Title: Managing high blood pressure in acute stroke: The
1Managing high blood pressure in acute stroke The
Efficacy of Nitric Oxide in Stroke (ENOS) trial
- Philip Bath
- Chief Investigator
- Version 1.0
2From 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
3SBP in acute ischaemic stroke IST
- High blood pressures is very common in acute
ischaemic stroke affecting 80 of patients
Leonardi-Bee et al. Stroke 2002331315-20
N17,398
4High 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
5Systolic BP outcome IST
- Both low and high BP are associated independently
with early death and late death/disability
N17,398
Leonardi-Bee et al. Stroke 2002331315-20
6SBP early recurrence TAIST
- High blood pressure is associated with an
increased risk of early recurrence after
ischaemic stroke
10
N1,384
Sprigg et al. J Hypertension 2006241413-17
7To lower or not lower BP in acute stroke
Arch Neurology 198542999-1002
8Guidelines 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 SBPgt200-220
- if DBPgt120-130
- to MBP120-140
- MBP by lt 20
9Completed 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, Sgt200 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 Sgt170 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
10ACCESS
- Candesartan vs. placebo for 7 days (then
candesartan for all for 1 year) - 500 patients - trial stopped early after 339 for
safety - SBPgt200 and/or DBPgt110 or 2x gt180 and/or gt105
- Conscious, motor weakness, lt72 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 200334,1699-1703
N339
11CCBs
- CCB in acuteischaemic stroke
- No effect on outcome
Horn Limburg. Cochrane Library 2002
12Multimodality 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 2003341334-5
13Prior 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 -gt massive fall in BP
- Stop temporarily
- Rebound rise in BP?
- Remember to re-start for secondary prevention
- No completed trials
14Ongoing/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 Tri
al - 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
15NO path
Rashid et al. J Stroke Cerebrovasc Dis
20031282-7
16Nitric oxide (NOx) levels in acute stroke
- NOx levels low in stroke
- Low levels associated with a poor outcome
- Supplementing NO might improve outcome?
Rashid et al. J Stroke Cerebrovasc Dis
20031282-87
17NO in stroke
- Experimental stroke
- NO donors
- Reduce lesion size
- Increase regional CBF
- NO is neuroprotective?
Willmot et al. Nitric Oxide 200512141-9
18Cerebral 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
19Glyceryl trinitrate (GTN) left infarct
- BP lowered by 10 with GTN CBF measured using
xenon CT CBF Perfusion did not fall
N18
Willmot et al. Hypertension 2006epub
20GTN left haemorrhage
- And the same in primary intracerebral haemorrhage
N18
Willmot et al. Hypertension 2006epub
21Transdermal 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 200111265-72
N37
22Transdermal glyceryl trinitrate (NO donor) in
acute stroke
- Acute stroke (lt96 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 lt0.001
- MCA velocity (m/s) 26.3 24.6 NS
- Pulsatility index 1.42 1.41 NS
- Augmentation index 132.7 115.7 lt0.001
- GTN
- Lowered BP
- Did not alter middle cerebral artery blood flow
velocity - Reduced augmentation index, i.e. increases aortic
compliance
N90
Rashid et al. J Stroke Cerebrovasc Dis
200313143-51
23GTN 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 200615245-9
24Efficacy 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/
25ENOS 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/
26ENOS 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, gt160
- Timing of treatment (hours) lt12, 12-48
www.enos.ac.uk/
27ENOS Sample size
- Assumptions
- Alpha 5
- Power 90
- Control rate for mRSgt2 50
- GTN rate for mRSgt2 45
- Absolute treatment effect 5
- Losses to follow-up 5
- 5000 patients
- Analysis by intention-to-treat
www.enos.ac.uk/
28UK
Canada
China/ Hong Kong
Italy
Belgium
Poland
(Portugal)
(Russia)
(USA)
(Spain)
(Greece)
(Thailand)
(India)
(Nigeria)
(Mexico)
(Egypt)
Singapore
Philippines
New Zealand
Sri Lanka
(Brazil)
(Malaysia)
(Colombia)
(South Africa)
Australia
29- ENOS is worlds first acute stroke trial to use
the internet for randomisation and data collection
30ENOS 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 lt 24h () 31 29
www.enos.ac.uk/
31ENOS Stroke type
Non-adjudicated information from investigator Is
chaemic 82 Haemorrhage 14
www.enos.ac.uk/
N646
32ENOS 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)
www.enos.ac.uk/
N646/293
33ENOS Rankin, day 90
Planned mRS gt2 50
Current mRS gt2 48
Current mRS gt2 45
www.enos.ac.uk/
N573/258
34Systolic BP (mmHg)
World Congress of Neurology 2005
P0.002
N168
35ENOS 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
36ENOS 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
37ENOS 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/
38Funding
- 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)
39Thanks