1. Main results European 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

2. 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

3. 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 In-hospital vital signs, NIHSS, GCS and BP over 7 days Intensive BP lowering SBP <140 mmHg Standard BP management Guidelines 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

4. 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

5. 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 consent 12 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 consent 1 missing baseline data 5 lost to follow-up 4 withdrew consent 9 alive without mRS data

6. Baseline - Demographic and clinical* Variable Intensive (N=1399) Standard (N=1430) Time to randomisation, mean(SD)3.8(1.2) Age, mean(SD), yr63(13)64 (13) Male64%62% Chinese68% BP (mmHg)179/101 History of hypertension72%73% NIHSS median (iqr) score10 (6-15)11 (6-16) GCS median (iqr) score 14 (12-15) ICH volume median (iqr) mL11 (6-19)11 (6-20) Deep location83% Intraventricular extension29%28% 6 *all non-significant

7. Systolic BP time trends 1 hour - Δ14 mmHg (P<0.0001) 6 hour - Δ14 mmHg (P<0.0001) 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) 0 110 120 130 140 150 160 170 180 190 200 R153045606121824 234567 Standard Intensive // Minutes Hours Days / Time 164 153 150 139 am pmpm pmpm pmpm pmpm pmpm pmpm P<0.0001 beyond 15mins Target level 7

8. % 8 80% Variable Intensive (N=1399) Standard (N=1430) Any intravenous treatment90%43%* Combination bolus + infusion30%18%* Multiple agents26%8%* *P<0.001

9. Management - Baseline to Day 7 Variable Intensive (N=1399) Standard (N=1430) Intubation 7% ICU admission39%38% DVT prophylaxis22% Intravenous mannitol62%61% Surgery 6% evacuation/decompression 3% ventricular drain 3% *all non-significant 9

10. Primary clinical outcome Death or major disability (mRS 3-6) at 90 days % (N=1399) (N=1430) 52.0% 55.6% Odds ratio 0.87 (95%CI 0.75 to 1.01) P=0.06 10 Among survivors Odds Ratio 0.85 (95%CI 0.73-0.99) P=0.05

11. Key secondary outcome Ordinal shift in mRS scores (0-6) Odds ratio 0.87 (95%CI 0.77 to 1.00); P=0.04 11 18.0%18.8%16.6%19.0% \ 12.0% 8.0% 0 1 2 3 4 5 6 Intensive Standard Major disability Death Disability but independent 18.7% 15.9% 18.1% 6.0% 21.1% 8.1% 12.0% 7.6%

12. 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 0.06 0.12 0.03 0.09 0.04 0.08 0.5 1.0 2.0 Odds ratio (95% CI) Intensive Better Standard Better Number of events (%) Sensitivity analysis – crude and adjusted measures of primary endpoint and with different mRS cut-points 12 *adjusted for prognostic variables: age, NIHSS score, time from ICH to randomisation, haematoma volume and location, and intraventricular haemorrhage

13. 13 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 0.5 1.0 2.0 Odds Ratio (95%CI) Intensive Better Guideline Better Number of events (%) Pre-specified subgroups and primary endpoint

14. Health-related quality of life EuroQol EQ-5D domains ‘any problems’ versus ‘no problems ’ % with problems P=0.13 P=0.01 14 Health utility - 0.6 intensive vs 0.55 standard groups; P=0.002

15. Other secondary clinical outcomes Parameter Intensive (N=1399) Standard (N=1430)P Hospital stay, median (IQR) days20 (12-35)19 (11-33)0.43 Institutional care at 90 days 9% 0.80 Poor outcome at 28 days66%68%0.22 15 Neurological deterioration in first 24 hours (  ≥4 NIHSS or  ≥2 GCS) 66%68%0.22

16. Safety - cause-specific mortality, n(%) Cause of Death Intensive (N=1394) Standard (N=1421)P Direct effects of primary ICH event103 (7.4)111 (7.8)0.67 Cardiovascular disease 14 (1.0) 15 (1.1)0.90 ICH 0 (0.0) 2 (0.1) Ischaemic/undifferentiated stroke 1 (0.1) Acute MI/coronary event/other 3 (0.2) 1 (0.1) Other vascular disease 2 (0.1) Other cardiac disease 8 (0.6) 9 (0.6) Non-cardiovascular disease50 (3.6)45 (3.2)0.54 Renal failure 2 (0.1) Respiratory infections17 (1.2)12 (0.8) Sepsis (includes other infections) 6 (0.4) 4 (0.3) Non-vascular medical25 (1.8)27 (1.9) 16

17. Safety - non-fatal serious adverse events (SAEs), n(%) Serious Adverse Event 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) Ischaemic/undifferentiated stroke 8 (0.6) Acute MI/coronary event/other 5 (0.4) 5 (0.3) Other vascular disease13 (0.9)14 (1.0) Other cardiac disease 9 (0.6)12 (0.8) Non-cardiovascular disease160 (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) 17

18.  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  Major findings of INTERACT2 18

19.  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 19

20.  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 20

21.  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 21

22.  Patients and families  Investigators/coordinators  Networks (e.g. NIHR Stroke Research Network in the UK)  Project staff, Committees Acknowledgements 22