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Main results European Stroke Conference - London 29 May 2013

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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Main results European Stroke Conference - London 29 May 2013

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  1. 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

  2. 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

  3. 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)

  4. 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

  5. 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

  6. Baseline - Demographic and clinical* *all non-significant

  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

  8. *P<0.001 80% %

  9. Management - Baseline to Day 7 *all non-significant

  10. 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)

  11. 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

  12. 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

  13. 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

  14. 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

  15. Other secondary clinical outcomes

  16. Safety - cause-specific mortality, n(%)

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

  18. 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

  19. 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

  20. 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

  21. 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

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

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