TLN BPV revision3 supplementary tables and figures clean€¦ · 1 Supplementary webappendix This webappendix formed part of the original submission and has been peer reviewed. Supplement

Supplementary webappendixThis webappendix formed part of the original submission and has been peer reviewed. We post it as supplied by the authors.

Supplement to: Manning L, Hirakawa Y, Arima H, et al, for the INTERACT2 investigators. Blood pressure variability and outcome after acute intracerebral haemorrhage: a post-hoc analysis of INTERACT2, a randomised controlled trial. Lancet Neurol 2014; published online Feb 13. http://dx.doi.org/10.1016/S1474-4422(14)70018-3.

1

Supplementary webappendix

This webappendix formed part of the original submission and has been peer reviewed.

Supplement to: Manning L, Hirakawa Y, Arima H, et al. Blood pressure variability and outcome in acute intracerebral haemorrhage: post-hoc analysis of the INTERACT2 randomised controlled trial. Lancet Neurology 2014

2

INTERACT2 Investigators

The INTERACT2 investigators are as follows: Executive Committee: C.S. Anderson

(Principal Investigator), J. Chalmers (Chair), H. Arima, S. Davis, E. Heeley, Y. Huang, P.

Lavados, B. Neal, M.W. Parsons, R. Lindley, L. Morgenstern, T. Robinson, C. Stapf, C.

Tzourio, and J.G. Wang. National Leaders: China - Steering Committee: Y. Huang

(Chair), S. Chen, X.Y. Chen, L. Cui, Z. Liu, C. Lu, J. Wang, S. Wu, E. Xu, Q. Yang, C.

Zhang, J. Zhang. Europe - Austria: R. Beer, E. Schmutzhard; Belgium: P. Redondo;

Finland: M. Kaste, L. Soinne, T. Tatlisumak; France: C. Stapf; Germany: K. Wartenberg;

Italy: S. Ricci; The Netherlands: K. Klijn; Portugal: E. Azevedo; Spain: A. Chamorro;

Switzerland: M. Arnold, U. Fischer; India: S. Kaul, J. Pandian, H. Boyini, S. Singh; North

America – A.A. Rabinstein; South America - Argentina – C. Estol; Brazil – G. Silva;

Chile – P. Lavados, V.V. Olavarria; and United Kingdom – T.G. Robinson. Data Safety

and Monitoring Committee: R.J. Simes (Chair), M.-G. Bousser, G. Hankey, K.

Jamrozik (deceased), S.C. Johnston, and S. Li. Project Office Operations

Committee: E. Heeley (Study Director), C.S. Anderson, K. Bailey, J. Chalmers, T.

Cheung, C. Delcourt, S. Chintapatla, E. Ducasse, T. Erho, J. Hata, B. Holder, E. Knight,

R. Lindley, M. Leroux, T. Sassé, E. Odgers, R. Walsh, and Z. Wolfowicz. Endpoint

Adjudication Committee: C.S. Anderson, G. Chen, C. Delcourt, S. Fuentes, R.

Lindley, B. Peng, H.-M. Schneble, and M.-X. Wang. Statistical Analysis: H. Arima, L.

Billot, S. Heritier, Q. Li, and M. Woodward. CT Analyses: C. Delcourt (Chair), S.

Abimbola, S. Anderson, E. Chan, G. Cheng, P. Chmielnik, J. Hata, S. Leighton, J.-Y. Liu,

B. Rasmussen, A. Saxena, and S. Tripathy. Data Management and Programming: M.

Armenis, M.A. Baig, B. Naidu, G. Starzec, and S. Steley. Coordinating Centres:

International (The George Institute for Global Health, Sydney, Australia) – C.S.

Anderson, E. Heeley, M. Leroux, C. Delcourt, T. Sassé, E. Knight, K. Bailey, T. Cheung,

E. Odgers, E. Ducasse, B. Holder, Z. Wolfowicz, R. Walsh, S. Chintapatla, T. Erho;

Argentina, Buenos Aires (STAT Research) – C. Estol, A. Moles, A. Ruiz, M.

Zimmermann; Brazil, Fortaleza (Medicamenta MRS) – J. Marinho, S. Alves, R. Angelim,

J. Araujo, L. Kawakami; Chile, Santiago (Clínica Alemana, Universidad del Desarrollo) –

P. Lavados, V.V. Olavarria, C. Bustos, F. Gonzalez, P. Munoz Venturelli; China, Beijing

(The George Institute China incorporating George Clinical, and Peking University First

3

Hospital) – Y. Huang, X. Chen, Y. Huang, R. Jia, N. Li, S. Qu, Y. Shu, A. Song, J. Sun,

J. Xiao, and Y. Zhao; China, Shanghai (The Centre for Epidemiological Studies and

Clinical Trials, The Shanghai Institute of Hypertension, Rui Jin Hospital, Shanghai

Jiaotong University School of Medicine) - J.-G. Wang, Q. Huang; Europe, Paris (Unité

de Recherche Clinique, APHP - Hôpital Lariboisière) – C. Stapf, E. Vicaut, A. Chamam,

M.-C. Viaud, C. Dert, U. Fiedler, V. Jovis, S. Kabla, S. Marchand, A. Pena, V. Rochaud;

India, Hyderabad (The George Institute India) – K. Mallikarjuna H. Boyini, N. Hasan;

Norway, Oslo (Oslo University Hospital) – E. Berge, E.C. Sandset, A. S. Forårsveen;

United Kingdom (Department of Cardiovascular Sciences, University of Leicester) – T.

Robinson, D. Richardson, T. Kumar, S. Lewin; United Kingdom (London, Imperial

Clinical Trials Unit) - N. Poulter, J. Field, A. Anjum, A. Wilson,. Principal Investigators

and Coordinators (according to country and centre, with numbers of patients in

parentheses): Argentina (4) - Clínica Instituto Medico Adrogue (1): H. Perelmuter, A.M.

Agarie; Hospital Central de Mendoza (3): A.G. Barboza, L.A. Recchia, I.F. Miranda, S.G.

Rauek, R.J. Duplessis; Australia (73) - Austin Hospital (5): H. Dewey, L. Walker, S.

Petrolo; Box Hill (3): C. Bladin; Gosford Hospital (22): J. Sturm, D. Crimmins, D. Griffiths,

A. Schutz, V. Zenteno; John Hunter Hospital (10): M.W. Parsons, F. Miteff, N. Spratt, E.

Kerr, C.R. Levi; Monash Medical Centre (5): T.G. Phan, H. Ma, L. Sanders, C. Moran, K.

Wong; Royal Brisbane and Women's Hospital (3): S. Read, R. Henderson, A. Wong, R.

Hull, G. Skinner; Royal Melbourne Hospital (13): S. Davis, P. Hand, B. Yan, H. Tu, B.

Campbell; Royal Prince Alfred Hospital (4): C.S. Anderson, C. Delcourt; Sir Charles

Gairdner Hospital (4): D.J. Blacker; Western Hospital (4): T. Wijeratne, M. Pathirage, M.

Jasinararchchi, Z. Matkovic, S. Celestino; Austria (63) - Allgenmeines Krankenhaus

Linz (9): F. Gruber, M.R. Vosko, E. Diabl, S. Rathmaier; Innsbruck Medical University -

Department of Neurology (34): R. Beer, E. Schmutzhard, B. Pfausler, R. Helbok;

Medical University of Graz, Department of Neurology (20): F. Fazekas, R. Fischer, B.

Poltrum, B. Zechner, U. Trummer; Belgium (12) - Cliniques De L'Europe (Europe Clinic)

(1): M.P. Rutgers; UCL St Luc (5): A. Peeters, A. Dusart, M.-C. Duray, C. Parmentier, S.

Ferrao-Santos; Universitair Ziekenhuis Brussel (6): R. Brouns, S. De Raedt, A. De

Smedt, R.-J. Van Hooff, J. De Keyser; Brazil (17) - Hospital das Clínicas de Porto

Alegre (5): S.C.O. Martins, A.G. de Almeida, R. Broudani, N.F. Titton; Hospital Quinta

4

D'Or (1): G.R. de Freitas, F.M. Cardoso, L.M. Giesel, N.A. Lima Junior; Hospital Santa

Marcelina (3): A.C. Ferraz de Almeida, R.B. Gomes, T.S. Borges dos Santos, E.M.

Veloso Soares, O.L.A. Neto; Universidade Federal de São Paulo (7): G.S. Silva, D.L.

Gomes, F.A. de Carvalho, M. Miranda, A. Marques; Universidade Federal do Paraná

(1): V.F. Zétola, G. de Matia, M.C. Lange; Chile (29) - Clinica Alemana de Santiago (8):

J. Montes, A. Reccius, P. Munoz Venturelli, V.V. Olavarria, A. Soto; Clínica Alemana de

Temuco, Chile (3): R. Rivas, C. Klapp; Clínica Dávila (5): S. Illanes, C. Aguilera, A.

Castro; Complejo Asistencial Dr. Víctor Ríos Ruiz (12): C. Figueroa, J. Benavides, P.

Salamanca, M.C. Concha, J. Pajarito; Hospital Naval Almirante Nef (1): P. Araya, F.

Guerra; China (1926) - Baotou Central Hospital (225): Y. Li, G. Liu, B. Wang, J. Zhang,

Y. Chong; Beijing Shijitan Hospital (19): M. He, L. Wang, J. Liu; Beijing Tongren

Hospital (11): X. Zhang, C. Lai, H. Jiang, Q. Yang, S. Cui; Chang Ning District Central

Hospital (25): Q. Tao, Y. Zhang, S. Yao, M. Xu, Y. Zhang; Changsha Central Hospital

(42): Z. Liu, H. Xiao, J. Hu, J. Tang; Gongli Hospital, Pudong New Area, Shanghai (11):

J. Sun, H. Ji, M. Jiang; Haidian Hospital, Beijing (9): F. Yu, Y. Zhang, X. Yang, X. Guo;

Hejian City People's Hospital (158): Y. Wang, L. Wu, Z. Liu, Y. Gao, D. Sun; Hunan

Province Brain Hospital (14): X. Huang, Y. Wang, L. Liu, Y. Li, P. Li; Jiangsu Province

Hospital of Traditional Chinese Medicine (9): Y. Jiang, H. Li, H. Lu; Nanjing First

Hospital (10): J. Zhou, C. Yuan; Navy General Hospital (2): X. Qi, F. Qiu, H. Qian, W.

Wang, J. Liu; Peking University First Hospital (4): Y. Huang, W. Sun, F. Li, R. Liu, Q.

Peng; Peking University Shougang Hospital (8): Z. Ren, C. Fan, Y. Zhang, H. Wang, T.

Wang; People's Hospital of Beijing Daxing District (60): F. Shi, C. Duan, S. Chen, J.

Wang, Z. Chen; Pinggu County Hospital, Beijing (60): X. Tan, Z. Zhao, Y. Gao, J. Chen,

T. Han; Qinghai Province People's Hospital (12): S. Wu, L. Zhang, L. Wang, Q. Hu, Q.

Hou; Qinghai University Affiliated Hospital (41): X. Zhao, L. Wang, G. Zeng, L. Ma, F.

Wang; Ruijin Hospital Affiliated to Shanghai Jiaotong University School of Medicine (4):

S. Chen, L. Zeng, Z. Guo, Y. Fu, Y. Song; Second Hospital of Hebei Medical University

(83): L. Tai, X. Liu, X. Su, Y. Yang, R. Dong; Shijiazhuang 260 Hospital (25): Y. Xu, S.

Tian, S. Cheng, L. Su, X. Xie; The Affiliated Hospital of Xuzhou Medical College (39): T.

Xu, D. Geng, X. Yan, H. Fan, N. Zhao; The Branch Hospital of the First People's

Hospital (52): S. Wang, J. Yang; The Chinese PLA No. 263 Hospital (108): J. Zhang, M.

5

Yan, L. Li; The Fifth Affiliated Hospital Sun Yat-Sen University (26): Z. Li, X. Xu, F.

Wang; The First Affiliated Hospital of Baotou Medical College (81): L. Wu, X. Guo, Y.

Lian, H. Sun, D. Liu; The First Affiliated Hospital of Fujian Medical University (12): N.

Wang, Q. Tang; The First Affiliated Hospital of Wenzhou Medical College (68): Z. Han,

L. Feng; The Fourth Hospital of Jilin University (73): Y. Cui, J. Tian, H. Chang, X. Sun, J.

Wang; The Second Affiliated Hospital Suzhou University (31): C. Liu, Z. Wen; The

Second Affiliated Hospital of Guangzhou Medical College (38): E. Xu, Q. Lin; The

Second Affiliated Hospital of Wenzhou Medical College (21): X. Zhang, L. Sun, B. Hu, M.

Zou, Q. Bao; The Second Hospital of Qinghuangdao (51): X. Lin, L. Zhao, X. Tian, H.

Wang, X. Wang; The Second Hospital of Tianjin Medical University (12): X. Li, L. Hao, Y.

Duan, R. Wang, Z. Wei; Third Hospital of Hebei Medical University (20): J. Liu, S. Ren,

H. Ren, Y. Wang, Y. Dong; Tianjin Medical University General Hospital (27): Y. Cheng,

M. Zou, W. Liu, J. Han, C. Zhang; Tianjin Third Central Hospital (14): Z. Zhang, J. Zhu,

Y. Wang, Q. Li; Traditional Chinese Medicine Hospital, Zhangjiagang (10): J. Qian, Y.

Sun, K. Liu, F. Long; Wangcheng County People's Hospital of Hunan Province (8): X.

Peng, Q. Zhang, Z. Yuan, C. Wang, M. Huang; Wuxi People's Hospital (5): J. Zhang, F.

Wang, P. He, Y. You, X. Wang; Xiangya Hospital Central-South University (8): Q. Yang,

H. Wang, J. Xia, L. Zhou, Y. Hou; Xining First People's Hospital (21): Y. Wang, L. Liu, Y.

Qi, L. Mei, R. Lu; Xuzhou Central Hospital (128): G. Chen, L. Liu, L. Ping, W. Liu, S.

Zhou; Yutian County Hospital, Hebei Province (225): J. Wang, L. Wang, H. Li, S. Zhang,

L. Wang; Zengcheng People's Hospital (15): R. Zou, J. Guo, M. Li, W. Wei; Finland

(36) - Helsinki University Central Hospital (36): L. Soinne, S. Curtze, M. Saarela, D.

Strbian, F. Scheperjans; France (221) - Centre Hospitalier de Saint Denis - Hôpital

Delafontaine (11): T. De Broucker, C. Henry, R. Cumurciuc, N. Ibos-Augé; Centre

Hospitalier de Versailles André-Mignot (16): A.-C. Zéghoudi, F. Pico; CH Calais (12): O.

Dereeper, M.-C. Simian, C. Boisselier, A. Mahfoud; CHRU de Brest (6): S. Timsit, F.M.

Merrien; CHU de Nantes - Hôpital G&R Laënnec (13): B. Guillon, M. Sevin, F. Herisson,

C. Magne; Hôpital de Meaux (12): A. Ameri, C. Cret, S. Stefanizzi, F. Klapzcynski;

Hôpital Kremlin Bicêtre (7): C. Denier, M. Sarov-Riviere; Hôpital Lariboisière (37): C.

Stapf, P. Reiner, J. Mawet, D. Hervé, F. Buffon; Hôpital Ste-Anne (9): E. Touzé, V.

Domigo, C. Lamy, D. Calvet, M. Pasquini; Hôpital Tenon (12): S. Alamowitch, P.

6

Favrole, I.-P. Muresan; Pitié Salpêtrière (37): S. Crozier, C. Rosso, C. Pires, A. Leger, S.

Deltour; Roger Salengro Lille (30): C Cordonnier, H. Henon, C. Rossi; Service de

Neurologie et Neurovasculaire, Groupe Hospitalier Paris Saint Joseph (19): M. Zuber, M.

Bruandet, R. Tamazyan, C. Join-Lambert; Germany (141) - Charité-University Medicine

Berlin - Center for Stroke Research Berlin (CSB) (46): E. Juettler, T. Krause, S. Maul, M.

Endres, G.J. Jungehulsing; Department of Neurology University of Heidelberg UMM

Mannheim (23): M. Hennerici, M. Griebe, T. Sauer, K. Knoll; Department of Neurology,

University of Ulm (8): R. Huber, K. Knauer, C. Knauer, S. Raubold; Dresden University

of Technology, University Hospital, Department of Neurology (27): H. Schneider, H.

Hentschel, C. Lautenschläger, E. Schimmel, I. Dzialowski; Goethe University Hospital

Frankfurt (10): C. Foerch, M. Lorenz, O. Singer, I.M. R. Meyer dos Santos; Klinikum

Frankfurt (Oder) (1): A. Hartmann, A. Hamann, A. Schacht, B. Schrader, A. Teíchmann;

Martin Luther University (21): K.E. Wartenberg, T.J. Mueller; University Hospital

Düsseldorf (3): S. Jander, M. Gliem, C. Boettcher; University Medical Center Hamburg –

Eppendorf (2): M. Rosenkranz, C. Beck, D. Otto, G. Thomalla, B. Cheng; Hong Kong (1)

- Prince of Wales Hospital, Chinese University of Hong Kong (1): K.S. Wong, T.W.

Leung, Y.O.Y. Soo; India (97) - Apollo Hospitals (1): S. Prabhakar, S.R. Kesavarapu,

P.K. Gajjela, R.R. Chenna; Baby Memorial Hospital (13): K. Ummer, M. Basheer, A.

Andipet; CARE Hospital, Nampally (10): M.K.M. Jagarlapudi, A.U.R. Mohammed, V.G.

Pawar, S.S.K. Eranki; Christian Medical College & Hospital (17): J. Pandian, Y. Singh,

N. Akhtar; GNRC Hospitals (16): N.C. Borah, M. Ghose, N. Choudhury; Jehangir

Clinical Development Centre Pvt Ltd (2): N.R. Ichaporia, J. Shendge, S. Khese; Lalitha

Super Specialities Hospital (27): V. Pamidimukkala, P. Inbamuthaiah, S.R. Nuthakki,

N.M.R. Tagallamudi, A.K. Gutti; Postgraduate Institute of Medical Education &

Research (10): D. Khurana, P. Kesavarapu, V. Jogi, A. Garg, D. Samanta; St. John's

Medical College & Hospital (1): G.R.K. Sarma, R. Nadig, T. Mathew, M.A. Anandan;

Italy (47) - Central follow up for Italy: E. Caterbi; Nuovo Ospedale Civile, AUSL Modena

(15): A. Zini, M. Cavazzuti, F. Casoni, R. Pentore, F. Falzone; Ospedale di Branca (6):

S. Ricci, T. Mazzoli, L.M. Greco, C. Menichetti, F. Coppola; Ospedale di Città di

Castello (16): S. Cenciarelli, E. Gallinella, A. Mattioni, R. Condurso, I. Sicilia; San

Giovanni Battista (4): M. Zampolini, F. Corea, M. Barbi, C. Proietti; Sapienza University

7

Unità di Trattamento Neurovascolare (6): D. Toni, A. Pieroni, A. Anzini, A. Falcou, M.

Demichele; The Netherlands (2) - University Medical Center Utrecht (2): C.J.M. Klijn;

Norway (5) - Sørlandet Sykehus HF Kristiansand (2): A. Tveiten, E.T. Thortveit, S.

Pettersen; Sykehuset Innlandet HF Lillehammer (2): N. Holand, B. Hitland; University

Hospital North Norway (1): S.H. Johnsen, A. Eltoft; Pakistan (9) - Aga Khan University

(9): M. Wasay, A. Kamal, A. Iqrar, L. Ali, D. Begum; Portugal (22) - Centro Hospitalar

Sao Joao (21): G. Gama, E. Azevedo, L. Fonseca, G. Moreira; Centro Hospitalar Vila

Nova de Gaia (1): L.M. Veloso, D. Pinheiro, L. Paredes, C. Rozeira, T. Gregorio; Spain

(50) - Complejo Hospitalario Universitario de Albacete (6): T. Segura Martin, O. Ayo, J.

Garcia-Garcia, I. Feria Vilar, I. Gómez Fernández; Hospital Clinico de Barcelona (10): A.

Chamorro, S. Amaro, X. Urra, V. Obach, A. Cervera; Hospital Universitari de Girona, Dr

Josep Trueta (34): Y. Silva, J. Serena, M. Castellanos, M. Terceno, C. Van

Eendenburg; Switzerland (3) - University of Bern, Inselspital (3): U. Fischer, M. Arnold,

A. Weck, O. Findling, R. Lüdi; United Kingdom (70) - Addenbrookes Hospital (1): E.A.

Warburton, D. Day, N. Butler, E. Bumanlag; Bristol Royal Infirmary (1): S. Caine, A.

Steele, M. Osborn, E. Dodd, P. Murphy; County Durham & Darlington NHS Foundation

Trust (1): B. Esisi, E. Brown, R. Hayman, V. K.V. Baliga, M. Minphone; John Radcliffe

Hospital (3): J. Kennedy, I. Reckless, G. Pope, R. Teal, K. Michael; King's College

Hospital (8): D. Manawadu, L. Kalra, R. Lewis, B. Mistry, E. Cattermole; Leeds General

Infirmary (2): A. Hassan, L. Mandizvidza, J. Bamford, H. Brooks, C. Bedford; Musgrove

Park Hospital (1): R. Whiting, P. Baines, M. Hussain, M. Harvey; New Cross Hospital

(4): K. Fotherby, S. McBride, P. Bourke, D. Morgan, K. Jennings-Preece; Northumbria

Healthcare - Wansbeck and North Tyneside General Hospitals (2): C. Price, S. Huntley,

V.E. Riddell, G. Storey, R.L. Lakey; Nottingham University Hospital (2): G.

Subramanian; Royal Bournemouth Hospital (3): D. Jenkinson, J. Kwan, O. David, D.

Tiwari; Royal Devon and Exeter Hospital (3): M. James, S. Keenan, H. Eastwood; Royal

United Hospital Bath NHS Trust (6): L. Shaw, P. Kaye, D. Button, B. Madigan, D.

Williamson; Royal Victoria Infirmary Hospital NHS Foundation Trust (8): A. Dixit, J.

Davis, M.O. Hossain, G.A. Ford; Salford Royal NHS Foundation Trust (12): A. Parry-

Jones, V. O'Loughlin, R. Jarapa, Z. Naing; St George's Healthcare NHS Trust (1): C.

Lovelock, J. O'Reilly, U. Khan; St. Thomas Hospital (1): A. Bhalla, A. Rudd, J. Birns;

8

University College London Hospitals NHS Foundation Trust (6): D.J. Werring, R. Law, R.

Perry, I. Jones, R. Erande; University Hospital of North Staffordshire (2): C. Roffe, I.

Natarajan, N. Ahmad, K. Finney, J. Lucas; University Hospitals of Leicester NHS Trust

(3): A. Mistri, D. Eveson, R. Marsh, V. Haunton, T. Robinson; USA (11) - Mayo Clinic

(11): A.A. Rabinstein, J.E. Fugate, S.W. Lepore.

9

Supplementary table 1 Baseline characteristics and blood pressure lowering treatment by fifths (F) of SD-SBP in the hyperacute phase

SD-SBP in the hyperacute phase (first 24 hours after the onset of ICH) p

F1 (n=529) F2 (n=528) F3 (n=531) F4 (n=528) F5 (n=529)

Time from onset to randomisation, hr 3·9 (2·8-4·9) 3·9 (2·9-4·7) 3·7 (2·8-4·5) 3·6 (2·7, 4·6) 3·6 (2·8-4·8) 0·070

Age, yr 62·7 (12·2) 62·2 (12·8) 63·6 (12·8) 64·2 (13·2) 64·9 (13·2) 0·004

Male 64·3 67·6 58·0 59·5 61·2 0·010

Recruited from China 81·3 71·0 69·1 61·6 62·2 <0·0001

Systolic blood pressure, mmHg 175·0 (16·3) 176·0 (15·9) 177·6 (16·6) 180·0 (16·2) 186·3 (17·0) <0·0001

Diastolic blood pressure, mmHg 100·9 (14·0) 100·4 (13·3) 99·8 (14·8) 101·6 (14·4) 103·3 (16·1) 0·001

NIHSS score* 9 (5-14) 9 (5-14) 10 (5-15) 11 (6-16) 12 (7-17) <0·0001

GCS score† 14 (13-15) 14 (13-15) 14 (12-15) 14 (13-15) 14 (11-15) 0·0005

Hypertension 68·4 74·6 71·2 73·2 75·0 0·095

Medication of hypertension 40·8 47·5 43·7 47·1 45·6 0·170

Previous intracerebral haemorrhage 6·8 7·4 9·0 8·0 9·3 0·532

Previous ischaemic/undifferentiated stroke 11·5 10·4 11·9 11·2 11·7 0·951

Previous acute coronary event 3·4 3·0 2·4 3·0 2·3 0·796

Diabetes mellitus 10·4 9·3 11·5 12·0 9·6 0·562

Baseline haematoma volume, mL 9·9 (5·2-18·4) 10·3 (5·7-17·7) 10·6 (5·8-17·1) 11·2 (5·8-20·3) 11·7 (5·8-22·0) 0·116

Deep location of haematoma‡ 85·5 85·0 80·0 84·9 84·0 0·124

Intraventricular extension 26·6 25·0 28·1 28·3 31·1 0·279

Route of administration

Bolus injection 22.9 30.7 33.3 35.6 39.3 <0.0001

Continuous infusion 49.9 45.6 45.2 52.1 58.4 <0.0001

Number of intravenous agents

None 46.4 43.6 40.4 34.9 27.6

1 42.5 42.1 45.6 45.8 45.6

≥2 11.2 14.4 14.1 19.3 26.8 <0.0001

Number of oral agents

None 50.3 50.2 46.3 45.8 42.5

1 32.7 29.6 31.1 31.8 32.7

≥2 17.0 20.3 22.6 22.4 24.8 0.071

Values given as mean (SD) or median (interquartile range) for continuous variables, and number and percentage for categorical variables.

SD-SBP denoted SD for systolic blood pressure (BP). The difference between groups was tested using Kruskal-Wallis Test for continuous variables, and chi-square test for binomial variables.

*NIHSS denotes National Institute of Health stroke scale; scores range from 0 (normal neurological status) to 42 (coma with quadriplegia)

†GCS denotes Glasgow coma scale, scores range from 15 (fully conscious) to 0 (deep coma)

‡Deep location refers to location in the basal ganglia or thalamus

10

Supplementary table 2 Baseline characteristics and blood pressure lowering treatment by fifths (F) of SD-SBP in the acute phase

SD-SBP in the acute phase (Days 2-7 after the onset of ICH) p

F1 (n=469) F2 (n=470) F3 (n=470) F4 (n=469) F5 (n=469)

Time from onset to randomisation, hr 3·8 (2·8-4·9) 3·7 (2·8-4·6) 3·7 (2·8-4·8) 3·6 (2·7-4·5) 3·8 (3·0-4·8) 0·059

Age, yr 60·8 (11·9) 62·4 (12·2) 62·5 (12·4) 64·0 (12·6) 65·6 (13·4) <0·0001

Male,% 66·7 61·5 61·7 59·9 57·4 0·053

Recruited from China 83·8 79·4 73·2 67·8 61·0 <0·0001

Systolic blood pressure, mmHg 175·2 (16·9) 177·2 (16·7) 178·4 (17·1) 180·3 (16·7) 183·4 (16·4) <0·0001

Diastolic blood pressure, mmHg 101·4 (13·6) 101·5 (13·8) 101·8 (14·9) 102·1 (14·3) 101·1 (15·2) 0·837

NIHSS score* 9 (5-14) 10 (5-15) 10 (6-14) 11 (6-16) 12 (7-16.5) <0·0001

GCS score† 14 (13-15) 14 (13-15) 14 (13-15) 14 (12-15) 14 (12-15) 0·226

Hypertension 71·4 72·5 72·8 68·7 77·6 0·042

Medication of hypertension 44·6 45·8 41·7 42·4 46·5 0·507

Previous intracerebral haemorrhage 10·4 6·6 7·0 8·3 8·7 0·218

Previous ischaemic/undifferentiated stroke 12·2 13·9 10·6 10·0 10·9 0·368

Previous acute coronary event 2·3 1·9 3·8 2·1 2·3 0·357

Diabetes mellitus 8·7 10·0 11·7 11·3 10·9 0·599

Baseline haematoma volume, ml 9·9 (5·2-16·4) 10·5 (5·1-17·5) 10·6 (5·9-18·8) 10·8 (5·9-18·3) 10·8 (6·0-18·7) 0·335

Deep location of haematoma‡ 85·6 83·1 82·7 84·4 84·2 0·789

Intraventricular extension 26·5 25·5 25·8 26·7 30·8 0·390

Route of administration

Bolus injection 15.4 18.7 20.3 23.9 27.7 <0.0001

Continuous infusion 44.1 34.9 42.4 38.6 46.1 0.004

Number of intravenous agents

None 54.6 56.8 50.3 49.9 42.9

1 37.1 34.9 35.4 36.9 34.3

≥2 or more 8.3 8.3 14.3 13.2 22.8 <0.0001

Number of oral agents

None 27.3 28.9 24.5 18.1 13.2

1 36.7 31.1 27.3 28.4 25.2

≥2 or more 36.0 40.0 48.2 53.5 61.6 <0.0001

Values given as mean (SD) or median (interquartile range) for continuous variables, and number and percentage for categorical variables.

SD-SBP denoted SD for systolic blood pressure. The difference between groups was tested using Kruskal-Wallis Test for continuous variable, and chi-square test for binomial variable.

*NIHSS denotes National Institute of Health stroke scale; scores range from 0 (normal neurological status) to 42 (coma with quadriplegia)

†GCS denotes Glasgow coma scale, scores range from 15 (fully conscious) to 0 (deep coma)

‡Deep location refers to location in the basal ganglia or thalamus

11

Supplementary table 3 Inter-individual SBP variability by randomised group

Variables Guideline group Intensive group p

Mean SBP

Day 1 (1 to 24 hours, 5 readings) 154·7 (14·2) 141.6 (13·0) <0·0001

Day 2-7 (day 2 to 7, 12 readings) 148·6 (13·0) 140 (11·3) <0·0001

SD of SBP

Day 1 (1 to 24 hours, 5 readings) 14·9 (7·5) 13·7 (7·2) 0·0002

Day 2-7 (day 2 to 7, 12 readings) 13·7 (5·0) 12·4 (4·9) <0·0001

Maximum of SBP

Day 1 (1 to 24 hours, 5 readings) 173·6 (18·1) 159·6 (19·0) <0·0001

Day 2-7 (day 2 to 7, 12 readings) 172·0 (18·1) 161·2 (17·8) <0·0001

CV of SBP

Day 1 (1 to 24 hours, 5 readings) 9.7 (5) 9·7 (4·9) 0·768

Day 2-7 (day 2 to 7, 12 readings) 9.2 (3·3) 8·8 (3·3) 0·0019

VIM of SBP

Day 1 (1 to 24 hour, 5 readings) 14.5 (7·3) 14.2 (7·2) 0·439

Day 2-7 (day 2 to 7, 12 readings) 13.2 (4·8) 12.8 (4·8) 0·026

SBP, systolic blood pressure; SD, standard deviation; CV, coefficient of variation; VIM, variability independent of mean

Values were given by mean (SD)

The difference between groups was tested using Wilcoxon two-sample test.

12

Supplementary table 4 Association of SD-SBP (by fifths [F]) on the primary outcome, by treatment group

Variables SD-SBP

F1

SD-SBP

F2

SD-SBP

F3

SD-SBP

F4

SD-SBP

F5 p for trend

p for interaction†

Hyperacute phase (Day 1)

Intensive group

N of outcomes / subjects 111 / 262 126 / 263 126 / 263 138 / 263 161 / 262

OR (95% CI)* 1·0 (ref) 1·27 (0·84-1·91) 1·17 (0·77-1·77) 1·07 (0·70-1·63) 1·74 (1·14-2·67) 0·0562

Guideline group


OR (95% CI)* 1·0 (ref) 1·22 (0·80-1·84) 1·36 (0·89-2·06) 1·46 (0·96-2·23) 1·27 (0·84-1·94) 0·1661 0·5044

Acute phase (Days 2-7)

Intensive group


OR (95% CI)* 1·0 (ref) 0·88 (0·57-1·36) 0·75 (0·48-1·16) 1·04 (0·67-1·62) 1·55 (0·98-2·47) 0·0513

Guideline group


OR (95% CI)* 1·0 (ref) 0·86 (0·55-1·34) 0·79 (0·51-1·22) 0·94 (0·61-1·47) 1·37 (0·87-2·16) 0·1675 0·7599

SD-SBP, standard deviation of systolic blood pressure; OR, odds ratio; CI, confidence interval

SD-SBP was defined using the SD of 5 measurements in hyperacute phase and 12 measurements in acute phase and divided into 5 groups by fifths (quintiles).

*Adjustments were made for age, sex, region, haematoma volume at baseline, high National Institute of Health stroke scale (>15), and mean SBP in each phase.

†The interaction between SD-SBP category and randomised group on outcome was assessed by adding the interaction term to the statistical model.

Patients who died during the first 1 day were excluded in the analysis of hyperacute phase; those who died during first 7 days were excluded in the analysis of acute phase.

13

Supplementary table 5 Likelihood ratio test for improvement in the fitted model for each variable on the primary outcome

DF, degree of freedom; SBP, systolic blood pressure; SD, standard deviation; VIM, variability independent of mean; RSD, residual standard deviation; ARV, average real variability

Model 2 vs. model 1 Model 3 vs. model 2

Partial chi-square DF p Partial chi-square DF p

SBP variability in hyperacute phase (Day 1)

Mean 478.7070304 3 <0.0001 - -

SD 463.7588825 3 <0.0001 8.9823534 1 0.0027

CV 467.7964248 3 <0.0001 12.831981 1 0.0003

Maximum 464.2009413 3 <0.0001 0.0799576 1 0.7774

Minimum 485.9629855 3 <0.0001 20.576212 1 <0.0001

VIM 466.6204855 3 <0.0001 11.785088 1 0.0006

RSD 462.618056 3 <0.0001 9.8696744 1 0.0017

ARV 465.8284737 3 <0.0001 9.1078682 1 0.0025

SBP variability in acute phase (Day 2-7)

Mean 380.4778157 3 <0.0001 - -

SD 373.1921319 3 <0.0001 4.1131438 1 0.0426

CV 379.6427428 3 <0.0001 7.9293169 1 0.0049

Maximum 371.5218274 3 <0.0001 0.0095541 1 0.9221

Minimum 395.4978907 3 <0.0001 14.408588 1 0.0001

VIM 381.4047787 3 <0.0001 8.9493722 1 0.0028

RSD 370.6491387 3 <0.0001 4.392424 1 0.0361

ARV 375.6730089 3 <0.0001 6.3297246 1 0.0119

14

Supplementary table 6 Likelihood ratio test for improvement in the fitted model for each variable on the secondary outcome

DF, degree of freedom; SBP, systolic blood pressure; SD, standard deviation; VIM, variability independent of mean; RSD, residual standard deviation; ARV, average real variability

Model 2 vs. Model 1 Model 3 vs. Model 2

Partial Chi-square DF p Partial chi-square DF p

SBP variability in hyperacute phase (Day 1)

Mean 700.5384513 3 <0.0001 - -

SD 676.0414283 3 <0.0001 21.480812 1 <0.0001

CV 681.7704353 3 <0.0001 28.031801 1 <0.0001

Maximum 676.5765998 3 <0.0001 0.7402814 1 0.3896

Minimum 708.321585 3 <0.0001 32.737022 1 <0.0001

VIM 680.1034285 3 <0.0001 26.33815 1 <0.0001

RSD 676.8716957 3 <0.0001 23.114049 1 <0.0001

ARV 680.0222866 3 <0.0001 22.251608 1 <0.0001

SBP variability in acute phase (Day 2-7)

Mean 545.7946094 3 <0.0001 - -

SD 541.9097267 3 <0.0001 5.867835 1 0.0154

CV 550.1556995 3 <0.0001 11.578637 1 0.0007

Maximum 535.7667889 3 <0.0001 0.0068478 1 0.934

Minimum 566.7849063 3 <0.0001 20.000989 1 <0.0001

VIM 552.3050707 3 <0.0001 13.066928 1 0.0003

RSD 537.7643606 3 <0.0001 7.0205933 1 0.0081

ARV 542.073474 3 <0.0001 9.0448424 1 0.0026

15

Supplementary Table 7 Associations of SD-SBP (by fifths [F]) in hyperacute and acute phases on the primary outcome, stratified by region.

Variables SD-SBP

F1 SD-SBP

F2 SD-SBP

F3 SD-SBP

F4 SD-SBP

F5 p for trend p for interaction†

Hyperacute phase (Day 1)

Non-China


OR (95% CI)* 1·0 (ref) 1.33 (0.8, 2.24) 1.68 (0.98, 2.86) 1.96 (1.15, 3.33) 2.22 (1.27, 3.9) 0·0015

China


OR (95% CI)* 1·0 (ref) 1.16 (0.81, 1.64) 1.17 (0.82, 1.67) 1.15 (0.81, 1.64) 1.25 (0.87, 1.78) 0·2859 0·0654

Acute phase (Days 2-7)

Non-China


OR (95% CI)* 1·0 (ref) 1.16 (0.65, 2.07) 1.36 (0.75, 2.46) 2.91 (1.55, 5.47) 2.06 (1.09, 3.89) 0·0010

China


OR (95% CI)* 1·0 (ref) 0.66 (0.46, 0.95) 0.82 (0.57, 1.17) 0.62 (0.43, 0.9) 1.12 (0.78, 1.63) 0·6669 0·0114

SD-SBP, standard deviation of systolic blood pressure; OR, odds ratio; CI, confidence interval

SD-SBP was defined using the SD of 5 measurements in hyperacute phase, and 12 measurements in acute phase.

SD-SBP was divided into 5 groups by quintiles.

*Adjustment was made for age, sex, randomised treatment, region, haematoma volume at baseline, high National Institutes of Health stroke scale (NIHSS, >15), mean SBP in each period. Patients who died during first 1 day were excluded in the analysis of hyperacute phase, and those who died during first 7 days were excluded in the analysis of acute phase †The interaction between SD-SBP category and randomised group on outcome was assessed by adding the interaction term in the model.

16

Supplementary table 8 SBP variability and the secondary outcome

Model 1 Model 2 Model 3

OR (95%CI) p OR (95%CI) p OR (95%CI) p

SBP variability in the hyperacute phase (Day 1)*

Mean 1·24 (1·15, 1·34) <0·0001 1·23 (1·14, 1·34) <0·0001 - -

SD 1·26 (1·18, 1·35) <0·0001 1·16 (1·08, 1·25) <0·0001 1·14 (1·06, 1·22) 0·0006

CV 1·22 (1·14, 1·31) <0·0001 1·13 (1·05, 1·21) 0·0013 1·14 (1·06, 1·23) 0·0004

Maximum 1·34 (1·25, 1·44) <0·0001 1·26 (1·16, 1·36) <0·0001 1·20 (1·06, 1·36) 0·0051

Minimum† 0·95 (0·89, 1·02) 0·1927 0·92 (0·85, 1·00) 0·0401 1·25 (1·09, 1·42) 0·0010

VIM 1·23 (1·15, 1·32) <0·0001 1·14 (1·06, 1·22) 0·0006 1·14 (1·06, 1·22) 0·0004

RSD 1·24 (1·16, 1·33) <0·0001 1·13 (1·05, 1·22) 0·0007 1·12 (1·04, 1·20) 0·0029

ARV 1·24 (1·16, 1·33) <0·0001 1·15 (1·07, 1·23) 0·0002 1·13 (1·05, 1·21) 0·0014

SBP variability in the acute phase (Day 2-7)* Mean 1·26 (1·16, 1·36) <0·0001 1·16 (1·07, 1·25) 0·0004 - -

SD 1·29 (1·20, 1·39) <0·0001 1·20 (1·11, 1·30) <0·0001 1·17 (1·08, 1·27) 0·0002

CV 1·23 (1·15, 1·33) <0·0001 1·16 (1·07, 1·26) 0·0002 1·16 (1·07, 1·25) 0·0003

Maximum 1·32 (1·22, 1·42) <0·0001 1·20 (1·11, 1·30) <0·0001 1·20 (1·05, 1·38) 0·0085

Minimum† 0·95 (0·89, 1·03) 0·2143 0·97 (0·90, 1·05) 0·4756 1·19 (1·06, 1·33) 0·0037

VIM 1·22 (1·13, 1·31) <0·0001 1·15 (1·06, 1·24) 0·0004 1·15 (1·07, 1·25) 0·0003

RSD 1·29 (1·20, 1·38) <0·0001 1·17 (1·08, 1·26) <0·0001 1·14 (1·05, 1·23) 0·0019

ARV 1·24 (1·15, 1·33) <0·0001 1·11 (1·02, 1·20) 0·0106 1·08 (0·99, 1·17) 0·0797

SD, standard deviation; SBP, systolic blood pressure; CV, coefficient of variation; VIM, variability independent of mean; RSD, residual standard deviation; ARV, average real variability; OR, odds ratio; CI, confidence interval

Model 1 was adjusted for age, sex, and randomised group; model 2 was adjusted for variables in model 1 plus region, haematoma volume at baseline, high NIHSS; model 3 was adjusted for all variables in model 2 and mean SBP in each phase.

Patients who died during the first 1 day were excluded in the analysis of the hyperacute phase; those who died during first 7 days were excluded in the analysis of the acute phase.

*Five SBP measurements at 1, 6, 12, 18, and 24 hours, and 12 measurements from days 2 to 7 (twice each day) after randomisation were used to calculate the variability in the hyperacute and acute phases, respectively. †per 1 SD decrement.

17

Supplementary Table 9 Spearman’s correlation coefficients between delta systolic BP (baseline to 1 hour), and systolic BP at baseline and systolic BP variability

Delta SBP was calculated as systolic BP at 1 hour subtracted by systolic BP at baseline. Mean delta systolic BP was -22.

BP, blood pressure; SD, standard deviation; CV, coefficient of variation, VIM, variability independent of mean; RSD, residual standard deviation; ARV, average real variability

Systolic BP parameter Delta SBP

Baseline -0.37

Systolic BP variability in hyperacute phase (day 1)

Mean systolic BP 0.45

SD of systolic BP 0.21

CV of systolic BP 0.13

Maximum systolic BP 0.48

Minimum systolic BP 0.32

VIM of systolic BP 0.15

RSD of systolic BP 0.15

ARV of systolic BP 0.14

Systolic BP variability in acute phase (days 2-7)

Mean systolic BP 0.21

SD of systolic BP 0.07

CV of systolic BP 0.02

Maximum systolic BP 0.18

Minimum systolic BP 0.15

VIM of systolic BP 0.01

RSD of systolic BP 0.04

ARV of systolic BP 0.03

18

Additional Table 10 Spearman’s correlation coefficients between measures of visit-to-visit variability, maximum, minimum and mean SBP in the hyperacute phase (upper right triangle) and in the acute phase (lower left triangle, italic).

Mean SD Maximum Minimum CV VIM RSD ARV

Mean 0.15 0.84 0.82 -0.04 0.01 0.10 0.12

SD 0.30 0.58 -0.34 0.98 0.99 0.87 0.88

Maximum 0.84 0.67 0.50 0.43 0.47 0.48 0.49

Minimum 0.73 -0.28 -0.49 -0.46 -0.33 -0.33

CV 0.08 0.97 0.44 -0.47 1.00 0.86 0.86

VIM 0.02 0.95 0.45 -0.51 1.00 0.87 0.87

RSD 0.28 0.93 0.63 -0.27 0.90 0.88 0.94

ARV 0.27 0.83 0.58 -0.23 0.80 0.79 0.90

SBP, systolic blood pressure; SD, standard deviation; CV, coefficient of variation; VIM, variation independent of mean; RSD, residual standard deviation; ARV, average real variability

19

Supplementary Table 11 Associations of 1SD increment of indices of DBP variability on the primary outcome


OR (95%CI) p OR (95%CI) p OR (95%CI) p

DBP variability in hyperacute phase (Day 1)* Mean 1.06 (0.96, 1.16) 0.2520 1.17 (1.04, 1.32) 0.0070 - - SD 1.16 (1.07, 1.26) 0.0002 1.10 (1.00, 1.21) 0.0432 1.09 (0.99, 1.20) 0.0636 CV 1.16 (1.07, 1.25) 0.0004 1.07 (0.97, 1.18) 0.1648 1.10 (1.00, 1.22) 0.0540 Maximum 1.15 (1.06, 1.26) 0.0017 1.20 (1.07, 1.33) 0.0012 1.20 (0.98, 1.46) 0.0724 Minimum† 1.01 (0.93, 1.11) 0.7804 1.03 (0.96, 1.11) 0.1432 0.92 (0.83, 1.03) 0.1014 VIM 1.16 (1.07, 1.26) 0.0002 1.10 (1.00, 1.21) 0.0578 1.09 (1.00, 1.20) 0.0623 RSD 1.20 (1.11, 1.30) <0.0001 1.16 (1.05, 1.27) 0.0028 1.15 (1.04, 1.26) 0.0045 ARV 1.16 (1.05, 1.27) <0.0001 1.16 (1.05, 1.27) 0.0026 1.15 (1.04, 1.26) 0.0044

DBP variability in acute phase (Day 2-7)* Mean 0.97 (0.88, 1.06) 0.4712 1.05 (0.94, 1.19) 0.3755 - - SD 1.22 (1.12, 1.33) <0.0001 1.15 (1.04, 1.27) 0.0065 1.14 (1.03, 1.27) 0.0091 CV 1.25 (1.15, 1.37) <0.0001 1.15 (1.04, 1.28) 0.0069 1.16 (1.05, 1.29) 0.0043 Maximum 1.13 (1.03, 1.24) 0.0079 1.17 (1.05, 1.30) 0.0049 1.36 (1.14, 1.62) 0.0007 Minimum† 1.08 (0.99, 1.18) 0.0990 0.98 (0.88, 1.10) 0.7884 1.06 (0.89, 1.26) 0.5268 VIM 1.23 (1.13, 1.34) <0.0001 1.15 (1.04, 1.27) 0.0063 1.15 (1.04, 1.27) 0.0074 RSD 1.22 (1.12, 1.33) <0.0001 1.16 (1.05, 1.28) 0.0037 1.15 (1.04, 1.28) 0.0051 ARV 1.20 (1.10, 1.30) <0.0001 1.15 (1.05, 1.27) 0.0044 1.15 (1.04, 1.27) 0.0058

SD, standard deviation; DBP, diastolic blood pressure; CV, coefficient of variation; VIM, variability independent of mean; RSD, residual standard deviation; ARV, average real variability; OR, odds ratio; CI, confidence interval

Model 1 was adjusted for age, sex, and randomised group; model 2 was adjusted for variables in model 1 plus region, haematoma volume at baseline, high scores on the National Institutes of Health Stroke Scale; model 3 was adjusted for all variables in model 2 and mean diastolic BP in each phase.

*Five SBP measurements at 1, 6, 12, 18, and 24 hours, and 12 measurements from days 2 to 7 (twice each day) after randomisation were used to calculate the variability in the hyperacute and acute phases, respectively. Patients who died during the first 24 hours were excluded in the analysis of day1; those who died during first 7 days were excluded in the analysis of day 2-7. †per 1 SD decrement

20

Supplementary table 12 Associations of 1SD increment of indices of DBP variability on the secondary outcome


OR (95%CI) P OR (95%CI) P OR (95%CI) P

DBP variability in hyperacute phase (Day 1)* Mean 1.06 (0.96, 1.16) 0.2520 1.17 (1.04, 1.32) 0.0070 1.17 (1.04, 1.32) 0.0070 SD 1.16 (1.07, 1.26) 0.0002 1.10 (1.00, 1.21) 0.0432 1.09 (0.99, 1.20) 0.0636 CV 1.16 (1.07, 1.25) 0.0004 1.07 (0.97, 1.18) 0.1648 1.10 (1.00, 1.22) 0.0540 Maximum 1.15 (1.06, 1.26) 0.0017 1.20 (1.07, 1.33) 0.0012 1.20 (0.98, 1.46) 0.0724 Minimum† 1.19 (0.97, 1.47) 0.7804 0.96 (0.88, 1.04) 0.1432 1.22 (1.04, 1.43) 0.1014 VIM 1.16 (1.07, 1.26) 0.0002 1.10 (1.00, 1.21) 0.0578 1.09 (1.00, 1.20) 0.0623 RSD 1.20 (1.11, 1.30) <0.0001 1.16 (1.05, 1.27) 0.0028 1.15 (1.04, 1.26) 0.0045 ARV 1.20 (1.11, 1.30) <0.0001 1.16 (1.05, 1.27) 0.0026 1.15 (1.04, 1.26) 0.0044

DBP variability in acute phase (Day 2-7)* Mean 0.97 (0.89, 1.05) 0.4276 1.03 (0.94, 1.12) 0.5820 1.03 (0.94, 1.12) 0.5820 SD 1.23 (1.15, 1.33) <0.0001 1.16 (1.07, 1.25) 0.0002 1.16 (1.07, 1.25) 0.0002 CV 1.27 (1.18, 1.36) <0.0001 1.17 (1.08, 1.26) 0.0002 1.17 (1.08, 1.27) <0.0001 Maximum 1.12 (1.04, 1.21) 0.0033 1.13 (1.04, 1.23) 0.0042 1.30 (1.14, 1.49) 0.0001 Minimum† 1.10 (1.02, 1.19) 0.0178 1.03 (0.94, 1.12) 0.5566 1.12 (0.97, 1.28) 0.1101 VIM 1.25 (1.16, 1.34) <0.0001 1.16 (1.07, 1.25) 0.0002 1.16 (1.07, 1.25) 0.0002 RSD 1.22 (1.13, 1.31) <0.0001 1.14 (1.06, 1.23) 0.0008 1.14 (1.05, 1.23) 0.0010 ARV 1.20 (1.12, 1.29) <0.0001 1.14 (1.05, 1.23) 0.0009 1.14 (1.05, 1.23) 0.0011

SD, standard deviation; DBP, diastolic blood pressure; CV, coefficient of variation; VIM, variability independent of mean; RSD, residual standard deviation; ARV, average real variability; OR, odds ratio; CI, confidence interval

Model 1 was adjusted for age, sex, and randomised group; model 2 was adjusted for variables in model 1 plus region, haematoma volume at baseline, high scores on the National Institutes of Health Stroke Scale; model 3 was adjusted for all variables in model 2 and mean diastolic BP in each phase.

*Five SBP measurements at 1, 6, 12, 18, and 24 hours, and 12 measurements from days 2 to 7 (twice each day) after randomisation were used to calculate the variability in the hyperacute and acute phases, respectively. Patients who died during the first 24 hours were excluded in the analysis of day1; those who died during first 7 days were excluded in the analysis of day 2-7. †per 1 SD decrement

21

Supplementary Table 13 Studies of BP variability and outcome in intracerebral haemorrhage

Study design Population Number of patients

Parameter of BP variability

Outcome OR (95%CI)

Rodriguez et al.18 Single-centre observational Supratentorial ICH 117 SD SBP in the first 24 hours

Death or early neurological deterioration*

1·20 (1·05-1·38)

INTERACT2 Cohort of a multicentre randomised controlled trial

Moderate-severe ICH

2645 SD SBP in the first 24 hours

Death or major disability at 90 days

1·16 (1·05-1·28)†

OR, odds ratio; CI, confidence interval; ICH, intracerebral haemorrhage; SD, standard deviation; SBP, systolic blood pressure

*Early neurological deterioration was defined as an increase of ≥4 points on the National Institutes of Health stroke scale over 7 days from the onset of ICH. †per 1 SD increase

22

Supplementary figure 1 SD-SBP (fifths) and primary outcome in the intensive group

SD, standard deviation; SBP systolic blood pressure; SD-SBP, SD of SBP

Patients who died during the first 24 hours were excluded in the analysis of hyperacute phase on day 1, while those who died during the first 7 days were excluded in the analysis of acute phase on day 2-7.

SD was estimated using 5 measurements at 1, 6, 12, 18, and 24 hours in the hyperacute phase on day 1, and 12 measurements from Day 2 to 7 (morning and evening each day) in the acute phase on Day 2-7, respectively.

A was adjusted for age, sex; B was adjusted for variables in A plus region, haematoma volume at baseline, high scores on the National Institutes of Health Stroke Scale; C was adjusted for all variables in A and mean SBP in each phase.

The range of SD for each group was <7·6, 7·6 to 11·0, 11·1 to 14·5, 14·6 to 19·3, ≥19·4 respectively for hyperacute phase, <8·0, 8·0 to 10·7, 10·8 to 12·9, 13·0 to 16·5, ≥16·6 respectively for acute phase.

P=0.0002 for trend

(ref.)

P=0.0096 for trend

(ref.)

P=0.0562 for trend

(ref.)

0.5

1.0

2.0

4.0

0.5

1.0

2.0

4.0

0.5

1.0

2.0

4.0

1 2 3 4 5 1 2 3 4 5 1 2 3 4 5

A B C

Odd

s R

atio

(95

% C

I)

Fifths of SD-SBP

Hyperacute Phase

P<0.0001 for trend

(ref.)

P=0.0040 for trend

(ref.)

P=0.0513 for trend

(ref.)

0.5

1.0

2.0

4.0

0.5

1.0

2.0

4.0

0.5

1.0

2.0

4.0

1 2 3 4 5 1 2 3 4 5 1 2 3 4 5

A B C

Odd

s R

atio

(95

% C

I)

Fifths of SD-SBP

Acute Phase

23

Supplementary figure 2 SD-SBP and primary outcome in the guideline group


Patients who died during the first 24 hours were excluded in the analysis of hyperacute phase on day 1, while those who died during first 7 days were excluded in the analysis of acute phase on day 2-7.

SD was estimated using 5 measurements at 1, 6, 12, 18, and 24 hours in the hyperacute phase on day 1, and 12 measurements from day 2 to 7 (morning and evening each day) in the acute phase on day 2-7, respectively.



P=0.0004 for trend

(ref.)

P=0.0296 for trend

(ref.)

P=0.1281 for trend

(ref.)

0.5

1.0

2.0

4.0

0.5

1.0

2.0

4.0

0.5

1.0

2.0

4.0

1 2 3 4 5 1 2 3 4 5 1 2 3 4 5

A B C

Odd

s R

atio

(95

% C

I)

Fifths of SD-SBP

Hyperacute Phase

P=0.0173 for trend

(ref.)

P=0.0170 for trend

(ref.)

P=0.0465 for trend

(ref.)

0.5

1.0

2.0

4.0

0.5

1.0

2.0

4.0

0.5

1.0

2.0

4.0

1 2 3 4 5 1 2 3 4 5 1 2 3 4 5

A B C

Odd

s R

atio

(95

% C

I)

Fifths of SD-SBP

Acute Phase

24

Supplementary figure 3 SD-SBP and the secondary outcome


Patients who died during the first 24 hours were excluded in the analysis of hyperacute phase on day1, while those who died during first 7 days were excluded in the analysis of acute phase on day 2-7.



The range of SD for each group was <8·1, 8·1 to 11·4, 11·5 to 15·0, 15·1 to 19·9, ≥20·0 respectively for hyperacute phase, <8·8, 8·8 to 11·3, 11·4 to 13·7, 13·8 to 17·0, ≥17·1 respectively for acute phase

P<0.0001 for trend

(ref.)

P=0.0002 for trend

(ref.)

P=0.0014 for trend

(ref.)

0.5

1.0

2.0

4.0

0.5

1.0

2.0

4.0

0.5

1.0

2.0

4.0

1 2 3 4 5 1 2 3 4 5 1 2 3 4 5

A B C

Odd

s R

atio

(95

% C

I)

Fifths of SD-SBP

Hyperacute Phase

P<0.0001 for trend

(ref.)

P=0.0003 for trend

(ref.)

P=0.0044 for trend

(ref.)

0.5

1.0

2.0

4.0

0.5

1.0

2.0

4.0

0.5

1.0

2.0

4.0

1 2 3 4 5 1 2 3 4 5 1 2 3 4 5

A B C

Odd

s R

atio

(95

% C

I)

Fifths of SD-SBP

Acute Phase

25

Supplementary figure 4 SD-SBP and death at 90 days



SD was estimated using 5 measurements at 1, 6, 12, 18, and 24 hours in the hyperacute phase on DAY 1, and 12 measurements from Day 2 to 7 (morning and evening each day) in the acute phase on Day 2-7, respectively.



P=0.0004 for trend

(ref.)

P=0.0296 for trend

(ref.)

P=0.1281 for trend

(ref.)

0.5

1.0

2.0

4.0

0.5

1.0

2.0

4.0

0.5

1.0

2.0

4.0

1 2 3 4 5 1 2 3 4 5 1 2 3 4 5

A B C

Odd

s R

atio

(95

% C

I)

Fifths of SD-SBP

Hyperacute Phase

P=0.0173 for trend

(ref.)

P=0.0170 for trend

(ref.)

P=0.0465 for trend

(ref.)

0.5

1.0

2.0

4.0

0.5

1.0

2.0

4.0

0.5

1.0

2.0

4.0

1 2 3 4 5 1 2 3 4 5 1 2 3 4 5

A B C

Odd

s R

atio

(95

% C

I)

Fifths of SD-SBP

Acute Phase

26

Supplementary figure 5 SD-SBP and major disability at 90 days

SD, standard deviation; SBP systolic blood pressure; SD-SBP, SD of SBP.


SD was estimated using 5 measurements at 1, 6, 12, 18, and 24 hours in the hyperacute phase on day 1, and 12 measurements from day 2 to 7 (morning and evening each day) in the acute phase on Day 2-7, respectively.

A was adjusted for age, sex, and randomised group; B was adjusted for variables in A plus region, haematoma volume at baseline, high scores on the National Institutes of Health Stroke Scale; C was adjusted for all variables in B and mean SBP in each phase.


P=0.0092 for trend

(ref.)

P=0.1812 for trend

(ref.)

P=0.2101 for trend

(ref.)

0.5

1.0

2.0

4.0

0.5

1.0

2.0

4.0

0.5

1.0

2.0

4.0

1 2 3 4 5 1 2 3 4 5 1 2 3 4 5

A B C

Odd

s R

atio

(95

% C

I)

Fifths of SD-SBP

Hyperacute Phase

P<0.0001 for trend

(ref.)

P=0.0369 for trend

(ref.)

P=0.0937 for trend

(ref.)

0.5

1.0

2.0

4.0

0.5

1.0

2.0

4.0

0.5

1.0

2.0

4.0

1 2 3 4 5 1 2 3 4 5 1 2 3 4 5

A B C

Odd

s R

atio

(95

% C

I)

Fifths of SD-SBP

Acute Phase

27

Supplementary figure 6 Associations of SD-SBP for the hyperacute phase including BP measurements in the first 1 hour and primary outcome


Patients who died during the first 24 hours were excluded in the analysis of hyperacute phase on day 1.

SDn was estimated using 9 measurements at 0, 15, 30 and 45 minutes, at 1, 6, 12, 18 and 24 hours in the hyperacute phase on day 1.

A was adjusted for age, sex, and randomised group; B was adjusted for variables in A plus region, haematoma volume at baseline, high scores on the National Institutes of Health Stroke Scale; C was adjusted for all variables in A and mean SBP in each phase.

The range of SD for each group was <12·0, 12·0 to 15·5, 15·6 to 19·2, 19·3 to 23·9, ≥24·0 respectively for hyperacute phase.

P<0.0001 for trend

(ref.)

P=0.0692 for trend

(ref.)

P=0.3344 for trend

(ref.)

0.5

1.0

2.0

4.0

0.5

1.0

2.0

4.0

0.5

1.0

2.0

4.0

1 2 3 4 5 1 2 3 4 5 1 2 3 4 5

A B C

Odd

s R

atio

(95

% C

I)

Fifths of SD-SBP

Hyperacute Phase (0,15,30 and 45 minutes, 1, 6, 12, 18, 24 hours)

28

Supplementary figure 7 SD-DBP and the primary outcome

SD, standard deviation; DBP, diastolic blood pressure; SD-DBP, SD of DBP


SD was estimated using 5 measurements at 1, 6, 12, 18, and 24 hours in the hyperacute phase on day 1, and 12 measurements from Day 2 to 7 (morning and evening each day) in the acute phase on Day 2-7, respectively.

A was adjusted for age, sex, and randomised group; B was adjusted for variables in A plus region, haematoma volume at baseline, high scores on the National Institutes of Health Stroke Scale; C was adjusted for all variables in B and mean DBP in each phase.


P=0.0099 for trend

(ref.)

P=0.1676 for trend

(ref.)

P=0.2049 for trend

(ref.)

0.5

1.0

2.0

4.0

0.5

1.0

2.0

4.0

0.5

1.0

2.0

4.0

1 2 3 4 5 1 2 3 4 5 1 2 3 4 5

A B C

Odd

s R

atio

(95

% C

I)

Fifths of SD-DBP

Hyperacute Phase

P=0.0004 for trend

(ref.)

P=0.0521 for trend

(ref.)

P=0.0673 for trend

(ref.)

0.5

1.0

2.0

4.0

0.5

1.0

2.0

4.0

0.5

1.0

2.0

4.0

1 2 3 4 5 1 2 3 4 5 1 2 3 4 5

A B C

Odd

s R

atio

(95

% C

I)

Fifths of SD-DBP

Acute Phase

29

Supplementary figure 8 SD-DBP and the secondary outcome

SD, standard deviation; DBP, diastolic blood pressure; SD-DBP, SD of DBP



A was adjusted for age, sex, and randomised group; B was adjusted for variables in A plus region, haematoma volume at baseline, high scores on the National Institutes of Health Stroke Scale; C was adjusted for all variables in A and mean DBP in each phase.


P=0.0003 for trend

(ref.)

P=0.0283 for trend

(ref.)

P=0.0414 for trend

(ref.)

0.5

1.0

2.0

4.0

0.5

1.0

2.0

4.0

0.5

1.0

2.0

4.0

1 2 3 4 5 1 2 3 4 5 1 2 3 4 5

A B C

Odd

s R

atio

(95

% C

I)

Fifths of SD-DBP

Hyperacute Phase

P<0.0001 for trend

(ref.)

P=0.0036 for trend

(ref.)

P=0.0043 for trend

(ref.)

0.5

1.0

2.0

4.0

0.5

1.0

2.0

4.0

0.5

1.0

2.0

4.0

1 2 3 4 5 1 2 3 4 5 1 2 3 4 5

A B C

Odd

s R

atio

(95

% C

I)

Fifths of SD-DBP

Acute Phase

30

Supplementary figure 9 Mean arterial pressure (fifths) and the primary outcome

SD, standard deviation; MAP, mean arterial pressure; SD-MAP, SD of MAP

Pulse pressure was calculated by adding diastole persists for 2/3 and systole for 1/3 (PP=1/3*SBP-2/3*DBP).



A was adjusted for age, sex, and randomised group; B was adjusted for variables in A plus region, haematoma volume at baseline, high scores on the National Institutes of Health Stroke Scale; C was adjusted for all variables in B and mean MAP in each phase.

The range of SD for each group are <5·7, 7·7 to 8·1, 8·2 to 10·4, 10·5 to 13·6, ≥13·7 respectively for hyperacute phase, and <6·4, 6·4 to 8·0, 8·1 to 9·7, 9·8 to 11·6, ≥11·7 respectively for acute phase.

P<0.0001 for trend

(ref.)

P=0.0296 for trend

(ref.)

P=0.0469 for trend

(ref.)

0.5

1.0

2.0

4.0

0.5

1.0

2.0

4.0

0.5

1.0

2.0

4.0

1 2 3 4 5 1 2 3 4 5 1 2 3 4 5

A B C

Odd

s R

atio

(95

% C

I)

Fifths of SD-MAP

Hyperacute Phase

P=0.0002 for trend

(ref.)

P=0.0344 for trend

(ref.)

P=0.0851 for trend

(ref.)

0.5

1.0

2.0

4.0

0.5

1.0

2.0

4.0

0.5

1.0

2.0

4.0

1 2 3 4 5 1 2 3 4 5 1 2 3 4 5

A B C

Odd

s R

atio

(95

% C

I)

Fifths of SD-MAP

Acute Phase

31

Supplementary figure 10 Mean arterial pressure (fifths) and the secondary outcome

SD, standard deviation; MAP, mean arterial pressure; SD-MAP, SD of mean arterial pressure

Pulse pressure was calculated by adding diastole persists for 2/3 and systole for 1/3 (PP=1/3*SBP-2/3*DBP).


Standard deviation was estimated using 5 measurements at 1, 6, 12, 18, and 24 hours in the hyperacute phase on day 1, and 12 measurements from Day 2 to 7 (morning and evening each day) in the acute phase on day 2-7, respectively.

A was adjusted for age, sex, and randomised group; B was adjusted for variables in A plus region, haematoma volume at baseline, high scores on the National Institutes of Health Stroke Scale; C was adjusted for all variables in A and mean MAP in each phase.

The range of SD for each group was <5·7, 7·7 to 8·1, 8·2 to 10·4, 10·5 to 13·6, ≥13·7 respectively for hyperacute phase, and <6·4, 6·4 to 8·0, 8·1 to 9·7, 9·8 to 11·6, ≥11·7 respectively for acute phase.

P<0.0001 for trend

(ref.)

P=0.0061 for trend

(ref.)

P=0.0128 for trend

(ref.)

0.5

1.0

2.0

4.0

0.5

1.0

2.0

4.0

0.5

1.0

2.0

4.0

1 2 3 4 5 1 2 3 4 5 1 2 3 4 5

A B C

Odd

s R

atio

(95

% C

I)

Fifths of SD-MAP

Hyperacute Phase

P<0.0001 for trend

(ref.)

P=0.0025 for trend

(ref.)

P=0.0076 for trend

(ref.)

0.5

1.0

2.0

4.0

0.5

1.0

2.0

4.0

0.5

1.0

2.0

4.0

1 2 3 4 5 1 2 3 4 5 1 2 3 4 5

A B C

Odd

s R

atio

(95

% C

I)

Fifths of SD-MAP

Acute Phase

32

Supplementary figure 11 SD-SBP in hyperacute phase and haematoma growth at 24 hours

1 included SBP measurement in the first hour; 2 includes all SBP measurements from baseline to 24 hours; 3 includes SBP measurements from 1 to 24 hours. Adjustments were made for age, sex, Chinese region, haematoma location, baseline hematoma volume, time from ICH onset to baseline CT scan and randomised treatment.

P=0.3384 for trend P=0.2496 for trend P=0.0277 for trend

-2.0

0.0

2.0

4.0

6.0

8.0

-2.0

0.0

2.0

4.0

6.0

8.0

-2.0

0.0

2.0

4.0

6.0

8.0

1 2 3 4 5 1 2 3 4 5 1 2 3 4 5

1.From 0 to 1 hour 2.From 0 to 24 hours 3.From 1 to 24 hours

Hae

mat

oma

grow

th(9

5% C

I),m

l

Fifths of SD-SBP

Haematoma Growth at 24 Hours for each category of SD-SBP during the priod

Documents

TLN BPV revision3 supplementary tables and figures clean€¦ · 1 Supplementary webappendix This webappendix formed part of the original submission and has been peer reviewed. Supplement