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Managing high blood pressure in acute stroke: The

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Conscious, motor weakness, 72 hours. No effect on BP? ... Horn & Limburg. Cochrane Library 2002. CCBs: CCB in acute. ischaemic stroke: No effect on outcome ... – PowerPoint PPT presentation

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Title: Managing high blood pressure in acute stroke: The


1
Managing high blood pressure in acute stroke The
Efficacy of Nitric Oxide in Stroke (ENOS) trial
  • Philip Bath
  • Chief Investigator
  • Version 1.0

2
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

3
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 2002331315-20
N17,398
4
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

5
Systolic 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
6
SBP 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
7
To lower or not lower BP in acute stroke
  • An old debate!

Arch Neurology 198542999-1002
8
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
  • Reduce
  • if SBPgt200-220
  • if DBPgt120-130
  • to MBP120-140
  • MBP by lt 20

9
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, 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
10
ACCESS
  • 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
11
CCBs
  • CCB in acuteischaemic stroke
  • No effect on outcome

Horn Limburg. Cochrane Library 2002
12
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 2003341334-5
13
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 -gt massive fall in BP
  • Stop temporarily
  • Rebound rise in BP?
  • Remember to re-start for secondary prevention
  • No completed trials

14
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 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

15
NO path
Rashid et al. J Stroke Cerebrovasc Dis
20031282-7
16
Nitric 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
17
NO in stroke
  • Experimental stroke
  • NO donors
  • Reduce lesion size
  • Increase regional CBF
  • NO is neuroprotective?

Willmot et al. Nitric Oxide 200512141-9
18
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
19
Glyceryl 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
20
GTN left haemorrhage
  • And the same in primary intracerebral haemorrhage

N18
Willmot et al. Hypertension 2006epub
21
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 200111265-72
N37
22
Transdermal 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
23
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 200615245-9
24
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/
25
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

www.enos.ac.uk/
26
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, gt160
  • Timing of treatment (hours) lt12, 12-48

www.enos.ac.uk/
27
ENOS 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/
28
UK
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

30
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 lt 24h () 31 29

www.enos.ac.uk/
31
ENOS Stroke type
Non-adjudicated information from investigator Is
chaemic 82 Haemorrhage 14
www.enos.ac.uk/
N646
32
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)

www.enos.ac.uk/
N646/293
33
ENOS Rankin, day 90
Planned mRS gt2 50
Current mRS gt2 48
Current mRS gt2 45
www.enos.ac.uk/
N573/258
34
Systolic BP (mmHg)
World Congress of Neurology 2005
P0.002
N168
35
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

36
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

37
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/
38
Funding
  • 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)

39
Thanks
  • Questions?
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