managing high blood pressure in acute stroke: the ‘efficacy of nitric oxide in stroke’ (enos)...

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 BathChief Investigator

Version 1.0

From bench to patient to populationFrom 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: ISTSBP in acute ischaemic stroke: IST

4.2

14.2

27.926.1

16.9

10.7

0

5

10

15

20

25

30

<120 120-139 140-159 160-179 180-199 >200

Systolic blood pressure

%

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

High blood pressure in acute strokeHigh blood pressure in acute stroke

BP falls over the first 1-2 weeks (in 2/3 patients)BP levels are very variable during this timeSee example patient with acute stroke

Systolic BP & outcome: ISTSystolic BP & outcome: IST

Leonardi-Bee et al. Stroke 2002;33:1315-20N=17,398

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

SBP & early recurrence: TAISTSBP & early recurrence: TAIST

Sprigg et al. J Hypertension 2006;24:1413-17N=1,384

10High blood pressure is associated with an increased

risk of early recurrence after ischaemic stroke

To lower or not lower BP in acute strokeTo lower or not lower BP in acute stroke

QuickTime™ and aTIFF (Uncompressed) decompressor

are needed to see this picture.









Arch Neurology 1985;42:999-1002

An old debate!

Guidelines for managementGuidelines 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%

Completed randomised trialsCompleted randomised trials

Class Intervention N/C InclusionOutcome Trial

ACE-i Perindopril 24/1 S170-250; 7d TCD DykerACE-I Lisinopril 38/1 1d BP EvesonARA Candesartan 339/+ IS, S>200; 3d Vasc. event ACCESSARA 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 FaganCCB Nimodipine 90/1 1d iv/po UzunerDiur. Bendroflu. 40/1 4d BP PotterNO GTN 37/1 5d BP, platelets BathNO GTN 90/1 S100-230; 4d BP, dose RashidNO GTN 18/1 S140-220 BP, xenon CBF WillmotSANS Phenylephrine 15/1 D/P mismatch Lesion vol. Hillis

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

Schrader et al. Stroke 2003;34,1699-1703N=339

ACCESSACCESS

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

Horn & Limburg. Cochrane Library 2002

CCBs:CCBs:

CCB in acuteischaemicstroke:

No effect onoutcome

Multimodality of drugsMultimodality of drugs

BP modifying drugs have other actions:

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

ARA Neuroprotection, block tissue effectsß-RA Antiplatelet, negative inotropeCCB 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 hypertensionPrior 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 trialsOngoing/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) 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 pathNO path

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

Nitric oxide (NOx) levels in acute strokeNitric oxide (NOx) levels in acute stroke

0

20

40

60

80

100

120

Control (n=38) Ischaemic stroke(n=228)

Brain bleed (n=49)

NOx (umol/l)

****

0

10

20

30

40

50

60

70

80

90

Home (n=153) Dead or institution (n=97)

NOx (umol/l)

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?

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

NO in strokeNO in stroke

Experimental stroke

NO donors: Reduce lesion size Increase regional CBF

NO is neuroprotective?

Cerebral autoregulationCerebral 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

0

20

40

60

80

BP

CBF

50 220

Strandgaard et al. Br Med J 1973Barry & Lassern. J Hypertension 1984

Glyceryl trinitrate (GTN): left infarctGlyceryl 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

GTN: left haemorrhageGTN: left haemorrhage

N=18

Willmot et al. Hypertension 2006;epub

And the same in primary intracerebral haemorrhage

Transdermal glyceryl trinitrate (NO Transdermal glyceryl trinitrate (NO donor) on BP in acute strokedonor) on BP in acute strokeTransdermal glyceryl trinitrate (NO Transdermal glyceryl trinitrate (NO donor) on BP in acute strokedonor) 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])

Transdermal glyceryl trinitrate (NO Transdermal glyceryl trinitrate (NO donor) in acute strokedonor) in acute strokeTransdermal glyceryl trinitrate (NO Transdermal glyceryl trinitrate (NO donor) in acute strokedonor) 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 pSubjects 30 60Mean BP (mmHg) 110.5 104.3 <0.001MCA velocity (m/s) 26.3 24.6 NSPulsatility index 1.42 1.41 NSAugmentation index 132.7 115.7 <0.001

GTN:Lowered BPDid not alter middle cerebral artery blood flow velocityReduced augmentation index, i.e. increases aortic compliance

N=90 Rashid et al. J Stroke Cerebrovasc Dis 2003;13:143-51

GTN on blood pressureGTN 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

Efficacy of Nitric Oxide inStroke (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

www.enos.ac.uk/

ENOS: Aims / interventionsENOS: 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: OutcomesENOS: 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 sizeENOS: Sample size

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-treatwww.enos.ac.uk/

UKCanada China/ 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)

Singapore Philippines

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

www.enos.ac.uk/

ENOS: BaselineENOS: Baseline

GTN/no GTN Continue/stopSubjects 659 297Age (mean) 69 70Male (%) 57 53 Recent nitrate (%) 6 11Prior high BP (%) 67 93SBP (mmHg) 168 167AF (%) 11 15Severity (SSS) 38 39Time < 24h (%) 31 29

ENOS: Stroke typeENOS: Stroke type

No CT1%

Awaiting CT2%Non-stroke

1%

PICH14%

HTI3%

Infarct58%

No lesion21%

www.enos.ac.uk/N=646

Non-adjudicatedinformation frominvestigator:

Ischaemic 82%Haemorrhage 14%

ENOS: Outcomes, day 7ENOS: Outcomes, day 7

% GTN/no GTN Continue/stopDeath 2.5 0.7Recurrence 1.9 2.4

Infarction 1.1 1.7Haemorrhage 0.5 0.3Unknown 0.3 0.3

Deterioration 7.7 6.1SNSS (/58) 45 46

(at baseline 38 39)

www.enos.ac.uk/N=646/293

ENOS: Rankin, day 90ENOS: Rankin, day 90

9.3

8.7 20.6

22.5

22.7

15.1

16.2

14

14.7

7

7

9.3

10.1

22.9

0% 20% 40% 60% 80% 100%

Stop/continue

GTN/no GTN

0 1 2 3 4 5 Death

Current mRS >2 = 48%

www.enos.ac.uk/

Planned mRS >2 = 50%

N=573/258

Current mRS >2 = 45%

Systolic BP (mmHg)Systolic BP (mmHg)

140

145

150

155

160

165

170

175

0 1 2 3 4 5 6 7

Days since randomisation

Stop ContinueP=0.002 N=168

World Congress of Neurology 2005

ENOS: Sub-studiesENOS: 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 ChinaENOS in China

National Coordinating Centre: Tiantan, Beijing

Local centres: Patients Beijing, Tiantan 16 Hong Kong 4 Wenzhou 67

China RestNumber 87 615Age 64 70Male (%) 71 55Scandinavian Stroke Scale (/57) 35 35Intracerebral haemorrhage (%) 49 11mRS (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!

www.enos.ac.uk/

FundingFunding

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)

ThanksThanks

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managing high blood pressure in acute stroke: the ‘efficacy of nitric oxide in stroke’ (enos)...

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