Main resultsEuropean Stroke Conference - London

29 May 2013

Funding from the National Health and Medical Research Council (NHMRC) of Australia

An international collaborative project of

Craig Anderson

for the INTERACT2 Investigators at 144 hospitals in 21 countries

The second, main phase, INTEnsive blood pressure Reduction in Acute Cerebral haemorrhage Trial

Primary aim To determine if a management policy of:

early intensive blood pressure (BP) lowering (target of <140 mmHg systolic) as compared to the

guideline-recommended ‘standard’ control of BP (target of <180 mmHg systolic) improves

survival free of major disability in acute spontaneous intracerebral haemorrhage (ICH)

Standardised treatment protocols – locally available intravenous (IV) BP lowering agents of physician’s choice

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Protocol schemafrom INTERACT1 (Lancet Neurol 2008) and (Int J Stroke 2010)

Acute spontaneous ICH confirmed by CT/MRIDefinite time of onset within 6 hours

Systolic BP 150 to 220 mmHgNo indication/contraindication to treatment

In-hospital vital signs, NIHSS, GCS and BP over 7 days

Intensive BP loweringSBP <140 mmHg

Standard BP managementGuidelines SBP <180 mmHg)

R

3

Independent 90 day outcome with modified Rankin scale (mRS)

N=2800 gives 90% power for 7% absolute (14% relative) decrease (50% standard vs 43% intensive) in outcome

Statistical analysis plan (Completed August 2012; published Int J Stroke in 2013)

Primary outcome – unadjusted - mRS 0-2 vs 3-6 Key secondary - unadjusted - ordinal shift, logistic

regression, mRS Sensitivity – adjusted analysis on primary and other mRS

cut-points Other - death, HRQoL on EuroQol (EQ-5D), length of

hospital stay, institutional care, poor outcome at 28 days, neurological deterioration and SAEs

Subgroups - age , ethnicity, time to randomisation, systolic BP, history of hypertension, NIHSS, haematoma volume and location

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Patient Flow – 2839 patients recruited October 2008 to August 2012

1382 (98.5%) for primary outcome 1412 (98.3%) for primary outcome

2839 Randomised

28,829 Total estimated screened

3 no consent 1 missing baseline data 2 lost to follow-up 3 withdrew consent12 alive without mRS data

Reasons for exclusion (n=3572) 39% Outside time window 16% Judged unlikely to benefit 11% BP outside criteria 8% Planned early surgery 5% Refused 21% Other reasons

6411 Screening logs completed

5

1403 Intensive BP lowering

1436 Standard BP lowering

5 no consent1 missing baseline data5 lost to follow-up4 withdrew consent9 alive without mRS data

Baseline - Demographic and clinical*

VariableIntensive(N=1399)

Standard(N=1430)

Time to randomisation, mean(SD) 3.8(1.2) 3.8(1.2)Age, mean(SD), yr 63(13) 64 (13)Male 64% 62%Chinese 68% 68%BP (mmHg) 179/101 179/101History of hypertension 72% 73%NIHSS median (iqr) score 10 (6-15) 11 (6-16)GCS median (iqr) score 14 (12-15) 14 (12-15)ICH volume median (iqr) mL 11 (6-19) 11 (6-20)Deep location 83% 83%Intraventricular extension 29% 28%

6*all non-significant

Systolic BP time trends1 hour - Δ14 mmHg (P<0.0001)6 hour - Δ14 mmHg (P<0.0001)

Systolic BP controlMedian (iqr) time to treatment, hr - intensive 4 (3-5), standard 5 (3-7)

Intensive group to target (<140mmHg)462 (33%) at 1 hour731 (53%) at 6 hours

Mea

n S

ysto

lic B

lood

Pre

ssur

e (m

m H

g)

0

110

120

130

140

150

160

170

180

190

200

R 15 30 45 60 6 12 18 24 2 3 4 5 6 7

StandardIntensive

////

Minutes Hours Days / Time

164

153

150

139

am pm am pm am pm am pm am pm am pm

P<0.0001beyond 15mins

Target level

7

α antagonists (

urapidil)

CCB (nica

rdipine)

α & β blockers

(labetal

ol)GTN

Diuretic (fru

semide)

nitroprussi

de

hydral

azine

β blockers (m

etoprolol)

other05

10152025303540

36.1

1816 16.6

12.4 12.1

6.5

1.3

5

31

20

14

107

2

8

2 3

Intensive Standard

%

80%

VariableIntensive(N=1399)

Standard(N=1430)

Any intravenous treatment 90% 43%*Combination bolus + infusion 30% 18%*Multiple agents 26% 8%*

*P<0.001

Management - Baseline to Day 7

VariableIntensive(N=1399)

Standard(N=1430)

Intubation 7% 7%ICU admission 39% 38%DVT prophylaxis 22% 22%Intravenous mannitol 62% 61%Surgery 6% 6% evacuation/decompression 3% 3% ventricular drain 3% 3%

*all non-significant

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Primary clinical outcomeDeath or major disability (mRS 3-6) at 90 days

Intensive Standard0

10

20

30

40

50

60

12.0 12.0

40.0 43.6

Major Disability

(3-5)

Death (6)

%

(N=1399) (N=1430)

52.0%55.6%

Odds ratio 0.87 (95%CI 0.75 to 1.01) P=0.06

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Among survivors Odds Ratio 0.85

(95%CI 0.73-0.99) P=0.05

Key secondary outcomeOrdinal shift in mRS scores (0-6)

Odds ratio 0.87 (95%CI 0.77 to 1.00); P=0.04

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18.0% 18.8% 16.6% 19.0%

\

12.0%8.0%

0 1 2 3 4 5 6

Intensive

Standard

Major disability DeathDisability but independent

18.7% 15.9% 18.1% 6.0%21.1%8.1% 12.0%

7.6%

Standard (0-2 vs 3-6) Crude Adjusted*

Other (0-1 vs 2-6) Crude Adjusted*

Other shift analysis 0 1 2 3 versus 4+5+6 Crude Adjusted*

Intensive

719 (52.0)

978 (70.8)

112 (8.1) 292 (21.1) 259 (18.7) 220 (15.9) 499 (36.1)

Standard

785 (55.6)

1051 (74.4)

107 (7.6) 254 (18.0) 266 (18.8) 234 (16.6) 551 (39.0)

Odds ratio (95%CI)

0.87 (0.75 to 1.01)0.87 (0.74 to 1.04)

0.83 (0.70 to 0.98)0.85 (0.70 to 1.03)

0.87 (0.76 to 0.99)0.88 (0.76 to 1.02)

P value

0.060.12

0.030.09

0.040.08

0.5 1.0 2.0

Odds ratio (95% CI)

IntensiveBetter

StandardBetter

Number of events (%)

Sensitivity analysis – crude and adjusted measures of primary endpoint and with different mRS cut-points

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*adjusted for prognostic variables: age, NIHSS score, time from ICH to randomisation, haematoma volume and location, and intraventricular haemorrhage

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Age <65 years ≥65 yearsRegion Chinese OthersTime to randomisation <4 hours ≥4 hoursBaseline systolic BP <180 mmHg ≥180 mmHgHistory of hypertension Yes NoBaseline NIHSS score <15 ≥15Baseline haematoma volume <15 ml ≥15 mlBaseline haematoma location Deep Others

Total

Intensive

340 (43.3)379 (63.6)

431 (45.8)288 (65.5)

435 (54.3)284 (48.9)

372 (50.0)347 (54.4)

524 (52.5)194 (50.7)

393 (39.8)324 (82.9)

285 (39.3)383 (69.1)

568 (53.1)100 (47.6)

719 (52.0)

Standard

352 (46.7)433 (65.7)

480 (49.6)305 (68.7)

465 (56.7)320 (54.1)

400 (53.8)385 (57.6)

555 (54.3)228 (58.9)

440 (44.3)341 (83.4)

309 (42.0)416 (73.4)

614 (56.9)111 (49.8)

785 (55.6)

Odds Ratio (95%CI)

0.87 (0.71 to 1.06)0.91 (0.72 to 1.15)

0.86 (0.72 to 1.03)0.86 (0.65 to 1.14)

0.91 (0.75 to 1.10)0.81 (0.65 to 1.02)

0.86 (0.70 to 1.05)0.88 (0.70 to 1.09)

0.93 (0.78 to 1.11)0.72 (0.54 to 0.95)

0.83 (0.70 to 0.99)0.96 (0.67 to 1.40)

0.90 (0.73 to 1.10)0.81 (0.63 to 1.05)

0.86 (0.73 to 1.02)0.92 (0.63 to 1.34)

0.87 (0.75 to 1.01)

P homog

0.76

 0.97

 

0.48 

0.90 

0.12 

0.48 

0.57 

0.76

0.5 1.0 2.0

Odds Ratio (95%CI)

IntensiveBetter

GuidelineBetter

Number of events (%)Pre-specified subgroups and primary endpoint

Health-related quality of lifeEuroQol EQ-5D domains ‘any problems’ versus ‘no problems’

mobility self-care usual activities pain/discomfortanxiety/depression0

10

20

30

40

50

60

70

80

64

47

61

40

34

67

52

66

45

38

Intensive Standard

P=0.02

P=0.006

P=0.05

% with problems

P=0.13

P=0.01

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Health utility - 0.6 intensive vs 0.55 standard groups; P=0.002

Other secondary clinical outcomes

ParameterIntensive(N=1399)

Standard(N=1430) P

Hospital stay, median (IQR) days 20 (12-35) 19 (11-33) 0.43Institutional care at 90 days 9% 9% 0.80

Poor outcome at 28 days 66% 68% 0.22

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Neurological deterioration in first 24 hours(≥4 NIHSS or ≥2 GCS)

66% 68% 0.22

Safety - cause-specific mortality, n(%)

Cause of Death Intensive(N=1394)

Standard(N=1421) P

Direct effects of primary ICH event 103 (7.4) 111 (7.8) 0.67Cardiovascular disease 14 (1.0) 15 (1.1) 0.90 ICH 0 (0.0) 2 (0.1) Ischaemic/undifferentiated stroke 1 (0.1) 1 (0.1) Acute MI/coronary event/other 3 (0.2) 1 (0.1) Other vascular disease 2 (0.1) 2 (0.1) Other cardiac disease 8 (0.6) 9 (0.6)

Non-cardiovascular disease 50 (3.6) 45 (3.2) 0.54 Renal failure 2 (0.1) 2 (0.1) Respiratory infections 17 (1.2) 12 (0.8) Sepsis (includes other infections) 6 (0.4) 4 (0.3) Non-vascular medical 25 (1.8) 27 (1.9)

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Safety - non-fatal serious adverse events (SAEs), n(%)

Serious Adverse EventIntensive(N=1399)

Standard(N=1430) P

Direct effects of primary ICH event 47 (3.4) 55 (3.8) 0.49Cardiovascular disease 37 (2.6) 41 (2.9) 0.72 ICH 4 (0.3) 4 (0.3) Ischaemic/undifferentiated stroke 8 (0.6) 8 (0.6) Acute MI/coronary event/other 5 (0.4) 5 (0.3) Other vascular disease 13 (0.9) 14 (1.0) Other cardiac disease 9 (0.6) 12 (0.8)Non-cardiovascular disease 160 (11.4) 152 (10.6) 0.49 Renal failure 5 (0.4) 7 (0.5) Severe hypotension 7 (0.5) 8 (0.6) 0.83 Respiratory infections 48 (3.4) 53 (3.7) Sepsis (includes other infections) 21 (1.5) 20 (1.4) Non-vascular medical /injury 132 (9.4) 125 (8.7)

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Early intensive BP lowering treatment is: safe - no increase in death or harms effective – borderline significant effect on the

primary endpointsecondary analyses - improved recovery of physical functioning and health-related quality of life in survivors

Consistent direction of effect in sensitivity analyses No heterogeneity of the treatment effect across

different patient and disease characteristics

Major findings of INTERACT2

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Treatment effect smaller (4%) than expected 7% absolute, but:

active-comparison study on background therapies, some with BP lowering properties (i.e. mannitol)

equates to NNT 25 (greater than aspirin and near late use of rtPA in ischaemic stroke)

No clear time-dependent relationship of treatment potential mechanisms beyond haematoma growth benefits of BP control may take several hours to manifest effects on haematoma growth and other results outlined in

Symposium this afternoon

INTERACT2 - issues

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INTERACT2 resolves longstanding uncertainty over the management of elevated BP in acute ICH

Provides evidence regarding safety and efficacy in a broad range of patients with ICH

Defines for the first time a medical therapy for the management of acute ICH

As BP lowering treatment is low cost, simple to implement, and widely applicable, the treatment should become standard of care to patients with ICH in hospitals all over the world

Conclusions

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BP lowering in acute ICH is safe, so …… Go early Go intensive (target systolic BP 140 mmHg) Go sustained (≥24 hours)

in most patients improves chances of better recovery in

survivors

Take home message

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Patients and families

Investigators/coordinators

Networks (e.g. NIHR Stroke Research Network in the UK)

Project staff, Committees

Acknowledgements

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