang, Y. Guo, J. Yu, S. Li, S. He, F, Mao, Q. Tan, S. Tan, N. Yu, R. Xu, M. Sun, B. Li, J. Guo, L Liu, H. Liu, M. Ouyang, L. Si, H. Arima, P.M. Bath, G.A. Ford, T. Robinson, E.C. Sandset, J.L. Saver, N. Sprig, H.8. van der Worp, and L. Song, for the INTERACTS investigators* a