Craig S Anderson1, Yining Huang2, Richard I Lindley3, Xiaoying Chen4, Hisatomi Arima5, Guofang Chen6, Qiang Li7, Laurent Billot7, Candice Delcourt4, Philip M Bath8, Joseph P Broderick9, Andrew M Demchuk10, Geoffrey A Donnan11, Alice C Durham12, Pablo M Lavados13, Tsong-Hai Lee14, Christopher Levi15, Sheila O Martins16, Veronica V Olavarria17, Jeyaraj D Pandian18, Mark W Parsons19, Octavio M Pontes-Neto20, Stefano Ricci21, Shoichiro Sato22, Vijay K Sharma23, Federico Silva24, Lili Song25, Nguyen H Thang26, Joanna M Wardlaw27, Ji-Guang Wang28, Xia Wang7, Mark Woodward29, John Chalmers7, Thompson G Robinson30. 1. The George Institute for Global Health, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia; Neurology Department, Royal Prince Alfred Hospital, Sydney Health Partners, Sydney, NSW, Australia; The George Institute China at Peking University Health Sciences Centre, Beijing, China. Electronic address: canderson@georgeinstitute.org.au. 2. Department of Neurology, Peking University First Hospital, Beijing, China. 3. Westmead Clinical School, University of Sydney, Sydney, NSW, Australia; Sydney Medical School, University of Sydney, Sydney, NSW, Australia. 4. The George Institute for Global Health, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia; Sydney Medical School, University of Sydney, Sydney, NSW, Australia. 5. The George Institute for Global Health, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia; Department of Preventive Medicine and Public Health, Faculty of Medicine, Fukuoka University, Fukuoka, Japan. 6. Department of Neurology, Xuzhou Central Hospital, Xuzhou, Jiangsu, China. 7. The George Institute for Global Health, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia. 8. Stroke Trials Unit, Division of Clinical Neuroscience, University of Nottingham, Nottingham, UK. 9. Department of Neurology and Rehabilitation Medicine, University of Cincinnati Gardner Neuroscience Institute, University of Cincinnati, Cincinnati, OH, USA. 10. Departments of Clinical Neurosciences and Radiology, Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada. 11. The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, VIC, Australia. 12. Department of Cardiovascular Sciences, University of Leicester, Leicester, UK. 13. Department of Neurology and Psychiatry, Clinica Alemana de Santiago, Clínica Alemana Universidad del Desarrollo School of Medicine, Santiago, Chile; Department of Neurological Sciences, School of Medicine, Universidad de Chile, Santiago, Chile. 14. Stroke Centre and Department of Neurology, Linkou Chang Gung Memorial Hospital and College of Medicine, Chang Gung University, Taoyuan, Taiwan. 15. University of Newcastle, School of Medicine and Public Health, Newcastle, NSW, Australia; Hunter Medical Research Institute, Newcastle, NSW, Australia; The Sydney Partnership for Health, Education, Research and Enterprise, Ingham Institute for Applied Medical Research, Sydney, NSW, Australia. 16. Federal University of Rio Grande do Sul, Neurology Service of Hospital de Clinicas de Porto Alegre and Hospital Moinhos de Vento, Porto Alegre, Rio Grande do Sul, Brazil. 17. Department of Neurology and Psychiatry, Clinica Alemana de Santiago, Clínica Alemana Universidad del Desarrollo School of Medicine, Santiago, Chile. 18. Department of Neurology, Christian Medical College, Ludhiana, Punjab, India. 19. Neurology Department, Royal Melbourne Hospital, University of Melbourne, Melbourne, VIC, Australia. 20. University of São Paulo, Ribeirao Preto Medical School, Department of Neurosciences and Behavioural Sciences, Ribeirao Preto, São Paulo, Brazil. 21. Uo Neurologia, Unità Sanitaria Locale Umbria 1, Sedi di Citta di Castello e Branca, Italy. 22. Department of Cerebrovascular Medicine, National Cerebral and Cardiovascular Centre, Suita, Osaka, Japan. 23. Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Division of Neurology, National University Health System, Singapore. 24. Neurovascular Sciences Group, Neurosciences Department, International Hospital of Colombia, Bucaramanga, Colombia. 25. The George Institute for Global Health, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia; The George Institute China at Peking University Health Sciences Centre, Beijing, China. 26. Department of Cerebrovascular Disease, 115 People's Hospital, Ho Chi Minh City, Vietnam. 27. Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK. 28. Shanghai Institute of Hypertension, Rui Jin Hospital and Shanghai Jiaotong University School of Medicine, Shanghai, China. 29. The George Institute for Global Health, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia; Department of Epidemiology, Johns Hopkins University, Baltimore, MD, USA; The George Institute for Global Health, University of Oxford, Oxford, UK. 30. Department of Cardiovascular Sciences, University of Leicester, Leicester, UK; NIHR Leicester Biomedical Research Centre, The Glenfield Hospital, Leicester, UK.
Abstract
BACKGROUND:Systolic blood pressureof 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 pressure150 mmHg 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 pressure130-140 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.
RCT Entities:
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.
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