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Lancet. 2019 Mar 2;393(10174):877-888. doi: 10.1016/S0140-6736(19)30038-8. Epub 2019 Feb 7.

Intensive blood pressure reduction with intravenous thrombolysis therapy for acute ischaemic stroke (ENCHANTED): an international, randomised, open-label, blinded-endpoint, phase 3 trial.

Collaborators (618)

Anderson CS, Huang Y, Lindley RI, Chen X, Arima H, Chen G, Li Q, Billot L, Delcourt C, Bath PM, Broderick JP, Demchuk AM, Donnan GA, Durham AC, Lavados PM, Lee TH, Levi C, Martins SO, Olavarria VV, Pandian JD, Parsons MW, Pontes-Neto OM, Ricci S, Sato S, Sharma VK, Silva F, Song L, Thang NH, Wardlaw JM, Wang JG, Wang X, Woodward M, Chalmers J, Robinson TG, Kim JS, Stapf C, Simes RJ, Hankey GJ, Sandercock P, Bousser MG, Wong KSL, Scaria A, Hirakawa Y, Moullaali TJ, Carcel C, Gordon P, Fuentes-Patarroyo SX, Benito D, Chen R, Cao Y, Kunchok A, Winters S, Coutts S, Yoshimura S, You S, Yang J, Wu G, Zhang S, Manning L, Mistri A, Haunton V, Minhas J, Malavera A, Lim J, Liu L, Kumar NN, Tay N, Jenson K, Richtering S, Tucker S, Knight E, Ivanova E, Thembani E, Odgers E, Sanders E, Small S, Vaghasiya R, Armenis M, Donnelly P, Baig MA, Blacklock N, Naidu B, Monaghan H, Smith P, Glass P, Bai X, Li Q, Zhu P, Kong L, He R, Zhao H, Lv J, Jia H, Xi Z, Cong Y, Cui B, Deng H, Guo Y, He L, Jia R, Li N, Li W, Liu M, Zhang M, Xu Z, Zhang T, Zhao Y, Gregory P, In Y, Kim SJ, Ahn JE, Kim SH, Hong YL, González-McCawley F, Martins MCO, Portales B, Wang CY, Ryu SJ, Aujla H, Lewin S, Kumar T, Barrows S, Ebraimo A, Uyen HH, Giang NA, Linh LTM, An LTT, Phuong DM, Ngoc PVB, Hang NM, Tran NTB, Hien HTT, Yen MB, Tram NTB, Truc TTT, Hoa NA, Thuan NTB, Oanh HTK, Arora D, Verma SJ, Krause M, Priglinger M, Day S, Jala S, Davies L, Ray E, Celestino S, Law LY, Wijeratne T, Ng G, Nagao K, Weiss G, Titton N, Batista C, Zãn D, Carbonera L, Ferreira K, Castro R, Martins Filho RK, Carvalho M, Libardi M, Martins G, Fagundes D, Baron G, Boehringer A, Barbosa J, Bazan R, Braga G, Luvizutto G, Ribeiro P, Winckler F, Moro C, Longo A, Liberato R, Barbosa R, Magalhães P, Portal M, Martin K, Souza A, Cuervo D, Perin D, Marques L, Oliveira F, Battaglini M, Lourenço F, Ferreira K, Silva G, Duarte L, Alves M, Sousa J, Uhehara M, Brunser A, Mazzón E, Spencer M, Acosta I, Rojo A, Rivas R, Klapp C, Carvallo L, Carvallo P, Mansilla E, Flores J, Alvarado M, Herrera A, Reyes C, Jurado F, Bustamante G, Bravo L, Matamala JM, Guerrero R, Zhou S, Ping L, Liu W, Liu L, Tian Y, Xu H, Wang J, Wang L, Zhen Z, Wang L, Zhang J, Yan M, Wang L, Zhang Q, Tao X, Liu C, Shi J, Zhang X, Tai L, Xu L, Lu H, Nie H, Li X, Zhou J, Liu Y, Gong P, Tian Y, Zhao H, Zhang J, Li R, Wang X, Chen Q, Li Y, Wu L, Zhang J, Jia L, Guo X, Li X, Chen G, Lin B, Zhu W, Yang K, Zhang J, Zhang Z, Xie C, Wu D, Zhang Z, Li X, Wang Y, Liu D, Liu Z, Liang L, Cao Q, Zhang X, Xia J, Li X, Weng Y, Li J, Xu T, Geng D, Yan X, Wang D, Zhao N, Li J, Wang D, Tang Z, Wang L, Yin W, Wang S, Wang D, Huang W, Yang Y, Song A, Hao Y, Zhang A, Qiao B, Yang J, Yan H, Wei X, Tao Z, Liu H, Lv Y, Yang H, Han L, Mao X, Ge L, Zhang Y, He S, Zhang Q, Zhao H, Jiang J, Yan M, Liu D, Wu W, Wang H, Wang Y, Yang L, Tang Y, Sun H, Li F, Li G, Sun Y, Zhang H, Wu Y, Huang L, Geng C, Jin Z, Zhu J, Zhang F, Zhang Y, Zhang Z, Zheng R, Shen H, Liu F, Chen C, Li G, Chen S, Zhou L, Hu B, Zou Z, Liu J, Zhang X, Chang X, Wang D, Zhang S, Huang Q, Liu X, Liu S, He W, Feng J, Li L, Chen X, Zhuang X, Liu Y, Zheng W, Lai Y, Zhou Y, Duan H, Cao Q, Yang Q, Du J, Lin Q, Xu E, Zhan L, Yang L, Huang Q, Wu J, Feng X, Wei C, He J, Wang B, Liu X, Li W, Chen P, Guo F, Dai H, Dai M, Zeng X, Wang D, Chen B, Long F, Su Q, Wang Y, Bao B, Wu T, Wu X, Shao Y, Nie H, Zhang X, Li S, Xu Y, Castellanos JA, Muñoz-Collazos M, Solano E, Leung WHT, Sureshbabu S, Sharma SN, George S, Shekhar S, Singla S, Saini L, Sunita -, Kate M, Sarvotham R, William AG, Deepak A, Bk M, Benny R, Bolegave V, Basle M, Gore S, George P, Kumaravelu S, Rahamath S, Raj PG, Devi AR, Sharma A, Prajapati J, Parmar M, Patel D, Panchal T, Gorthi SP, Prabhu V, Prabhu A, Chandran V, Chatterjee A, Nair R, Nambiar VK, Ts D, Tp S, Ajai V, Paul S, Natarajan PC, Chittibabu D, Borah NC, Ghose M, Choudhury N, Gohain P, Kalita K, Duberkar D, Pawar N, Bhaviskar R, Caterbi E, Cenciarelli S, Condurso R, Gallinella E, Greco L, Marando C, Mastrocola S, Mattioni A, Sacchini E, Sicilia I, Gallina A, Giannandrea D, Marsili E, Mazzoli T, Padiglioni C, Corea F, Guidubaldi A, Micheli S, Barbi M, Kim J, Song HJ, Jeong HS, Lim JG, Park SM, Lee KB, Hwang HW, Kwon SU, Kang DW, Kim YJ, Kim BJ, Park JM, Kang K, Kim B, Kwon O, Kim YW, Lee JJ, Hwang YH, Kwon HS, Koo J, Lee K, Kim T, Ahn A, Rha JH, Park HK, Yoon CW, Chan B, Teoh HL, Paliwal P, Wong LYJ, Chen JT, De Silva DA, Chang HM, Fabiaña N, Marti J, Delgado R, Martínez A, Prats L, Camps P, Liou CW, Tan TY, Liu CF, Cheng HH, Po HL, Lin YJ, Chou CL, Lin CH, Yen CC, Chang YT, Hsu YT, Lee JD, Lee M, Huang YC, Wu CY, Huang YC, Suwanwela NC, Chutinet A, Likitjaroen Y, Roongpiboonsopit D, Charnwut S, Dyker A, Hossain M, Muddegowda GK, Sanyal R, Roffe C, Natarajan I, Finney K, Sztriha L, Teo J, Chan FK, Lim J, Chitando B, Clarke B, Patel B, Khan U, Ghatala R, Trippier S, Kalra L, Manawadu D, Sikondari N, Aeron-Thomas J, Sunman W, Wilkes G, Richardson C, Buch A, Jackson B, Halse O, Mashate S, Wilding P, Nguyen V, Qadiri MR, Rashed K, Board S, Buckley C, Smith C, James M, Keenan S, Bouring A, England T, Donnelly R, Scott J, Maddula M, Beavan J, Perry R, Francia N, Watchhurst C, Banaras A, Ashton A, Mistri A, Musarrat K, Eveson D, Kallingal J, Perez J, Harrison L, Marsden T, Furnace J, Clarke R, Reid J, Warburton E, Macleod MJ, Mitchell J, Day D, Church N, Amis E, Price C, Rodgers H, Whiting R, Hussain M, Harvey M, Brown S, Foot J, Tryambake D, Broughton D, Bergin A, Annamalai A, Dixon L, Weir N, Blank C, Harkness K, Ali A, Richards E, Stocks K, Bruce DW, Wani M, Anjum T, Krishnan M, Nguyen Huy T, Le Tuan AT, Cam LDT, Kim TNT, Nguyen BP, Dat AN, Van CN, Duy TM, Viet PD, Tien DN, Van TV, Le Kim K, Ngoc TB, Le Thanh TT, Hoanh SN, Phuoc SP, Van TT, Thi BD, Thu HNT, Duy MN, Van DN.

Abstract

BACKGROUND:

Systolic blood pressure of more than 185 mm Hg is a contraindication to thrombolytic treatment with intravenous alteplase in patients with acute ischaemic stroke, but the target systolic blood pressure for optimal outcome is uncertain. We assessed intensive blood pressure lowering compared with guideline-recommended blood pressure lowering in patients treated with alteplase for acute ischaemic stroke.

METHODS:

We did an international, partial-factorial, open-label, blinded-endpoint trial of thrombolysis-eligible patients (age ≥18 years) with acute ischaemic stroke and systolic blood pressure 150 mm Hg or more, who were screened at 110 sites in 15 countries. Eligible patients were randomly assigned (1:1, by means of a central, web-based program) within 6 h of stroke onset to receive intensive (target systolic blood pressure 130-140 mm Hg within 1 h) or guideline (target systolic blood pressure <180 mm Hg) blood pressure lowering treatment over 72 h. The primary outcome was functional status at 90 days measured by shift in modified Rankin scale scores, analysed with unadjusted ordinal logistic regression. The key safety outcome was any intracranial haemorrhage. Primary and safety outcome assessments were done in a blinded manner. Analyses were done on intention-to-treat basis. This trial is registered with ClinicalTrials.gov, number NCT01422616.

FINDINGS:

Between March 3, 2012, and April 30, 2018, 2227 patients were randomly allocated to treatment groups. After exclusion of 31 patients because of missing consent or mistaken or duplicate randomisation, 2196 alteplase-eligible patients with acute ischaemic stroke were included: 1081 in the intensive group and 1115 in the guideline group, with 1466 (67·4%) administered a standard dose among the 2175 actually given intravenous alteplase. Median time from stroke onset to randomisation was 3·3 h (IQR 2·6-4·1). Mean systolic blood pressure over 24 h was 144·3 mm Hg (SD 10·2) in the intensive group and 149·8 mm Hg (12·0) in the guideline group (p<0·0001). Primary outcome data were available for 1072 patients in the intensive group and 1108 in the guideline group. Functional status (mRS score distribution) at 90 days did not differ between groups (unadjusted odds ratio [OR] 1·01, 95% CI 0·87-1·17, p=0·8702). Fewer patients in the intensive group (160 [14·8%] of 1081) than in the guideline group (209 [18·7%] of 1115) had any intracranial haemorrhage (OR 0·75, 0·60-0·94, p=0·0137). The number of patients with any serious adverse event did not differ significantly between the intensive group (210 [19·4%] of 1081) and the guideline group (245 [22·0%] of 1115; OR 0·86, 0·70-1·05, p=0·1412). There was no evidence of an interaction of intensive blood pressure lowering with dose (low vs standard) of alteplase with regard to the primary outcome.

INTERPRETATION:

Although intensive blood pressure lowering is safe, the observed reduction in intracranial haemorrhage did not lead to improved clinical outcome compared with guideline treatment. These results might not support a major shift towards this treatment being applied in those receiving alteplase for mild-to-moderate acute ischaemic stroke. Further research is required to define the underlying mechanisms of benefit and harm resulting from early intensive blood pressure lowering in this patient group.

FUNDING:

National Health and Medical Research Council of Australia; UK Stroke Association; Ministry of Health and the National Council for Scientific and Technological Development of Brazil; Ministry for Health, Welfare, and Family Affairs of South Korea; Takeda.

PMID:
30739745
DOI:
10.1016/S0140-6736(19)30038-8
[Indexed for MEDLINE]

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