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A collaboration led by

A collaboration led by. Interact2: Background and Rationale. Acute intracerebral haemorrhage (ICH). Accounts for: ~10-15% of strokes in Western countries (Feigin et al 2003) ~20-40% in African, Asian & Latin American populations (Zhang et al 2003, Saposnik et al 2003)

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A collaboration led by

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  1. A collaboration led by

  2. Interact2:Background and Rationale

  3. Acute intracerebral haemorrhage (ICH) • Accounts for: • ~10-15% of strokes in Western countries (Feigin et al 2003) • ~20-40% in African, Asian & Latin American populations (Zhang et al 2003, Saposnik et al 2003) • The most lethal type of stroke • No proven effective medical treatment • Continued controversy over role of surgery

  4. Hypertension in ICH • Most important risk factor for both incident and recurrent ICH • Consistent determinant of poor outcome • Uncertain benefits of therapeutic blood pressure (BP) lowering • Emerging evidence of safety and potential efficacy

  5. Near linear BP – ICH outcome associations in a Japanese clinical cohort n = 1097 Okumura et al, J Hypertension 2005; 23: 1217-23

  6. Systolic BP levels strongly associated with death and disability in ICH; reverse for ischaemic stroke Ischaemic stroke (n=2178) ICH stroke (n=1760) Zhang et al. J Hypertension 2008; 26: 1446-52

  7. Theoretical adverse effects of rapid BP lowering in the brain • Impaired cerebral blood flow autoregulation • Adverse effects on perihaematoma ‘ischaemia’

  8. Less potential hazard of rapid BP lowering in ICH compared with ischaemic stroke • Perihaematoma oedema is not an ischaemic penumbra • Imaging studies indicate perihaematoma oedema is plasma derived

  9. Various cerebral perfusion studies confirm safety of BP lowering on cerebral circulation Xe-CT PET TCD Butterworth et al Cerebrovasc Dis 2001 Dyker, A. G. et al Stroke 1997 Powers et al Neurology 2001 Willmot et al Hypertension 2006

  10. INTERACT – Pilot Study Lancet Neurology 2008; 7:391-399

  11. INTERACT • Aimed to determine if early intensive BP lowering is: • feasible • safe • attenuates haematoma expansion • Sample size (n=400) provided 80% power to detect 17% (≥60% reduction in relative risk) minimum absolute difference in proportional mean haematoma growth between randomised groups, assuming 30% (SD60) mean growth in guideline group.

  12. Blood Pressure Management • Study evaluated a management policy and NOT of a single agent • Pragmatic approach to treatment • Agents used are those available in hospitals • Agents that are approved for clinical use • Lower study costs versus packaging and use of placebo • BP management protocols provided to standardise therapies across countries

  13. INTERACT1 Protocol Schema Acute spontaneous ICH onset < 6 hours SBP ≥ 150 and ≤ 220 mmHg No definite indications or contraindications to treatment Able to be actively managed Provide informed consent R R Standard best practice stroke unit care IntensiveBP lowering Target systolic BP 140 mmHg within 1 hour and for 24+ hrs Standard BP management AHA Guideline-based (treatment if systolic BP >180 mmHg) Repeat CT scans 24 and 72 hrs Vital signs and BP over 7 days In-person 28 day and 3 month follow-up

  14. Measurement of haematoma parameters • Repeat CTs at 24 and 72 hrs • DICOM digital CT images sent to central core lab (Sydney) • Multi-slice planimetric technique using MIStar 3.2 software (Melbourne, Aust) • Analysed by 2 neurologist readers blind to clinical, centre, treatment and time of CT data • Inter-reader on 10% of CTs (ICC 0.97 ICH volume)

  15. INTERACT Patient Flow

  16. Patient characteristics

  17. Therapies and management

  18. INTERACT - Mean (95%CI) systolic BP differences between randomised groups 0-1 hr 1-24 hrs 2-7 days 28 + 90 days Δ 14 mmHg at 1 hour (P<0.0001)Δ 10.8 mmHg 1-24 hours (P<0.0001) 15m 145m 6h 18h 24h 2d 3d 4d 5d 6d 7d 28d 90d

  19. INTERACT – Adjusted* mean (95%CI) values for absolute and relative increase in haematoma volume 6 30 P=0.13 P=0.06 20 4 10 2 % ml 0 0 Δ-1.7ml Δ-10% *Adjusted for age, sex, haematoma location, baseline haematoma volume, time from onset to CT. -2 -5 Anderson et al. Lancet 2008; 7: 391-399

  20. INTERACT - Effects of early intensive BP lowering on haematoma (n=296) and perihaematoma oedema (n=270) over 72 hours Anderson et al. Stroke 2010; 41: 307-321

  21. INTERACT - Absolute increase in haematoma volume for tertiles of systolic BP, by baseline and achieved levels 8 8 6 6 4 4 Absolute increase (ml) 2 2 0 0 P trend=0.26 P trend=0.03 -2 -2 Baseline SBP (mmHg) Achieved SBP (mmHg) 150 160 170 180 190 200 210 120 130 140 150 160 170 180 Adjusted for age, sex, haematoma location, baseline haematoma volume, time from onset to CT, and study treatment. 21 Arima et al. J Hypertension 2010; 56:852-858

  22. INTERACT – Relative increase in haematoma volume for tertiles of systolic BP, by baseline and achieved levels 50 50 40 40 30 30 Proportional increase (%) 20 20 10 10 P trend=0.12 P trend=0.03 Baseline SBP (mmHg) Achieved SBP (mmHg) 0 0 Adjusted for age, sex, haematoma location, baseline haematoma volume, time from onset to CT, and study treatment. 150 160 170 180 190 200 210 120 130 140 150 160 170 180 Arima et al. J Hypertension 2010; 56:852-858

  23. INTERACT: Reduction in absolute hematoma growth over 72 hours according to time from onset to treatment Intensive -4.4 ml 0.1 ml -1.1 ml -0.2 ml Reduction in Volume 6.5 ml 3.3 ml 0.9 ml 0.6 ml Absolute growth Guideline 2.1 ml 3.4 ml -0.2 ml 0.4 ml Time from onset to treatment <2.9h 2.9-3.6h 3.7-4.8h ≥ 4.9h Time from onset to treatment Favors intensive Favors guideline Intensive Guideline 0 10 5 -5 15 Reduction in hematoma growth over 72h (ml) Unpublished data

  24. Interact: Reduction in relative hematoma growth over 72 hours according to time from onset to treatment P for trend 0.02 Intensive -10% 16% -6% 19% Relative growth Guideline 10% 31% 1% 22% Time from onset <2.9h 2.9-3.6h 3.7-4.8h ≥ 4.9h Reduction In volume 21% 15% 7% 4% Favors guideline Favors intensive Time from onset to treatment P for trend 0 20 10 -10 30 Reduction in hematoma growth over 72h (%) Unpublished data

  25. Adverse effects (90 days)

  26. Clinical outcomes (90 days)

  27. Conclusion • INTERACT1 shows consistency of the BP lowering treatment effect across various different analyses • BP lowering on haematoma growth at 24 and 72 hours • Haematoma rather than perihaematoma oedema is the principle therapeutic target • Lower BP levels (140-150 mmHg) are likely to produce greater benefits • Early BP lowering are likely to produce greater benefits

  28. Conclusion (cont.) • Early rapid BP lowering is: • clinically feasible • not associated with excess hazard • appears to reduce haematoma expansion • However, some limitations: • single study, mainly Chinese participants • potential play of chance • no effect on clinical outcomes, as in rFVIIa studies

  29. Conclusion (cont.) Recommendations Until ongoing clinical trials of BP intervention for ICH are completed, physicians must manage BP on the basis of the present incomplete efficacy evidence. Current suggested recommendations for target BP in various situations are listed in Table 6 and may be considered (Class IIb; Level of Evidence: C). (Unchanged from the previous guideline) In patients presenting with a systolic BP of 150 to 220 mmHg, acute lowering of systolic BP to 140 mmHg is probably safe (Class IIa; Level of Evidence: B). (New recommendation)

  30. Summary • INTERACT shows that early intensive BP lowering with careful monitoring is: • feasible, safe, and attenuates hematoma growth • As antihypertensive agents are inexpensive and widely available • widespread adoption of a standard policy could translate into high absolute benefits • A large-scale trial powered to evaluate modest but still worthwhile effects on clinical endpoints is required to influence clinical practice

  31. Acknowledgements • Patients and families • Participating hospitals and staff • Many project staff in multiple countries • Funding: • National Health and Medical Research Council of Australia • The George Institute for Global Health

  32. Acknowledgements Executive committee: Craig Anderson (Principal Investigator), John Chalmers (Chair), Hisatomi Arima, Stephen Davis, Emma Heeley, Yining Huang, Richard Lindley, Bruce Neal, Mark Parsons, Christian Stapf, Christophe Tzourio and Jiguang Wang. China steering committee: Yining Huang, Jiguang Wang, Liying Cui, Shengdi Chen, Zhenguo Liu, Chuanzhen Lu, Qidong Yang, En Xu, Jingfen Zhang, Chaodong Zhang, Shizheng Wu and Xining Yan Chen European advisory board: Austria – Ronny Beer, Erich Schmutzhard; Belgium – Patricia Redondo; Finland – Markku Kaste, Lauri Soinne, Turgut Tatlisumak; France – Christian Stapf, Christophe Tzourio, Eric Vicaut; Germany – Katja Wartenberg; Italy – Stefano Ricci; Netherlands – Karin Klijn; Portugal – Jose´ Ferro; Spain – Angel Chamorro; Switzerland – Marcel Arnold, Urs Fischer; UK – Tom Robinson. Operations committee: Emma Heeley, Candice Delcourt. International coordinators: Michelle Leroux, Tara Sasse, Jun Hata, Gouyjen, Tina Cheung, Cathy Boreham, Sarah Leighton. Regional coordinators: Americas – Alejandro Rabinstein; Argentina – Conrado J. Estol, Mariana Zimmermann; Brazil – Gisele Silva, Joyce Marinho; Chile – Pablo Lavados; China – Jian Sun, Nan Li, Zhao Yan, Chen Xiaoying; France – Sofiane Kabla, Cecile Dert; India –K Mallickarjuna, Najam Hassan, Jeyaraj Pandian. DSMB members: John Simes (Chair), Marie-Germaine Bousser, Graeme Hankey, Konrad Jamrozik (deceased in 2010), Claiborne Johnston and Li Shunwei. Statisticians: Laurent Billot, Stephane Heritier and Qiang Li.

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