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‘Efficacy of Nitric Oxide in Stroke’ (ENOS) Trial

‘Efficacy of Nitric Oxide in Stroke’ (ENOS) Trial. Philip Bath, ENOS Chief Investigator Sri Lanka 15 March 2010. www.enos.ac.uk/. Welcome. To: Existing, New, or Potential sites. Efficacy of Nitric Oxide in Stroke (ENOS). Does lowering blood pressure improve outcome?

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‘Efficacy of Nitric Oxide in Stroke’ (ENOS) Trial

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  1. ‘Efficacy of Nitric Oxide in Stroke’ (ENOS) Trial Philip Bath, ENOS Chief Investigator Sri Lanka 15 March 2010 www.enos.ac.uk/

  2. Welcome To: Existing, New, or Potential sites

  3. 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 • 1,719 patients, 128 centres, 16 countries, 5 continents (03/10) • New centres very welcome! • Funding: Hypertension Trust, BUPA Foundation, MRC ENOS Trial Investigators. Int J Stroke 2006;1:245-9 www.enos.ac.uk/

  4. 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: Inclusion criteria • Adult (age > 18 years) • Clinical stroke syndrome with limb weakness lasting >1 hour • So not likely to be a transient ischaemic attack • Residual limb weakness at the time of enrolment • Onset < 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 > 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 < 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/

  7. 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/

  8. ENOS: Status Start up commenced 4 July 2001 MRC grant commenced 1 Nov 2006 To date 14 March 2010 Patients 1,719 Continue-stop 840 (49%) Centres - ever recruited 90 Countries 16 Continents 5 Sri Lanka 50 2 centres www.enos.ac.uk/

  9. ENOS: Baseline GTN/none Continue/stop Subjects 1686 821 (49%) Age (mean) 70 72 Male (%) 58 52 Recent nitrate (%) 5 9 Prior high BP (%) 65 95 SBP (mmHg) 168 168 AF (%) 12 18 Severity (SSS) 34 34 Time < 24h (%) 34 33 www.enos.ac.uk/ As at 22/02/2010

  10. ENOS: Baseline, All patients RoW Sri Lanka Subjects 1636 50 Age (mean) 70 62 Male (%) 57 74 Recent nitrate (%) 5 2 Prior high BP (%) 65 50 SBP (mmHg) 168 171 AF (%) 13 0 Severity (SSS) 34 38 Time < 24h (%) 34 32 www.enos.ac.uk/ As at 23/02/2010

  11. ENOS: Baseline, All patients RoW India Subjects 1626 60 Age (mean) 70 59 Male (%) 58 65 Recent nitrate (%) 5 2 Prior high BP (%) 65 65 SBP (mmHg) 168 175 AF (%) 13 2 Severity (SSS) 35 30 Time < 24h (%) 34 43 www.enos.ac.uk/ As at 23/02/2010

  12. ENOS: Baseline, Continue/stop RoW Sri Lanka Subjects 808 (49%) 13 (26%) Age (mean) 73 59 Male (%) 52 77 Recent nitrate (%) 9 8 Prior high BP (%) 95 100 SBP (mmHg) 168 174 AF (%) 19 0 Severity (SSS) 34 37 Time < 24h (%) 33 54 www.enos.ac.uk/ As at 23/02/2010

  13. ENOS: Baseline, Continue/stop RoW India Subjects 821 (50%) 17 (28%) Age (mean) 72 65 Male (%) 53 41 Recent nitrate (%) 9 0 Prior high BP (%) 95 88 SBP (mmHg) 168 173 AF (%) 18 6 Severity (SSS) 34 33 Time < 24h (%) 34 53 www.enos.ac.uk/ As at 23/02/2010

  14. ENOS: Time Recruitment is often late: • Most patients recruited >24 hours • <12 hours 11% • <24 hours 34% ENOS needs: • Early patients if it is to answer the question of how to manage hyperacute BP

  15. ENOS: Stroke type Non-adjudicated information from investigator www.enos.ac.uk/ As at 11/2/2008, n=854

  16. 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 (>4) 7.5 6.6 SNSS (/58) 44 45 (at baseline 38 38) www.enos.ac.uk/ N=845/394

  17. ENOS: Rankin, day 90 Planned mRS >2 = 48% Current mRS >2 = 55% Current mRS >2 = 58% www.enos.ac.uk/ N=1,686 / 821

  18. ENOS: SAEs Total SAE 557 Adjudicated 479 Confirmed 475 Not SAE 4 SUSAR 0 As at 23/02/2010

  19. 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 ENOS: SAEs

  20. 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 Nov 2009 1550 Continue without modification www.enos.ac.uk/

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

  22. Expansion New country: Saudi Arabia Potential new countries: SCAST Belgium Denmark Norway Sweden

  23. Recruitment • Startup phase • Main phase

  24. 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: • 16 centres have rate: 1.3 to 4.0 pat/month • 1 x 12, 3 x 7, 3 x 6, 2 x 5, 7 x 4

  25. 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

  26. 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 -> massive fall in BP • Stop temporarily • Rise in BP? No • (Remember to re-start for secondary prevention)

  27. COSSACS • Continue vs. stop temporarily • Ischaemic or haemorrhage, <48 hours • Primary: Death or dependency at 2 weeks • UK only • N=763 (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

  28. MRC Extension to trial • Request to extend by 2 years • End October 2011 to end October 2013 • Intention to recruit at least 3,500+ patients • Ideally >3,500 up to 5,000 • 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)

  29. ENOS: Staff www.enos.ac.uk/

  30. Thanks. Any questions? We hope you will join/continue with the trial

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