Transcript INTERACT2

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
 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
2
Protocol schema
from INTERACT1 (Lancet Neurol 2008) and (Int J 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
Intensive BP lowering
SBP <140 mmHg
Standard BP management
Guidelines SBP <180 mmHg)
In-hospital vital signs, NIHSS, GCS and BP over 7 days
N=2800 gives 90% power for
7% absolute (14% relative)
decrease (50% standard vs
43% intensive) in outcome
Independent 90 day outcome with
modified Rankin scale (mRS)
3
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
4
Patient Flow – 2839 patients recruited
October 2008 to August 2012
28,829 Total estimated screened
6411 Screening logs completed
2839 Randomised
1403 Intensive BP lowering
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
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
1436 Standard BP lowering
5 no consent
1 missing baseline data
5 lost to follow-up
4 withdrew consent
9 alive without mRS data
1412 (98.3%) for primary outcome
Baseline - Demographic and clinical*
Intensive
(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%
179/101
179/101
History 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%
Variable
BP (mmHg)
*all non-significant
6
Systolic BP control
Median (iqr) time to treatment, hr - intensive 4 (3-5), standard 5 (3-7)
Intensive group to target (<140mmHg)
462 (33%) at 1 hour
731 (53%) at 6 hours
Mean Systolic Blood Pressure (mm Hg)
200
Systolic BP time trends
1 hour - Δ14 mmHg (P<0.0001)
6 hour - Δ14 mmHg (P<0.0001)
Standard
Intensive
190
180
170
164
160
153
150
150
140
Target level
139
130
120
P<0.0001
beyond 15mins
110
0
//
R
15
30
45
Minutes
60
//
6
12
18
Hours
24
am
pm
2
am
pm
3
am
pm
4
am
pm
5
am
6
pm
am
7
Days / Time
7
pm
Intensive
(N=1399)
Standard
(N=1430)
Any intravenous treatment
90%
43%*
Combination bolus + infusion
30%
18%*
Multiple agents
26%
8%*
Variable
40
35
*P<0.001
36
80%
31
Intensive
30
%
Standard
25
20
15
10
5
0
18
20
17
16
14
12
12
10
7
7
2
8
5
1
2
3
Management - Baseline to Day 7
Intensive
(N=1399)
Standard
(N=1430)
7%
7%
ICU admission
39%
38%
DVT prophylaxis
22%
22%
Intravenous mannitol
62%
61%
6%
6%
evacuation/decompression
3%
3%
ventricular drain
3%
3%
Variable
Intubation
Surgery
*all non-significant
9
Primary clinical outcome
Death or major disability (mRS 3-6) at 90 days
Odds ratio 0.87 (95%CI 0.75 to 1.01) P=0.06
60
55.6%
52.0%
50
40
% 30
40.0
Major
Disability
(3-5)
43.6
Death (6)
12.0
Among survivors
Odds Ratio 0.85
(95%CI 0.73-0.99)
P=0.05
20
10
12.0
0
Intensive
Standard
(N=1399)
(N=1430)
10
Key secondary outcome
Ordinal shift in mRS scores (0-6)
Odds ratio 0.87 (95%CI 0.77 to 1.00); P=0.04
0
1
Intensive
8.1%
21.1%
Standard
7.6%
18.0%
2
18.7%
18.8%
Disability but independent
3
15.9%
16.6%
4
18.1%
19.0%
Major disability
5
6
6.0%
\
12.0%
8.0%
12.0%
Death
11
Sensitivity analysis – crude and adjusted measures of
primary endpoint and with different mRS cut-points
Number of events (%)
Intensive Standard
Standard (0-2 vs 3-6)
719 (52.0) 785 (55.6)
Crude
Adjusted*
Other (0-1 vs 2-6)
Crude
Adjusted*
Other shift analysis
0
1
2
3
versus 4+5+6
Crude
Adjusted*
Odds ratio
(95% CI) Odds ratio (95%CI) P value
978 (70.8) 1051 (74.4)
112
292
259
220
499
(8.1)
(21.1)
(18.7)
(15.9)
(36.1)
107
254
266
234
551
*adjusted for prognostic variables: age, NIHSS score, time
from ICH to randomisation, haematoma volume and
location, and intraventricular haemorrhage
(7.6)
(18.0)
(18.8)
(16.6)
(39.0)
0.5
1.0
0.87 (0.75 to 1.01)
0.87 (0.74 to 1.04)
0.06
0.12
0.83 (0.70 to 0.98)
0.85 (0.70 to 1.03)
0.03
0.09
0.87 (0.76 to 0.99)
0.88 (0.76 to 1.02)
0.04
0.08
2.0
Intensive Standard
Better
Better
12
Pre-specified subgroups
and primary endpoint
Number of events (%)
Odds Ratio
(95%CI)
Intensive
Standard
<65 years
340 (43.3)
352 (46.7)
0.87 (0.71 to 1.06)
≥65 years
379 (63.6)
433 (65.7)
0.91 (0.72 to 1.15)
Chinese
431 (45.8)
480 (49.6)
0.86 (0.72 to 1.03)
Others
288 (65.5)
305 (68.7)
0.86 (0.65 to 1.14)
<4 hours
435 (54.3)
465 (56.7)
0.91 (0.75 to 1.10)
≥4 hours
284 (48.9)
320 (54.1)
0.81 (0.65 to 1.02)
<180 mmHg
372 (50.0)
400 (53.8)
0.86 (0.70 to 1.05)
≥180 mmHg
347 (54.4)
385 (57.6)
0.88 (0.70 to 1.09)
Yes
524 (52.5)
555 (54.3)
0.93 (0.78 to 1.11)
No
194 (50.7)
228 (58.9)
0.72 (0.54 to 0.95)
<15
393 (39.8)
440 (44.3)
0.83 (0.70 to 0.99)
≥15
324 (82.9)
341 (83.4)
0.96 (0.67 to 1.40)
Odds Ratio (95%CI) P homog
Age
0.76
Region
0.97
Time to randomisation
0.48
Baseline systolic BP
0.90
History of hypertension
0.12
Baseline NIHSS score
0.48
Baseline haematoma volume
<15 ml
285 (39.3)
309 (42.0)
0.90 (0.73 to 1.10)
≥15 ml
383 (69.1)
416 (73.4)
0.81 (0.63 to 1.05)
0.57
Baseline haematoma location
Deep
568 (53.1)
614 (56.9)
0.86 (0.73 to 1.02)
Others
100 (47.6)
111 (49.8)
0.92 (0.63 to 1.34)
719 (52.0)
785 (55.6)
0.87 (0.75 to 1.01)
Total
0.5
Intensive
Better
1.0
Guideline
Better
2.0
0.76
13
Health-related quality of life
EuroQol EQ-5D domains ‘any problems’ versus ‘no problems’
% with problems
80
70
P=0.13
67
60
64
50
40
30
20
10
0
Intensive
Standard
P=0.006
P=0.02
66
61
52
P=0.05
P=0.01
45
47
40
34
38
Health utility - 0.6 intensive vs 0.55 standard groups; P=0.002
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Other secondary clinical outcomes
Parameter
Intensive
(N=1399)
Standard
(N=1430)
P
Hospital stay, median (IQR) days
20 (12-35)
19 (11-33)
0.43
9%
9%
0.80
66%
68%
0.22
Institutional care at 90 days
Poor outcome at 28 days
Neurological deterioration
in first 24 hours
(≥4 NIHSS or ≥2 GCS)
66%
68%
0.22
15
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)
0.67
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)
50 (3.6)
45 (3.2)
2 (0.1)
2 (0.1)
17 (1.2)
12 (0.8)
6 (0.4)
4 (0.3)
25 (1.8)
27 (1.9)
Cardiovascular disease
Non-cardiovascular disease
Renal failure
Respiratory infections
Sepsis (includes other infections)
Non-vascular medical
0.54
16
Safety - non-fatal serious adverse events (SAEs), n(%)
Intensive
(N=1399)
Standard
(N=1430)
P
Direct effects of primary ICH event
47 (3.4)
55 (3.8)
0.49
Cardiovascular 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)
13 (0.9)
14 (1.0)
9 (0.6)
12 (0.8)
Serious Adverse Event
Other vascular disease
Other cardiac disease
Non-cardiovascular disease
160 (11.4)
152 (10.6)
Renal failure
5 (0.4)
7 (0.5)
Severe hypotension
7 (0.5)
8 (0.6)
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)
0.49
0.83
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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

18
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
19
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
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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
21
Acknowledgements
 Patients and families
 Investigators/coordinators
 Networks (e.g. NIHR Stroke Research Network in
the UK)
 Project staff, Committees
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