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Efficacy of Nitric Oxide in Stroke (ENOS) Trial

• Philip Bath, Chief Investigator
• for ENOS Investigators
• UK Stroke Forum Investigator Meeting
• 4 December 2009

www.enos.ac.uk/
2
Welcome

• To
• Existing, New, or Potential sites

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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
• 5,000 patients
• Internet Randomisation, data collection, trial
  management
• 1,566 patients, 128 centres, 16 countries, 5
  continents (11/09)
• New centres very welcome!
• Funding Hypertension Trust, BUPA Foundation, MRC

ENOS Trial Investigators. Int J Stroke
20061245-9 www.enos.ac.uk/
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ENOS Aims / interventions

• Does acute lowering of BP with GTN reduce death
  and dependency?
• GTN 5mg daily for 7 days or nothing
• Should prior antihypertensive medication be
  continued or temporarily stopped during the acute
  phase of stroke?
• Stop/continue prior treatment for 7 days
• On top of standard evidence-based acute medical
  and nursing care, and secondary prevention

www.enos.ac.uk/
5
ENOS Interventions

• No prior antihypertensive therapy (50)
• GTN
• No GTN
• Prior antihypertensive therapy (50)
• GTN / stop
• GTN / continue
• No GTN / stop
• No GTN / continue

www.enos.ac.uk/
6
ENOS Status
Start up commenced 4 July 2001 MRC grant
commenced 1 Nov 2006 To date 30 Nov
2009 Patients 1,566 Continue-stop 758
(48) Centres - ever recruited
90 Countries 16 Continents
5
www.enos.ac.uk/
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ENOS Baseline

• GTN Continue/stop
• Subjects 1562 756 (48)
• Age (mean) 70 72
• Male () 58 54
• Recent nitrate () 6 10
• Prior high BP () 67 94
• SBP (mmHg) 168 168
• AF () 11 15
• Severity (SSS) 37 37
• (NIHSS) 10 10
• Time lt 24h () 34 33

www.enos.ac.uk/
As at 30/11/2009
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ENOS Time

• Recruitment is often late
• Most patients recruited gt24 hours
• lt12 hours 11
• lt24 hours 34
• ENOS needs
• Early patients if it is to answer the question of
  how to manage hyperacute BP

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ENOS Rankin, day 90
Planned mRS gt2 47.5
Current mRS gt2 59.2
Current mRS gt2 45
www.enos.ac.uk/
N1,408 / 673
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ENOS SAEs

• Total SAE 557
• Adjudicated 479
• Confirmed 475
• Not SAE 4
• SUSAR 0

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ENOS Data MonitoringCommittee

• Members
• Professor Peter Sandercock Chair, Neurologist
• Professor Kjell Asplund Stroke Physician
• Dr Colin Baigent Epidemiologist
• Ms Laura Gray, Dr Paul Silcocks Statistician
• Date N Comment
• Dec 2002 67 Continue
• May 2003 113 Continue, data quality
• Nov 2003 174 Continue
• Nov 2004 282 Continue, data quality
• Nov 2005 380 Continue
• April 2006 463 Continue, congratulations MRC
• Dec 2006 520 Continue
• May 2007 658 Continue
• Dec 2007 795 Continue, data quality
• May 2008 1000 Continue
• Dec 2008 1065 Commend investigators for data
• May 2009 1231 No concerns

www.enos.ac.uk/
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Current UK Centres

• Aberdeen
• Airdrie
• Altnagelvin
• Antrim
• Bangor
• Bath
• Barnsley
• Bishop Auckland
• Blackpool
• Boston
• Belfast
• Birmingham
• Bristol
• Bury
• Carlisle
• Chertsey
• Chester
• Chesterfield
• Coventry

• Harrow
• Hereford
• Hemel Hempstead
• Ipswich
• Kirkcaldy
• Lancaster
• Leeds
• Leicester
• Lincoln
• Liverpool - Aintree
• Liverpool - Royal
• London - Charing Cross
• London - Guys St Thomas
• London - Homerton
• London - Newham
• London - Kings
• London - Royal
• Macclesfield
• Manchester - Royal

• Rochdale
• Rotherham
• Scarborough
• Scunthorpe
• Stafford
• Stirling
• Stockport
• Stoke-on-Trent
• Solihull
• Southport
• Taunton
• Torbay
• Truro
• Watford
• Weston Super Mare
• Whitehaven
• Wirral
• Wishaw
• Wolverhampton

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UK
Canada
China/ Hong Kong
Italy
Poland
Eire
(Georgia)
Philippines
(USA)
Spain
(Saudi Arabia)
Romania
India
Malaysia
Singapore
New Zealand
Sri Lanka
Egypt
Australia
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Recruitment

• Startup phase
• Main phase

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Competing trials

• Time (hr) lt6 IST3, ENOS, TARDIS, CLOTS3
• lt12 ENOS, TARDIS, CLOTS3
• lt48 ENOS, TARDIS, CLOTS3
• Stroke IS IST3, ENOS, CLOTS3
• ICH ENOS, CLOTS3
• TIA TARDIS
• Signs Motor IST3, ENOS, TARDIS, CLOTS3
• Dysphasia only TARDIS

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Centres and recruitment

• Ever recruited 90
• UK 61
• Overseas 29
• Active within last 90 days 43
• Not recruited in last 90 days 46
• UK 30 (49)
• Overseas 16 (55)
• Recruited in last 90 days
• 17 centres have rate 1.3 to 3 pat/month
• 1 x 10, 1 x 7, 3 x 6, 3 x 5, 9 x 4

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ENOS Nurse consent

• ENOS does not preclude consent by nurses
• GTN spray/patches/tablets widely used
• By patients
• Dispensed by nurses
• Consent by nurses occurs at some centres
• Requires local agreement
• MREC, GCP does not exclude it

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ENOS Nurse consent
ENOS Protocol, Version 1.5, as approved by MREC
and MHRA
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ENOS Data quality

• OCSP/Bamford
• Need to record hemianopia, inattention, brain
  stem
• Stroke type
• Hospital event ischaemic, haemorrhagic, or
  unknown
• CT scan different
• TOAST
• Not entered, no carotid doppler data

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ENOS Repatriation

• Stroke services evolving into hub-spoke models
• Admission to comprehensive/acute centres
• Rehabilitation at these or at local centres
• Repatriation
• If you repatriate, please ensure all local
  centres are part of ENOS let us know
• Models
• Same Trust proximal acute local centres
• Same Trust distant acute local centres
• Different Trusts - acute local centres

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Pre-stroke hypertension

• 50 patients on antihypertensive medication
• Continue
• Lower blood pressure with potential
  benefits/hazards?
• Beneficial drug classes ACE-I, ARA, NO ?
• Detrimental/neutral drug classes CCBs, ß-RA ?
• Effects on cerebral blood flow
• Administration in presence of dysphagia
• Prior non-compliance -gt massive fall in BP
• Stop temporarily
• Rise in BP? No
• (Remember to re-start for secondary prevention)

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COSSACS

• Continue vs. stop temporarily
• Ischaemic or haemorrhage, lt48 hours
• Primary Death or dependency at 2 weeks
• UK only
• N763 (ENOS currently 758)
• But somewhat different patients
• Results to be presented ESC May 2010
• Implications for ENOS?
• Please keep recruiting into ENOS we will update
• Prospective individual patient meta-analysis

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MRC / EME Extension to trial

• Request to extend by 2 years
• End October 2011 to end October 2013
• Intention to recruit at least 3,500 patients
• More if possible
• Sample size 5,000 to 3,500
• Use ordinal shift, not binary, analysis of mRS
• Adjust baseline for covariates
• Maintain statistical power at 90
• 80 for binary analysis
• If positive, ordinal NNT for GTN 10 (at 6 pp)
• Awaiting to hear from MRC/EME

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ENOS Staff
www.enos.ac.uk/
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TARDIS

• Triple Antiplatelets for Reducing Dependency
  after Ischaemic Stroke
• N5,000, ischaemic stroke, TIA lt48 hours motor
  weakness, dysphasia UK,
• Interventions (for mean 7-8 years) partial
  factorial design
• Clopidogrel versus none on top of best therapy
• Aspirin (300 mg load po/ng/pr, 75 mg thereafter)
• Dypyridamole (MR 200 mg bd po, 100 mg qds po/ng)
• Primary outcome
• Stroke recurrence/severity
• Secondary outcomes
• Bleeding events/severity MI event/severity
  Vascular event/severity
• Status
• Country 1 Centres 7/50 Patients 20/360

www.tardistrial.org/ IRCTN 47823388
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PODCAST

• Prevention of Dementia Cognitive decline After
  Stroke trial
• N4,000, ischaemic stroke, primary intracerebral
  haemorrhage (3-7/12), age 70. UK,
• Interventions (for mean 7-8 years) partial
  factorial design
• SBP lowering lt125 mmHg vs. lt140 mmHg
• TC/LDL lowering (IS only) lt4/2 mmol/l vs. lt5/3
  mmol/l
• Primary outcome
• Addenbrookes Cognitive Examination global
  cognition
• Secondary outcomes
• Individual cognitive domains global TICS,
  attention trail making A/B, attention/executive
  - Stroop, informant (IQCODE)
• Stroke recurrence, function (mRS), QoL, mood

www.podcast-trial.org/ IRCTN85562386
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Prizes
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Prizes

• Chesterfield 7 patients in 90 days

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Prizes

• Chesterfield 7 patients in 90 days
• Dublin 3 in November

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Prizes

• Chesterfield 7 patients in 90 days
• Dublin 3 in November
• First ever ENOS patient
• Bangor

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Prizes

• Chesterfield 7 patients in 90 days
• Dublin 3 in November
• First ever ENOS patient
• Bangor
• Bristol

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Prizes

• Chesterfield 7 patients in 90 days
• Dublin 3 in November
• First ever ENOS patient
• Bangor
• Bristol
• Leeds

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Prizes

• Chesterfield 7 patients in 90 days
• Dublin 3 in November
• First ever ENOS patient
• Bangor
• Bristol
• Leeds
• Liverpool Royal

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Prizes

• Chesterfield 7 patients in 90 days
• Dublin 3 in November
• First ever ENOS patient
• Bangor
• Bristol
• Leeds
• Liverpool Royal
• London Royal

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Prizes

• Chesterfield 7 patients in 90 days
• Dublin 3 in November
• First ever ENOS patient
• Bangor
• Bristol
• Leeds
• Liverpool Royal
• London Royal
• Rochdale

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Prizes

• Chesterfield 7 patients in 90 days
• Dublin 3 in November
• First ever ENOS patient
• Bangor
• Bristol
• Leeds
• Liverpool Royal
• London Royal
• Rochdale
• Taunton

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Prizes

• Chesterfield 7 patients in 90 days
• Dublin 3 in November
• First ever ENOS patient
• Bangor
• Bristol
• Leeds
• Liverpool Royal
• London Royal
• Rochdale
• Taunton
• York

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Thanks. Any questions?

• We hope you will join/continue with the trial

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ENOS Inclusion criteria

• Adult (age gt 18 years)
• Clinical stroke syndrome with limb weakness
  lasting gt1 hour
• So not likely to be a transient ischaemic attack
• Residual limb weakness at the time of enrolment
• Onset lt 48 hours. If the time of onset is
  unknown, apply the time when the patient was last
  known to be well
• Conscious (Glasgow Coma Scale gt 8)
• Systolic blood pressure 140-220 mmHg inclusive
• In at least one of the three pre-randomisation
  measures
• Independent prior to stroke
• Pre-morbid modified Rankin Scale lt 2
• Meaningful consent
• Or proxy consent from a relative or carer, or
  proxy consent from an independent physician if
  patient unable to give meaningful consent
• E.g. If dysphasia, confusion, or reduced
  conscious level

www.enos.ac.uk/
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ENOS Exclusion criteria

• Need for nitrate
• Myocardial infarction, unstable angina, heart
  failure
• Contraindication to nitrate
• Dehydration/hypovolaemia, HOCM, sildenafil
• Need for prior antihypertensive therapy
• Definite need for new antihypertensive
• New antihypertensive commenced post stroke
• Expected to need for surgery
• Known intracranial pathology other than stroke
• Pregnant females
• Not available for follow-up

www.enos.ac.uk/
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ENOS SAEs

• SAE (n)
• Total 178
• SUSAR 0
• During treatment 80
• Relationship to treatment
• Definite 1
• Probable 1
• Possible 22

• Category ()
• Cardiovascular 30
• CNS 71
• Extension 17
• Recurrence 15
• GI 8
• GU 10
• Respiratory 36
• Miscellaneous 26

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ENOS Stroke type
Non-adjudicated information from investigator
www.enos.ac.uk/
As at 11/2/2008, n854
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ENOS Outcomes, day 7

• GTN Stop/continue
• Death 2.3 1.0
• Recurrence 2.5 3.3
• Infarction 1.8 2.5
• Haemorrhage 0.4 0.4
• Unknown 0.4 0.5
• Deterioration 8.0 6.8
• Worsening of SSS (gt4) 7.5 6.6
• SNSS (/58) 44 45
• (at baseline 38 38)

www.enos.ac.uk/
N845/394