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.
QuickTime™ and aTIFF (Uncompressed) decompressor
are needed to see this picture.
QuickTime™ and aTIFF (Uncompressed) decompressor
are needed to see this picture.
QuickTime™ and aTIFF (Uncompressed) decompressor
are needed to see this picture.
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
QuickTime™ and aTIFF (Uncompressed) decompressor
are needed to see this picture.
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
Questions?