1. Managing high blood pressure in acute stroke: The ‘Efficacy of Nitric Oxide in Stroke’ (ENOS) trial Philip Bath Chief Investigator Version 1.0

2. From bench to patient to population EpidemiologyIST/TAIST/BASC  Pre-clinical: experimentalNitric oxide donors  Pre-clinical: meta-analysisNitric oxide donors  Phase I, human volunteersSNP SPECT trial  Phase II, dose escalation, safetyGTN/Xenon CT trials  Clinical: meta-analysisCochrane Library  Phase III, safety and efficacyENOS trial  Clinical: meta-analysisCochrane Library

3. SBP in acute ischaemic stroke: IST Leonardi-Bee et al. Stroke 2002;33:1315-20N=17,398 High blood pressures is very common in acute ischaemic stroke affecting ~80% of patients

4. High blood pressure in acute stroke BP falls over the first 1-2 weeks (in 2/3 patients) BP levels are very variable during this time See example patient with acute stroke

5. Systolic BP & outcome: IST Leonardi-Bee et al. Stroke 2002;33:1315-20 N=17,398 Both low and high BP are associated independently with early death and late death/disability

6. SBP & early recurrence: TAIST Sprigg et al. J Hypertension 2006;24:1413-17 N=1,384 10 High blood pressure is associated with an increased risk of early recurrence after ischaemic stroke

7. To lower or not lower BP in acute stroke Arch Neurology 1985;42:999-1002 An old debate!

8. Guidelines for management Guidelines are expert-based, Encephalopathy, heart failure/ischaemia, aortic dissection Other hypertensive stroke patients not evidence-based  Reduce BP  Do not lower:  BP at all  SBP below 160  Reduce:  if SBP>200-220  if DBP>120-130  to MBP=120-140  MBP by < 20%

9. Completed randomised trials ClassInterventionN/CInclusionOutcomeTrial ACE-iPerindopril24/1S170-250; 7dTCDDyker ACE-ILisinopril38/11dBPEveson ARACandesartan339/+IS, S>200; 3dVasc. eventACCESS ARALosartan24/1M110-145BP, SPECT CBFNazir (ß-RAAtenolol/prop358/12dDisabilityBEST) CCBNicardipine16/1IS; S>170; 3dCBF (SPECT)Lisk (CCBNimodipine295/+IS; 1dADL (BI)INWEST) CCBNimodipine19/?IS; ?dDoseFagan CCBNimodipine90/11div/poUzuner Diur.Bendroflu.40/14dBPPotter NOGTN37/15dBP, plateletsBath NOGTN90/1S100-230; 4d BP, doseRashid NOGTN18/1S140-220BP, xenon CBFWillmot SANSPhenylephrine15/1D/P mismatchLesion vol.Hillis Blood pressure in Acute Stroke Collab. (BASC) II. Cochrane Library

10. Schrader et al. Stroke 2003;34,1699-1703 N=339 ACCESS  Candesartan vs. placebo for 7 days (then candesartan for all for 1 year)  500 patients - trial stopped early after 339 for ‘safety’  SBP>200 and/or DBP>110; or 2x >180 and/or >105  Conscious, motor weakness, <72 hours  No effect on BP?  No effect on functional outcome at 3 months (primary outcome)  Reduced vascular events at 1 year

11. Horn & Limburg. Cochrane Library 2002 CCBs: CCB in acute ischaemic stroke: No effect on outcome

12. Multimodality of drugs BP modifying drugs have other actions: ACE-INeuroprotection, block tissue effects, (antiplatelet) ARANeuroprotection, block tissue effects ß-RAAntiplatelet, negative inotrope CCBAntiplatelet, negative inotrope, ‘cerebral steal’ NONeuroprotection, cerebral vasodilator, anti-platelet, (antileucocyte) SANSInotrope, chronotrope, vasoconstrictor, platelet agonist Bath P. Stroke 2003;34:1334-5

13. Prior hypertension 50% of patients are on antihypertensive medication before stroke Should we continue or stop these during acute phase of stroke?  Continue  Lower blood pressure with potential benefits/hazards?  ‘Beneficial’ drug classes:ACE-I, ARA, NO ?  ‘Detrimental/neutral’ drug classes:CCBs, ß-RA ?  Administration in presence of dysphagia  Prior non-compliance -> massive fall in BP  Stop temporarily  ‘Rebound’ rise in BP?  Remember to re-start for secondary prevention  No completed trials

14. Ongoing/planned trials There are several large ongoing trials of antihypertensive agents in acute stroke: RxN aimC aimN nowC nowInclusionOutcomeTrial Continue 2900100+ 530 26IS/PICH + HT mRSCOSSACS vs. stop 2500200+ 290 34IS/PICH + HT mRSENOS GTN 5000200+ 680 36 IS/PICH + HTmRSENOS (Telmi-2000064020133644IS + 120-180strokePRoFESS) sartan Cande- 2500100+ 886 79IS/PICH + HTmRSSCAST sartanstroke ‘Usual’ 400 70 300+?PICH + HTmRSINTERACT-p 3000PICH + HT mRSINTERACT

15. NO path Rashid et al. J Stroke Cerebrovasc Dis 2003;12:82-7

16. Nitric oxide (NOx) levels in acute stroke ** Rashid et al. J Stroke Cerebrovasc Dis 2003;12:82-87 *  NOx levels low in stroke  Low levels associated with a poor outcome  Supplementing NO might improve outcome?

17. Willmot et al. Nitric Oxide 2005;12:141-9 NO in stroke Experimental stroke NO donors:  Reduce lesion size  Increase regional CBF  NO is neuroprotective?

18. Cerebral autoregulation Cerebral perfusion normally maintained independently of BP Curve right-shifted in chronic high BP Autoregulation lost following stroke Local perfusion becomes dependent on BP Strandgaard et al. Br Med J 1973 Barry & Lassern. J Hypertension 1984

19. Glyceryl trinitrate (GTN): left infarct Willmot et al. Hypertension 2006;epub N=18 BP lowered by 10% with GTN; CBF measured using xenon CT CBF: Perfusion did not fall

20. GTN: left haemorrhage N=18 Willmot et al. Hypertension 2006;epub And the same in primary intracerebral haemorrhage

21. Transdermal glyceryl trinitrate (NO donor) on BP in acute stroke Bath et al. Cerebrovasc Dis 2001;11:265-72N=37 GTN lowers BP in acute stroke (measured using ambulatory BP measuring [ABPM])

22. Transdermal glyceryl trinitrate (NO donor) in acute stroke  Acute stroke (<96 hours)  Ischaemic or haemorrhagic stroke  GTN (7 days): 5mg; 5 mg for 4d then 10mg; 10 mg Day 1ControlGTNp Subjects 30 60 Mean BP (mmHg)110.5104.3<0.001 MCA velocity (m/s) 26.3 24.6 NS Pulsatility index 1.42 1.41 NS Augmentation index132.7115.7<0.001 GTN: Lowered BP Did not alter middle cerebral artery blood flow velocity Reduced augmentation index, i.e. increases aortic compliance N=90 Rashid et al. J Stroke Cerebrovasc Dis 2003;13:143-51

23. GTN on blood pressure Gray et al. J Stroke Cerebrovasc Dis 2006;15:245-9 GTN lowered systolic BP (systematic review):  Top: Measured over 24 hours (ABPM)  Bottom: Measures 2 hours after placement of GTN

24. Efficacy of Nitric Oxide in Stroke (ENOS)  Assess if lowering blood pressure improves outcome  Interventions (for 7 days):  Transdermal glyceryl trinitrate (5 mg daily) or control  Continue / stop prior antihypertensive therapy  Ischaemic or haemorrhagic stroke within 48 hours  5,000 patients  Internet: Randomisation, data collection, trial management  711 patients, 41 centres, 13 countries, 4 continents (1/7/07)  Start-up funding by Hypertension Trust, BUPA Foundation  Main phase funding by MRC Nov 2006-Oct 2011 www.enos.ac.uk/

25. ENOS: Aims / interventions 1. Does acute lowering of BP with GTN reduce death and dependency?  GTN 5mg daily versus nothing for 7 days 2. Should prior antihypertensive medication be continued or temporarily stopped during the acute phase of stroke?  Continue versus stop prior treatment for 7 days On top of standard evidence-based acute medical and nursing care, and secondary prevention www.enos.ac.uk/

26. ENOS: Outcomes Primary (3 months):  Modified Rankin Scale: 0-2 versus 3-6 Secondary outcomes:  Efficacy: disability, institutionalisation, early recurrence, QoL, mood, cognition  Safety: death, deterioration, CT lesion size Primary outcome in sub-groups:  Ischaemic, haemorrhagic stroke  Systolic BP levels (mmHg): 140-160, >160  Timing of treatment (hours): <12, 12-48 www.enos.ac.uk/

27. ENOS: Sample size Assumptions:  Alpha 5%  Power90%  Control rate for mRS>250%  GTN rate for mRS>245%  Absolute treatment effect 5%  Losses to follow-up 5%  5000 patients  Analysis by intention-to-treat www.enos.ac.uk/

28. UKCanadaChina/ Hong Kong Italy (India) Sri Lanka (Thailand) (USA) (Brazil) New Zealand (Malaysia) (Nigeria) Belgium (Spain) (Mexico) (Colombia)(South Africa) (Egypt) Australia Poland(Portugal)(Russia) (Greece) SingaporePhilippines

29. ENOS is world’s first acute stroke trial to use the internet for randomisation and data collection

30. www.enos.ac.uk/ ENOS: Baseline GTN/no GTNContinue/stop Subjects659 297 Age (mean) 69 70 Male (%) 57 53 Recent nitrate (%) 6 11 Prior high BP (%) 67 93 SBP (mmHg)168167 AF (%) 11 15 Severity (SSS) 38 39 Time < 24h (%) 31 29

31. ENOS: Stroke type www.enos.ac.uk/ N=646 Non-adjudicated information from investigator: Ischaemic82% Haemorrhage14%

32. ENOS: Outcomes, day 7 %GTN/no GTNContinue/stop Death 2.5 0.7 Recurrence 1.9 2.4 Infarction 1.1 1.7 Haemorrhage 0.5 0.3 Unknown 0.3 0.3 Deterioration 7.7 6.1 SNSS (/58)4546 (at baseline3839) www.enos.ac.uk/ N=646/293

33. ENOS: Rankin, day 90 CurrentmRS >2 = 48% www.enos.ac.uk/ PlannedmRS >2 = 50% N=573/258 CurrentmRS >2 = 45%

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

35. ENOS: Sub-studies  MR substudy  Chris Chen, Singapore, funded 1/05  Lawrence Wong, Kong Kong, submitted for funding  GTN on lesion volume, diffusion, perfusion  CT substudy  GTN on lesion volume, recurrence  Pharmacogenetics  GTN effects on BP by genotype, e.g. eNOS  Surrogate markers of efficacy  GTN on serum biomarkers, e.g. NSE & S-100  …

36. ENOS in China National Coordinating Centre: Tiantan, Beijing Local centres:Patients  Beijing, Tiantan16  Hong Kong 4  Wenzhou67 ChinaRest Number87615 Age64 70 Male (%)71 55 Scandinavian Stroke Scale (/57)35 35 Intracerebral haemorrhage (%)49 11 mRS (mean) 2.4 2.7

37. ENOS: ‘streamlined’  Melds with other trials: hyperacute, high-tech  Wide time-window, 1-48 hours  Ischaemic and haemorrhagic stroke  Any clinical syndrome, pathophysiology  Can be given with rt-PA (nitrates in NINDS!)  Easy intervention: transdermal / dysphagia  Can be led by nurses  Modest data collection: days 0, 7, 90 (SAE)  Internet randomisation / data registration  ASTN, CSC, UKSRN approved  This trial needs you! www.enos.ac.uk/

38. Funding Source:  The Stroke Association  Time of some staff  University of Nottingham  Website/database  The Hypertension Trust  Xenon CT sub-study  BUPA Foundation  Start-up phase  Medical Research Council  Main phase (from 1/11/6)

39. Thanks Questions?