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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

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


SBP in acute ischaemic stroke: IST

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

N=17,398

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

N=17,398

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

10

N=1,384

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

Reduce:

if SBP>200-220

if DBP>120-130

to MBP=120-140

MBP by < 20%

Guidelines for management


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


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

ACCESS

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

N=339


CCB in acuteischaemicstroke:

No effect onoutcome

CCBs:

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)

sartan

Cande- 2500100+ 886 79IS/PICH + HTmRSSCAST

sartanstroke

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

3000PICH + HT mRSINTERACT


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

N=18

Willmot et al. Hypertension 2006;epub


GTN: left haemorrhage

And the same in primary intracerebral haemorrhage

N=18

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])

N=37

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

    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


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

www.enos.ac.uk/


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/


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/


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/


Canada

(Portugal)

UK

Belgium

Poland

Italy

(Russia)

China/ Hong Kong

(USA)

(Spain)

(Greece)

(Thailand)

(Mexico)

(Nigeria)

(Egypt)

(India)

Singapore

Philippines

New Zealand

(Colombia)

(Brazil)

(South Africa)

Sri Lanka

(Malaysia)

Australia


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

www.enos.ac.uk/


ENOS: Stroke type

Non-adjudicated

information from

investigator:

Ischaemic82%

Haemorrhage14%

www.enos.ac.uk/

N=646


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


ENOS: Rankin, day 90

PlannedmRS >2 = 50%

CurrentmRS >2 = 48%

CurrentmRS >2 = 45%

www.enos.ac.uk/

N=573/258


Systolic BP (mmHg)

World Congress of Neurology 2005

P=0.002

N=168


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

    ChinaRest

    Number87615

    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!

www.enos.ac.uk/


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)

Funding


Thanks

Questions?


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