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Managing high blood pressure in acute stroke: The ‘Efficacy of Nitric Oxide in Stroke’ (ENOS) trial. Philip Bath Chief Investigator Version 1.0. From bench to patient to population. EpidemiologyIST/TAIST/BASC  Pre-clinical: experimentalNitric oxide donors 

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Managing high blood pressure in acute stroke: The ‘Efficacy of Nitric Oxide in Stroke’ (ENOS) trial

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Managing high blood pressure in acute stroke: The ‘Efficacy of Nitric Oxide in Stroke’ (ENOS) trial

Philip Bath

Chief Investigator

Version 1.0

From bench to patient to population


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

SBP in acute ischaemic stroke: IST

High blood pressures is very common in acute ischaemic stroke affecting ~80% of patients


Leonardi-Bee et al. Stroke 2002;33:1315-20

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

Systolic BP & outcome: IST

Both low and high BP are associated independently with early death and late death/disability


Leonardi-Bee et al. Stroke 2002;33:1315-20

SBP & early recurrence: TAIST

High blood pressure is associated with an increased risk of early recurrence after ischaemic stroke



Sprigg et al. J Hypertension 2006;24:1413-17

To lower or not lower BP in acute stroke

An old debate!

Arch Neurology 1985;42:999-1002

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


if SBP>200-220

if DBP>120-130

to MBP=120-140

MBP by < 20%

Guidelines for management

Completed randomised trials


ACE-iPerindopril24/1S170-250; 7dTCDDyker


ARACandesartan339/+IS, S>200; 3dVasc. eventACCESS

ARALosartan24/1M110-145BP, SPECT CBFNazir


CCBNicardipine16/1IS; S>170; 3dCBF (SPECT)Lisk

(CCBNimodipine295/+IS; 1dADL (BI)INWEST)

CCBNimodipine19/?IS; ?dDoseFagan



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

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


Schrader et al. Stroke 2003;34,1699-1703


CCB in acuteischaemicstroke:

No effect onoutcome


Horn & Limburg. Cochrane Library 2002

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

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

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)


Cande- 2500100+ 886 79IS/PICH + HTmRSSCAST


‘Usual’ 400 70 300+?PICH + HTmRSINTERACT-p


NO path

Rashid et al. J Stroke Cerebrovasc Dis 2003;12:82-7

NOx levels low in stroke

Low levels associatedwith a poor outcome

Supplementing NO might improve outcome?

Nitric oxide (NOx) levels in acute stroke




Rashid et al. J Stroke Cerebrovasc Dis 2003;12:82-87

Experimental stroke

NO donors:

Reduce lesion size

Increase regional CBF

NO is neuroprotective?

NO in stroke

Willmot et al. Nitric Oxide 2005;12:141-9

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

Glyceryl trinitrate (GTN): left infarct

BP lowered by 10% with GTN; CBF measured using xenon CT CBF: Perfusion did not fall


Willmot et al. Hypertension 2006;epub

GTN: left haemorrhage

And the same in primary intracerebral haemorrhage


Willmot et al. Hypertension 2006;epub

Transdermal glyceryl trinitrate (NO donor) on BP in acute stroke

GTN lowers BP in acute stroke (measured using ambulatory BP measuring [ABPM])


Bath et al. Cerebrovasc Dis 2001;11:265-72

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


    Lowered BP

    Did not alter middle cerebral artery blood flow velocity

    Reduced augmentation index, i.e. increases aortic compliance


Rashid et al. J Stroke Cerebrovasc Dis 2003;13:143-51

GTN on blood pressure

GTN lowered systolic BP (systematic review):

  • Top: Measured over 24 hours (ABPM)

  • Bottom: Measures 2 hours after placement of GTN

Gray et al. J Stroke Cerebrovasc Dis 2006;15:245-9

Efficacy of Nitric Oxide inStroke (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

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

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

ENOS: Sample size


  • 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








China/ Hong Kong











New Zealand



(South Africa)

Sri Lanka



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

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

ENOS: Stroke type


information from





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)


ENOS: Rankin, day 90

PlannedmRS >2 = 50%

CurrentmRS >2 = 48%

CurrentmRS >2 = 45%


Systolic BP (mmHg)

World Congress of Neurology 2005



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

ENOS in China

National Coordinating Centre: Tiantan, Beijing

Local centres:Patients

  • Beijing, Tiantan16

  • Hong Kong 4

  • Wenzhou67



    Age64 70

    Male (%)71 55

    Scandinavian Stroke Scale (/57)35 35

    Intracerebral haemorrhage (%)49 11

    mRS (mean) 2.4 2.7

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!


The Stroke Association

Time of some staff

University of Nottingham


The Hypertension Trust

Xenon CT sub-study

BUPA Foundation

Start-up phase

Medical Research Council

Main phase (from 1/11/6)




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