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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. Epidemiology IST/TAIST/BASC  Pre-clinical: experimental Nitric oxide donors 

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Managing high blood pressure in acute stroke the efficacy of nitric oxide in stroke enos trial l.jpg

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 l.jpg
From bench to patient to population ‘Efficacy of Nitric Oxide in Stroke’ (ENOS) trial

Epidemiology IST/TAIST/BASC

Pre-clinical: experimental Nitric oxide donors

Pre-clinical: meta-analysis Nitric oxide donors

Phase I, human volunteers SNP SPECT trial

Phase II, dose escalation, safety GTN/Xenon CT trials

Clinical: meta-analysis Cochrane Library

Phase III, safety and efficacy ENOS trial

Clinical: meta-analysis Cochrane Library


Sbp in acute ischaemic stroke ist l.jpg
SBP in acute ischaemic stroke: IST ‘Efficacy of Nitric Oxide in Stroke’ (ENOS) trial

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 l.jpg
High blood pressure in acute stroke ‘Efficacy of Nitric Oxide in Stroke’ (ENOS) trial

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 l.jpg
Systolic BP & outcome: IST ‘Efficacy of Nitric Oxide in Stroke’ (ENOS) trial

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 l.jpg
SBP & early recurrence: TAIST ‘Efficacy of Nitric Oxide in Stroke’ (ENOS) trial

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 l.jpg
To lower or not lower BP in acute stroke ‘Efficacy of Nitric Oxide in Stroke’ (ENOS) trial

An old debate!

Arch Neurology 1985;42:999-1002


Guidelines for management l.jpg

Guidelines are expert-based, ‘Efficacy of Nitric Oxide in Stroke’ (ENOS) trial

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 l.jpg
Completed randomised trials ‘Efficacy of Nitric Oxide in Stroke’ (ENOS) trial

Class Intervention N/C Inclusion Outcome Trial

ACE-i Perindopril 24/1 S170-250; 7d TCD Dyker

ACE-I Lisinopril 38/1 1d BP Eveson

ARA Candesartan 339/+ IS, S>200; 3d Vasc. event ACCESS

ARA Losartan 24/1 M110-145 BP, SPECT CBF Nazir

(ß-RA Atenolol/prop 358/1 2d Disability BEST)

CCB Nicardipine 16/1 IS; S>170; 3d CBF (SPECT) Lisk

(CCB Nimodipine 295/+ IS; 1d ADL (BI) INWEST)

CCB Nimodipine 19/? IS; ?d Dose Fagan

CCB Nimodipine 90/1 1d iv/po Uzuner

Diur. Bendroflu. 40/1 4d BP Potter

NO GTN 37/1 5d BP, platelets Bath

NO GTN 90/1 S100-230; 4d BP, dose Rashid

NO GTN 18/1 S140-220 BP, xenon CBF Willmot

SANS Phenylephrine 15/1 D/P mismatch Lesion vol. Hillis

Blood pressure in Acute Stroke Collab. (BASC) II. Cochrane Library


Access l.jpg

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


Slide11 l.jpg

CCB in acute for 1 year)ischaemic stroke:

No effect on outcome

CCBs:

Horn & Limburg. Cochrane Library 2002


Multimodality of drugs l.jpg
Multimodality of drugs for 1 year)

BP modifying drugs have other actions:

ACE-I Neuroprotection, block tissue effects, (antiplatelet)

ARA Neuroprotection, block tissue effects

ß-RA Antiplatelet, negative inotrope

CCB Antiplatelet, negative inotrope, ‘cerebral steal’

NO Neuroprotection, cerebral vasodilator, anti-platelet, (antileucocyte)

SANS Inotrope, chronotrope, vasoconstrictor, platelet agonist

Bath P. Stroke 2003;34:1334-5


Prior hypertension l.jpg
Prior hypertension for 1 year)

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 l.jpg
Ongoing/planned trials for 1 year)

There are several large ongoing trials of antihypertensive agents in acute stroke:

Rx N aim C aim N now C now Inclusion Outcome Trial

Continue 2900 100+ 530 26 IS/PICH + HT mRS COSSACS

vs. stop 2500 200+ 290 34 IS/PICH + HT mRS ENOS

GTN 5000 200+ 680 36 IS/PICH + HT mRS ENOS

(Telmi- 20000 640 20133 644 IS + 120-180 stroke PRoFESS)

sartan

Cande- 2500 100+ 886 79 IS/PICH + HT mRS SCAST

sartan stroke

‘Usual’ 400 70 300+ ? PICH + HT mRS INTERACT-p

3000 PICH + HT mRS INTERACT


No path l.jpg
NO path for 1 year)

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


Nitric oxide nox levels in acute stroke l.jpg

NOx levels low in stroke for 1 year)

Low levels associated with 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


No in stroke l.jpg

Experimental stroke for 1 year)

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 l.jpg
Cerebral autoregulation for 1 year)

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 l.jpg
Glyceryl trinitrate (GTN): left infarct for 1 year)

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 l.jpg
GTN: left haemorrhage for 1 year)

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 l.jpg
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 l.jpg
Transdermal glyceryl trinitrate (NO donor) in acute stroke stroke

  • Acute stroke (<96 hours)

  • Ischaemic or haemorrhagic stroke

  • GTN (7 days): 5mg; 5 mg for 4d then 10mg; 10 mg

    Day 1 Control GTN p

    Subjects 30 60

    Mean BP (mmHg) 110.5 104.3 <0.001

    MCA velocity (m/s) 26.3 24.6 NS

    Pulsatility index 1.42 1.41 NS

    Augmentation index 132.7 115.7 <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 l.jpg
GTN on blood pressure stroke

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 in stroke enos l.jpg
Efficacy of Nitric Oxide in strokeStroke (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 l.jpg
ENOS: Aims / interventions stroke

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 l.jpg
ENOS: Outcomes stroke

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 l.jpg
ENOS: Sample size stroke

Assumptions:

  • Alpha 5%

  • Power 90%

  • Control rate for mRS>2 50%

  • GTN rate for mRS>2 45%

  • Absolute treatment effect 5%

  • Losses to follow-up 5%

  • 5000 patients

  • Analysis by intention-to-treat

www.enos.ac.uk/


Slide28 l.jpg

Canada stroke

(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


Slide29 l.jpg

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


Enos baseline l.jpg
ENOS: Baseline internet for randomisation and data collection

GTN/no GTN Continue/stop

Subjects 659 297

Age (mean) 69 70

Male (%) 57 53

Recent nitrate (%) 6 11

Prior high BP (%) 67 93

SBP (mmHg) 168 167

AF (%) 11 15

Severity (SSS) 38 39

Time < 24h (%) 31 29

www.enos.ac.uk/


Enos stroke type l.jpg
ENOS: Stroke type internet for randomisation and data collection

Non-adjudicated

information from

investigator:

Ischaemic 82%

Haemorrhage 14%

www.enos.ac.uk/

N=646


Enos outcomes day 7 l.jpg
ENOS: internet for randomisation and data collectionOutcomes, day 7

% GTN/no GTN Continue/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) 45 46

(at baseline 38 39)

www.enos.ac.uk/

N=646/293


Enos rankin day 90 l.jpg
ENOS: Rankin, day 90 internet for randomisation and data collection

Planned mRS >2 = 50%

Current mRS >2 = 48%

Current mRS >2 = 45%

www.enos.ac.uk/

N=573/258


Systolic bp mmhg l.jpg
Systolic BP (mmHg) internet for randomisation and data collection

World Congress of Neurology 2005

P=0.002

N=168


Enos sub studies l.jpg
ENOS: Sub-studies internet for randomisation and data collection

  • 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 l.jpg
ENOS in China internet for randomisation and data collection

National Coordinating Centre: Tiantan, Beijing

Local centres: Patients

  • Beijing, Tiantan 16

  • Hong Kong 4

  • Wenzhou 67

    China Rest

    Number 87 615

    Age 64 70

    Male (%) 71 55

    Scandinavian Stroke Scale (/57) 35 35

    Intracerebral haemorrhage (%) 49 11

    mRS (mean) 2.4 2.7


Enos streamlined l.jpg
ENOS: ‘streamlined’ internet for randomisation and data collection

  • 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/


Funding l.jpg

Source: internet for randomisation and data collection

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 l.jpg

Thanks internet for randomisation and data collection

Questions?