MRC Efficacy of Nitric Oxide in acute Stroke (ENOS) trial Philip Bath For ENOS Investigators

Efficacy of Nitric Oxide in Stroke (ENOS) Does lowering blood pressure improve outcome? Interventions (for 7 days): Transdermal glyceryl trinitrate (5 mg daily) or control Continue / stop prior antihypertensive therapy (in those on antihypertensives prior to stroke) Ischaemic or haemorrhagic stroke within 48 hours 3,500+ participants Internet: Randomisation, data collection, trial management N=2,346/1,151; 130 sites; 17 countries, 5 continents 25/5/11 Funding: Hypertension Trust, BUPA Foundation, MRC ENOS Trial Investigators. Int J Stroke 2006;1:245-9 www.enos.ac.uk/

Eire Italy (Norway) (Sweden) (Georgia) China / Hong Kong Canada Spain UK (Belgium) Denmark Poland Romania Philippines International picture FYI. India have just joined the trial and recruited their first patient. They have several more centres submitting for ethics & will join the trial soon. Spain are waiting for their final part of their regulatory approval and Investigator Mtg was held there in April. China - March this year, we recruited a local coordinator in Beijing to promote the trial in China. However, there is currently a shortage of GTN in China. Once this is resolved, we hope another 5 centres will join. Egypt has an Investigator Meeting scheduled for November. Other possible interest from Romania, Greece, Germany and Thailand. (Greece) India Malaysia Singapore New Zealand Egypt Sri Lanka Australia 3

ENOS: Baseline characteristics GTN/none Continue/stop Subjects 2336 1145 (49%) Age (mean) 70 73 Male (%) 58 53 Recent nitrate (%) 5 8 Prior high BP (%) 64 95 SBP (mmHg) 168 168 AF (%) 12 18 Severity (SSS) 35 34 (~NIHSS 11 11) Time < 24h (%) 37 36 As at 23/3/2011 www.enos.ac.uk/

ENOS: Stroke type Non-adjudicated information from investigator As at 23/5/2011, n = 2,336 www.enos.ac.uk/

ENOS: Rankin, day 90 Planned mRS >2 = 48% Current mRS >2 = 62% As at 23/5/2011, n = 2,164 / 1,067 www.enos.ac.uk/

Continue/stop recruitment As at 24/5/2011 www.enos.ac.uk/

ENOS: Carotid stenosis / events No/Mild Severe 2p Subjects 273 34 Recurrent stroke NS Ischaemic 5 0 Unknown type 1 0 Deterioration, SSS Decrease>4 (%) 21 (7.7) 2 (5.9) 0.53 Impairment, SSS Baseline (/58) 41 (17) 34 (21) 0.12 Day 7 (/58) 46 (19) 38 (20) 0.05 Only ~25% participants with carotid scans Please do carotid studies on all ischaemic stroke We will pay for carotid study if not clinically indicated Please remember to enter data Sare et al. BP Monitoring 2009;14:20-25 www.enos.ac.uk/

SCAST: Functional outcome Modified Rankin Scale (mRS) Shift analysis Adjustment for 2 co-primary outcomes Significance at p<0.025 Common OR 1.17 (1.00-1.38) p=0.048 non-significant Sandset et al. Lancet 11 Feb 2011

SCAST: Blood pressure, sub-groups Sandset et al. Lancet 11 Feb 2011

ENOS & SCAST 11/3/2011

ENOS: Recruitment Recruit patients: On antihypertensives prior to their stroke Presenting with a haemorrhage With very high BP, i.e. >180 mmHg Early, i.e. day 1, not day 2 Need to address hyperacute/acute BP lowering With severe strokes, i.e. SSS<30 Need to address BP lowering in severe stroke None of these subgroups were shown to be hazardous in COSSACS and SCAST

ENOS: Things to do Do carotid scans on all ischaemic stroke Be careful when calling a SAE a SUSAR Is it really ‘unexpected’ - check with list on website Submit as much information as possible for SAEs Adjudicated on line with no other data Do a day 7 CT CT scan Be current with GCP 2 yearly

ENOS: Welcome Countries who are about to start recruiting: Belgium Denmark Georgia Greece Norway Sweden

ENOS: Special thanks to City Total 3m Assiut, Egypt 24 24 Mures, Romania 46 9 Oradea, Romania 41 6 Glasgow Western, UK 7 5 JIPMER, India 5 5 Ludhiana, India 50 5 Perugia, Italy 12 5 Menoufiya, Egypt 7 4 Fogolyan, Romania 34 4 Columbo, Sri Lanka 26 4 Lincoln, UK 97 4 Harrow, UK 35 4 City Total Nottingham, UK 252 Singapore 155 Warsaw, Poland 98 Lincoln, UK 97 Darlington, UK 87 Wenzhou, China 87 Aberdeen, UK 83 Boston, UK 55 Stoke, UK 55 Ragama, Sri Lanka 54 Derby, UK 52 Ludihana, India 50

ENOS: 4 patients 20/4-23/5 Centre No Assiut, Egypt 9 Glasgow Western, UK 5

TARDIS: ADC AD (or C) AD (or C) AD (or C) www.tardistrial.org Triple Antiplatelets for Reducing Dependency after Ischaemic Stroke Multicentre, parallel-group, prospective, randomised, open-label, blinded-endpoint controlled trial in acute ischaemic stroke or TIA Intensive (triple) vs guideline antiplatelets Aspirin 300 / 75 mg od; dipyridamole MR 200 mg bd; clopidogrel 300 / 75 mg od; all for one month Safety and efficacy Start up phase (3 years): 419 recruited; 350+ patients in UK Main Phase: ~3,500 patients Day 0 Day 7 Day 30 Day 90 Central FU ADC AD (or C) R AD (or C) AD (or C) www.tardistrial.org 17 17

Question & comments on ENOS

SCAST: Design, patient flow Scandinavian Candesartan Acute Stroke Trial 146 centres, NW Europe 2,029 patients Acute stroke (IS, ICH) SBP > 140 mmHg <30 hours of onset Candesartan 4 to 16 mg (escalation) or placebo Co-primary outcomes Functional at 6/12 Vascular events at 6/12 Sandset et al. Lancet 11 Feb 2011

SCAST: Vascular events, death HR 1.09 (0.84-1.41), p=0.52 Sandset et al. Lancet 11 Feb 2011

Meta-analysis, including SCAST Sandset et al. Lancet 11 Feb 2011

SRN Impact on Studies open in Apr 2006

Current UK Centres (116)  23 23 Aberdeen Airedale Airdrie Antrim Bangor Barnsley Basingstoke Bath Bishop Auckland Blackburn Blackpool Boston Belfast Birmingham Bournemouth Bradford Bristol Bury Carlisle Carshalton Chertsey Chester Chesterfield Chichester Coventry Craigavon Derby Doncaster Dundee Edinburgh (Royal) Edinburgh (Western) Erne, Enniskillen Exeter Glasgow (Royal) Glasgow (Western) Glasgow (Stobhill) Glasgow (Hairmyres) Grantham Great Yarmouth Grimsby Harrogate Harrow Hereford Hemel Hempstead Ipswich Kettering Kirkcaldy Lancaster Leicester Leighton Lincoln Liverpool (Aintree) Liverpool (Royal) London (Charing Cross) London (Guy’s & St Thomas’) London (Hillingdon) London (Homerton) London (Newham) London (Kings) London (St George’s) London (West Middlesex) Londonderry (Altnagelvin) Macclesfield Manchester (Royal) Melrose Mansfield Middlesborough Newcastle Northampton Nottingham Norwich Oxford Poole Portsmouth Preston Rochdale Rotherham Salford Scarborough Scunthorpe Stafford Stirling Stockport Stoke-on-Trent Solihull Southport Taunton Telford Torbay Truro Watford Weston-Super-Mare Whiston Wigan Wirral Wishaw Wolverhampton Worthing Yeovil York  23 23

Rapid Intervention with Gtn in Hypertensive stroke Trial (RIGHT) Questions: Can stroke trials be done pre-hospital in ambulances? Does hyperacute GTN lower BP, and is it safe? Patients: 999 call for ‘stroke’ and FAST positive within 4 hours Intervention: Randomised to GTN or nothing (single blind) for 7 days Status: 24 of 80 patients recruited, single site (14/3/11) Funding: Nottingham University Hospitals & Division of Stroke

Physiology ENOS: Design: RCT phase III IS/ICH + SBP 140-220 Window <48 hours N=3,500+ Rx: GTN 5 mg for 7d Control: Gauze dressing Outcome: mRS @ 3/12 Status: On-going End: Sept 2013 Sites: Any Lead: Nottingham CI: Philip Bath INTERACT-2: Design: RCT phase III ICH + SBP 150-220 Window <6 hours N=2,800 Rx: SBP<140 by 1h Control: Treat SBP>180 Outcome: mRS Status: In set-up in UK End: Oct 2011 Sites: Any Lead: Leicester NC: Tom Robinson

Systolic BP (mmHg) World Congress of Neurology 2005 P=0.002 N=168