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

2. 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

3. Eire Italy (Norway) (Sweden) (Georgia) China / Hong Kong Canada SpainUK
(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

4. ENOS: Baseline characteristics
GTN/none Continue/stop
Subjects (49%)
Age (mean)
Male (%)
Recent nitrate (%)
Prior high BP (%)
SBP (mmHg)
AF (%)
Severity (SSS)
(~NIHSS )
Time < 24h (%)
As at 23/3/2011

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

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

7. Continue/stop recruitment
As at 24/5/2011

8. ENOS: Carotid stenosis / events
No/Mild Severe 2p
Subjects
Recurrent stroke NS
Ischaemic
Unknown type
Deterioration, SSS
Decrease>4 (%) (7.7) 2 (5.9) 0.53
Impairment, SSS
Baseline (/58) (17) 34 (21) 0.12
Day 7 (/58) (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

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

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

11. ENOS & SCAST
11/3/2011

12. 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

13. 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

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

15. ENOS: Special thanks to
City Total 3m
Assiut, Egypt
Mures, Romania
Oradea, Romania
Glasgow Western, UK
JIPMER, India
Ludhiana, India
Perugia, Italy
Menoufiya, Egypt
Fogolyan, Romania
Columbo, Sri Lanka
Lincoln, UK
Harrow, UK
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

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

17. 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) 17 17

18. Question & comments on ENOS

19. 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

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

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

22. SRN Impact on Studies open in Apr 2006

23. 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

24. 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

25. 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: 3/12
Status: On-going
End: Sept 2013
Sites: Any
Lead: Nottingham
CI: Philip Bath
INTERACT-2:
Design: RCT phase III
ICH + SBP
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

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