a collaboration led by. interact2: background and rationale
TRANSCRIPT
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
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)
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.