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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

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
From bench to patient to population

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
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
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
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
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
To lower or not lower BP in acute stroke

An old debate!

Arch Neurology 1985;42:999-1002

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


if SBP>200-220

if DBP>120-130

to MBP=120-140

MBP by < 20%

Guidelines for management
completed randomised trials
Completed randomised trials

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

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 acuteischaemic stroke:

No effect on outcome


Horn & Limburg. Cochrane Library 2002

multimodality of drugs
Multimodality of drugs

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
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
Ongoing/planned trials

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)


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

sartan stroke

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


no path
NO path

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

nitric oxide nox levels in acute stroke
NOx levels low in stroke

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
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 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
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
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
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
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 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


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 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 in stroke enos
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
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
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
ENOS: Sample size


  • 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









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
ENOS: Baseline

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

enos stroke type
ENOS: Stroke type


information from


Ischaemic 82%

Haemorrhage 14%


enos outcomes day 7
ENOS: Outcomes, 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)


enos rankin day 90
ENOS: Rankin, day 90

Planned mRS >2 = 50%

Current mRS >2 = 48%

Current mRS >2 = 45%


systolic bp mmhg
Systolic BP (mmHg)

World Congress of Neurology 2005



enos sub studies
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
ENOS in China

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
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)