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The second, main phase, INTEnsive blood pressure Reduction in Acute Cerebral haemorrhage Trial. Main results European Stroke Conference - London 29 May 2013. Craig Anderson f or the INTERACT2 Investigators at 144 hospitals in 21 countries. An international collaborative project of.

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slide1

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

Main results

European Stroke Conference - London

29 May 2013

Craig Anderson

for the INTERACT2 Investigators at 144 hospitals in 21 countries

An international collaborative project of

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

primary aim
Primary aim
  • To determine if a managementpolicy 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 intracerebralhaemorrhage (ICH)

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

slide3

Protocol schema

  • from INTERACT1 (Lancet Neurol2008) and (IntJ Stroke 2010)

Acute spontaneous ICH confirmed by CT/MRI

Definite time of onset within 6 hours

Systolic BP 150 to 220 mmHg

No indication/contraindication to treatment

R

IntensiveBP lowering

SBP <140 mmHg

Standard BP management

Guidelines SBP <180 mmHg)

In-hospital vital signs, NIHSS, GCSand BP over 7 days

  • N=2800 gives 90% power for 7% absolute (14% relative) decrease (50% standard vs43% intensive) in outcome

Independent 90 day outcome with modified Rankin scale (mRS)

statistical analysi s plan completed august 2012 published int j stroke in 2013
Statistical analysis plan(Completed August 2012; published Int J Strokein 2013)
  • Primary outcome– unadjusted - mRS0-2 vs 3-6
  • Key secondary - unadjusted - ordinal shift, logistic regression, mRS
  • Sensitivity – adjusted analysis on primary and other mRScut-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
slide5

Patient Flow – 2839 patients recruited October 2008 to August 2012

  • 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

28,829 Total estimated screened

6411 Screening logs completed

2839 Randomised

1436 Standard BP lowering

1403 Intensive BP lowering

5 no consent

1 missing baseline data

5 lost to follow-up

4 withdrew consent

9 alive without mRS data

3 no consent

1 missing baseline data

2 lost to follow-up

3 withdrew consent

12 alive without mRS data

1382 (98.5%) for primary outcome

1412 (98.3%) for primary outcome

systolic bp control median iqr time to treatment hr intensive 4 3 5 standard 5 3 7

200

190

180

170

160

Mean Systolic Blood Pressure (mm Hg)

150

140

130

120

110

0

R

15

30

45

60

6

12

18

24

2

3

4

5

6

7

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

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

6 hour - Δ14 mmHg (P<0.0001)

Intensive group to target (<140mmHg)

462 (33%) at 1 hour

731 (53%) at 6 hours

Standard

Intensive

164

153

150

Target level

139

P<0.0001

beyond 15mins

//

//

am

am

am

am

pm

pm

pm

pm

am

am

pm

pm

Hours

Minutes

Days / Time

management baseline to day 7
Management - Baseline to Day 7

*all non-significant

primary clinical outcome death or major disability mrs 3 6 at 90 days
Primary clinical outcomeDeath or major disability (mRS 3-6) at 90 days

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

55.6%

52.0%

Among survivors Odds Ratio 0.85

(95%CI 0.73-0.99) P=0.05

%

(N=1430)

(N=1399)

key secondary outcome ordinal shift in mrs scores 0 6
Key secondary outcomeOrdinal shift in mRS scores (0-6)

6

4

5

0

3

2

1

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

18.0%

18.8%

16.6%

19.0%

\

  • 12.0%

Intensive

12.0%

18.1%

18.7%

15.9%

6.0%

21.1%

8.1%

8.0%

Standard

7.6%

Disability but independent

Death

Major disability

slide12

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

Odds ratio (95% CI)

Number of events (%)

Intensive

719 (52.0)

978 (70.8)

112 (8.1)

292 (21.1)

259 (18.7)

220 (15.9)

499 (36.1)

P value

0.06

0.12

0.03

0.09

0.04

0.08

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)

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*

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

0.5

1.0

2.0

Intensive

Better

Standard

Better

slide13

Pre-specified subgroups and primary endpoint

Age

<65 years

≥65 years

Region

Chinese

Others

Time to randomisation

<4 hours

≥4 hours

Baseline systolic BP

<180 mmHg

≥180 mmHg

History of hypertension

Yes

No

Baseline NIHSS score

<15

≥15

Baseline haematoma volume

<15 ml

≥15 ml

Baseline 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

Number of events (%)

Odds Ratio (95%CI)

1.0

0.5

2.0

Intensive

Better

Guideline

Better

health related quality of life euroqol eq 5d domains any problems versus no problems
Health-related quality of lifeEuroQol EQ-5D domains ‘any problems’ versus ‘no problems’

% with problems

P=0.13

P=0.01

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

slide18

Major findings of INTERACT2

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

secondary 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
slide19

INTERACT2 - issues

  • 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
slide20

Conclusions

  • 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
slide21

Take home message

  • 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
slide22

Acknowledgements

  • Patients and families
  • Investigators/coordinators
  • Networks (e.g. NIHR Stroke Research Network in the UK)
  • Project staff, Committees