Background and Purpose: Early intensive blood pressure (BP) lowering has been shown to improve functional outcome in acute intracerebral hemorrhage (ICH), but the treatment effect is modest and without a clearly defined underlying explanatory mechanism. We aimed at more reliably quantifying the benefits of this treatment according to different time periods in the recovery of participants in the Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT) studies. Methods: Pooled analysis of the pilot INTERACT1 (n = 404) and main INTERACT2 (n = 2,839) involving patients with spontaneous ICH (<6 h) and elevated systolic BP (SBP 150-220 mm Hg) who were randomized to intensive (target SBP <140 mm Hg) or guideline-recommended (target SBP <180 mm Hg) BP lowering treatment. Treatment effects were examined according to repeated measures analysis of an ordinal (‘shift') across all 7 levels of the modified Rankin Scale (mRS) assessed during follow-up at 7, 28, and 90 days, post-randomization. Clinical trial registration information: http://www.clinicaltrials.gov, NCT00226096 and NCT00716079. Results: Intensive BP lowering resulted in a significant favorable distribution of mRS scores for better functioning (odds ratio 1.13, 95% confidence interval 1.00-1.26; p = 0.042) over 7, 28 and 90 days, and the effect was consistency for early (7-28 days) and later (28-90 days) time periods (p homogeneity 0.353). Treatment effects were also consistent across several pre-specified patient characteristic subgroups, with trends favoring those randomized early, and with higher SBP and milder neurological severity at baseline. Conclusions: Intensive BP lowering provides beneficial effects on physical functioning that manifests consistently through the early and later phases of recovery from ICH.

Keywords:
Intracerebral hemorrhage, Pattern of recovery, Blood pressure lowering, INTERACT, Clinical trial
1.
Krishnamurthi RV, Feigin VL, Forouzanfar MH, Mensah GA, Connor M, Bennett DA, Moran AE, Sacco RL, Anderson LM, Truelsen T, O'Donnell M, Venketasubramanian N, Barker-Collo S, Lawes CM, Wang W, Shinohara Y, Witt E, Ezzati M, Naghavi M, Murray C; Global Burden of Diseases, Injuries, Risk Factors Study 2010 (GBD 2010); GBD Stroke Experts Group: Global and regional burden of first-ever ischaemic and haemorrhagic stroke during 1990-2010: findings from the global burden of disease study 2010. Lancet Glob Health 2013;1:e259-e281.
2.
Liu M, Wu B, Wang WZ, Lee LM, Zhang SH, Kong LZ: Stroke in China: epidemiology, prevention, and management strategies. Lancet Neurol 2007;6:456-464.
3.
Flaherty ML, Haverbusch M, Sekar P, Kissela B, Kleindorfer D, Moomaw CJ, Sauerbeck L, Schneider A, Broderick JP, Woo D: Long-term mortality after intracerebral hemorrhage. Neurology 2006;66:1182-1186.
4.
Anderson CS, Heeley E, Huang Y, Wang J, Stapf C, Delcourt C, Lindley R, Robinson T, Lavados P, Neal B, Hata J, Arima H, Parsons M, Li Y, Wang J, Heritier S, Li Q, Woodward M, Simes RJ, Davis SM, Chalmers J; INTERACT2 Investigators: Rapid blood-pressure lowering in patients with acute intracerebral hemorrhage. N Engl J Med 2013;368:2355-2365.
5.
Anderson CS, Qureshi AI: Implications of INTERACT2 and other clinical trials: blood pressure management in acute intracerebral hemorrhage. Stroke 2015;46:291-295.
6.
Anderson CS, Huang Y, Wang JG, Arima H, Neal B, Peng B, Heeley E, Skulina C, Parsons MW, Kim JS, Tao QL, Li YC, Jiang JD, Tai LW, Zhang JL, Xu E, Cheng Y, Heritier S, Morgenstern LB, Chalmers J; INTERACT Investigators: Intensive blood pressure reduction in acute cerebral haemorrhage trial (INTERACT): a randomised pilot trial. Lancet Neurol 2008;7:391-399.
7.
Delcourt C, Huang Y, Wang J, Heeley E, Lindley R, Stapf C, Tzourio C, Arima H, Parsons M, Sun J, Neal B, Chalmers J, Anderson C; INTERACT2 Investigators: The second (main) phase of an open, randomised, multicentre study to investigate the effectiveness of an intensive blood pressure reduction in acute cerebral haemorrhage trial (INTERACT2). Int J Stroke 2010;5:110-116.
8.
Bamford JM, Sandercock PA, Warlow CP, Slattery J: Interobserver agreement for the assessment of handicap in stroke patients. Stroke 1989;20:828.
9.
Bath PM, Lees KR, Schellinger PD, Altman H, Bland M, Hogg C, Howard G, Saver JL; European Stroke Organisation Outcomes Working Group: Statistical analysis of the primary outcome in acute stroke trials. Stroke 2012;43:1171-1178.
10.
Woodward M: Epidemiology: Study Design and Data Analysis. America, Chapman & Hall/CRC, 2013.
11.
Hage V: The NIH stroke scale: a window into neurological status. NurseCom Nursing Spectrum (Greater Chicago), 2011, vol 24, pp 44-49.
12.
Weimar C, Roth M, Willig V, Kostopoulos P, Benemann J, Diener HC: Development and validation of a prognostic model to predict recovery following intracerebral hemorrhage. J Neurol 2006;253:788-793.
13.
Lees KR, Asplund K, Carolei A, Davis SM, Diener HC, Kaste M, Orgogozo JM, Whitehead J: Glycine antagonist (gavestinel) in neuroprotection (GAIN International) in patients with acute stroke: a randomised controlled trial. GAIN International Investigators. Lancet 2000;355:1949-1954.
14.
Manning L, Hirakawa Y, Arima H, Wang X, Chalmers J, Wang J, Lindley R, Heeley E, Delcourt C, Neal B, Lavados P, Davis SM, Tzourio C, Huang Y, Stapf C, Woodward M, Rothwell PM, Robinson TG, Anderson CS; INTERACT2 Investigators: Blood pressure variability and outcome after acute intracerebral haemorrhage: a post-hoc analysis of INTERACT2, a randomised controlled trial. Lancet Neurol 2014;13:364-373.
15.
Becker KJ, Baxter AB, Bybee HM, Tirschwell DL, Abouelsaad T, Cohen WA: Extravasation of radiographic contrast is an independent predictor of death in primary intracerebral hemorrhage. Stroke 1999;30:2025-2032.
16.
Kazui S, Minematsu K, Yamamoto H, Sawada T, Yamaguchi T: Predisposing factors to enlargement of spontaneous intracerebral hematoma. Stroke 1997;28:2370-2375.
17.
Mayer SA, Sacco RL, Shi T, Mohr JP: Neurologic deterioration in noncomatose patients with supratentorial intracerebral hemorrhage. Neurology 1994;44:1379-1384.
18.
Arima H, Huang Y, Wang JG, Heeley E, Delcourt C, Parsons M, Li Q, Neal B, Chalmers J, Anderson C; INTERACT1 Investigators: Earlier blood pressure-lowering and greater attenuation of hematoma growth in acute intracerebral hemorrhage: INTERACT pilot phase. Stroke 2012;43:2236-2238.
19.
Sato S, Arima H, Hirakawa Y, Heeley E, Delcourt C, Beer R, Li Y, Zhang J, Jüettler E, Wang J, Lavados PM, Robinson T, Lindley RI, Chalmers J, Anderson CS; INTERACT Investigators: The speed of ultraearly hematoma growth in acute intracerebral hemorrhage. Neurology 2014;83:2232-2238.
20.
Gebel JM Jr, Jauch EC, Brott TG, Khoury J, Sauerbeck L, Salisbury S, Spilker J, Tomsick TA, Duldner J, Broderick JP: Natural history of perihematomal edema in patients with hyperacute spontaneous intracerebral hemorrhage. Stroke 2002;33:2631-2635.
21.
Carhuapoma JR, Hanley DF, Banerjee M, Beauchamp NJ: Brain edema after human cerebral hemorrhage: a magnetic resonance imaging volumetric analysis. J Neurosurg Anesthesiol 2003;15:230-233.
22.
Arakawa S, Saku Y, Ibayashi S, Nagao T, Fujishima M: Blood pressure control and recurrence of hypertensive brain hemorrhage. Stroke 1998;29:1806-1809.
© 2015 S. Karger AG, Basel
2015
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.