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)

The most lethal type of stroke No proven effective medical treatment Continued controversy over role of surgery

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

Near linear BP – ICH outcome associations in a Japanese clinical cohort

Okumura et al, J Hypertension 2005; 23: 1217-23

n = 1097

Systolic BP levels strongly associated with death and disability in ICH; reverse for ischaemic stroke

Zhang et al. J Hypertension 2008; 26: 1446-52

Ischaemic stroke (n=2178)

ICH stroke(n=1760)

Theoretical adverse effects of rapid BP lowering in the brain

Impaired cerebral blood flow autoregulation

Adverse effects on perihaematoma ‘ischaemia’

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

Various cerebral perfusion studies confirm safety of BP lowering on cerebral circulation

Butterworth et alCerebrovasc Dis 2001

Dyker, A. G. et alStroke 1997

PET TCD Xe-CT

Willmot et alHypertension 2006

Powers et alNeurology 2001

INTERACT – Pilot Study

Lancet Neurology 2008; 7:391-399

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.

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

INTERACT1 Protocol Schema

Acute spontaneous ICHonset < 6 hours

SBP ≥ 150 and ≤ 220 mmHgNo definite indications or contraindications to treatment

Able to be actively managedProvide informed consent

Repeat CT scans 24 and 72 hrsVital signs and BP over 7 days

In-person 28 day and 3 month follow-up

Intensive BP loweringTarget systolic BP 140 mmHg within 1 hour and for 24+ hrs

Standard BP managementAHA Guideline-based

(treatment if systolic BP >180 mmHg)

R

Standard best

practice stroke unit

care

R

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)

INTERACT Patient Flow

Patient characteristics Standard(n = 201)

Intensive(n = 203)

Time to randomization, hr:min median (IQR) 3.4 (2.5-4.5) 3.4 (2.5-4.5)

Age (mean SD), yrs 62 13 63 12

Gender (male) 69% 61%

China 95% 95%

Systolic BP (mean SD) 182 19 180 18

Diastolic BP (mean SD) 105 15 101 14

Heart rate 79 79

NIHSS, median (IQR) 9 (5-16) 9 (5-14)

GCS, median (IQR) 14 (12-15) 14 (13-15)

History of hypertension 74% 74%

Use of antihypertensives 45% 42%

Deep location of hematoma 84% 83%

Therapies and management Standard(n = 201)

Intensive(n = 203)

Any blood pressure lowering 74% 98%

Method - bolus 48% 58%

- infusion 66% 73%

Single iv agents 34% 66%

Intubation 9% 7%

Intravenous fluids 98% 98%

Fever treated 39% 36%

Nasogastric feeding 21% 20%

Intravenous mannitol 86% 82%

Neurosurgery intervention 7% 7%

Use of FFP or vitamin K 5% 3%

Use of rFVIIa 3% 6 %

INTERACT - Mean (95%CI) systolic BP differences between randomised groups

Δ 14 mmHg at 1 hour (P<0.0001)Δ 10.8 mmHg 1-24 hours (P<0.0001)

1-24 hrs 2-7 days

28 + 90 days

0-1 hr

90d28d2d18h6h145m15m 3d 5d4d 6d 7d24h

INTERACT – Adjusted* mean (95%CI) values for

absolute and relative increase in haematoma volume

6

2

-2

30

10

-5

0

4 20

0

P=0.13 P=0.06

Δ-10%Δ-1.7ml

ml %

*Adjusted for age, sex, haematoma location, baseline haematoma volume, time from onset to CT.

Anderson et al. Lancet 2008; 7: 391-399

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

INTERACT - Absolute increase in haematoma volume for tertiles of systolic BP, by baseline and achieved levels

Arima et al. J Hypertension 2010; 56:852-858

21

8 8

Abso

lute

incr

ease

(m

l)

150 160 170 180 190 200 210-2

0

2

4

6

120 130 140 150 160 170 180-2

0

2

4

6

P trend=0.03P trend=0.26

Adjusted for age, sex, haematoma location, baseline haematoma volume, time from onset to CT, and study treatment.

Baseline SBP (mmHg) Achieved SBP (mmHg)

INTERACT – Relative increase in haematoma volume for

tertiles of systolic BP, by baseline and achieved levels

Pro

port

ional in

crease

(%

)

150 160 170 180 190 200 2100

10

20

30

40

50

120 130 140 150 160 170 1800

50

10

20

30

40

P trend=0.03P trend=0.12

Baseline SBP (mmHg) Achieved SBP (mmHg)Adjusted for age, sex, haematoma location, baseline haematoma volume, time from onset to CT, and study treatment.

Arima et al. J Hypertension 2010; 56:852-858

INTERACT: Reduction in absolute hematoma growth

over 72 hours according to time from onset to treatment

Reductionin

Volume

6.5 ml

3.3 ml

0.9 ml

0.6 ml

Intensive

-4.4 ml

0.1 ml

-1.1 ml

-0.2 ml

Guideline

2.1 ml

3.4 ml

-0.2 ml

0.4 ml

Absolute growthTime from onset

to treatment

<2.9h

2.9-3.6h

3.7-4.8h

≥ 4.9h

Favors

intensive

Favors

guideline

Reduction in hematoma growth over 72h (ml)15 0 -510 5

Time from onset to treatment Intensive Guideline

Unpublished data

Interact: Reduction in relative hematoma growth over 72

hours according to time from onset to treatment

ReductionIn

volume

21%

15%

7%

4%

Intensive

-10%

16%

-6%

19%

Guideline

10%

31%

1%

22%

Favors

intensive

Relative growthFavors

guideline

Reduction in hematoma growth over 72h (%)30 0

P for

trend

0.02

Time from

onset

<2.9h

2.9-3.6h

3.7-4.8h

≥ 4.9h

-1020 10

Time from onset to treatment

P for trend

Unpublished data

Adverse effects (90 days)Standard(n = 201)

Intensive(n = 203)

p

Neurological deterioration to 72 hrs 15 15 0.94

Serious adverse events 21 21 0.40

Recurrent stroke 2 1

Other vascular event 1 1

Reported neurological deterioration 14 11

Renal failure 1 2

Non-vascular 10 8

Pneumonia 7 5

Other 2 3

Mild hypotension 0 1

Severe hypotension 2 1

Clinical outcomes (90 days)Standard(n = 201)

Intensive(n = 203)

p

Death or dependency 49 48 0.81

Death 12 10 0.51

Dependency 41 36 0.98

Modified Rankin Score, median 2 2 0.66

NIHSS, median 2 2 0.97

Barthel Index Score, median 95 95 0.77

MMSE, median 28 27 0.97

EuroQoL, EQ5D, median, % 78 75 0.97

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

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

Conclusion (cont.)

Recommendations1.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)

2.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)

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

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

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 ChenEuropean 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.