Stroke: advances in secondary prevention

Transcript Stroke: advances in secondary prevention

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  Pre-clinical: experimental  Pre-clinical: meta-analysis  Phase I, human volunteers  Phase II, dose escalation, safety  Clinical: meta-analysis 

Phase III, safety and efficacy

 Clinical: meta-analysis IST/TAIST/BASC Nitric oxide donors Nitric oxide donors SNP SPECT trial GTN/Xenon CT trials Cochrane Library

ENOS trial

Cochrane Library

SBP in acute ischaemic stroke: IST

High blood pressures is very common in acute ischaemic stroke affecting ~80% of patients

30 27.9

26.1

25 20 16.9

14.2

15 10 5 4.2

10.7

N=17,398

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

Leonardi-Bee et al. Stroke 2002;33:1315-20

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

Both low and high BP are associated independently with early death and late death/disability N=17,398 Leonardi-Bee et al. Stroke 2002;33:1315-20

SBP & early recurrence: TAIST

High blood pressure is associated with an increased risk of early recurrence after ischaemic stroke N=1,384 Sprigg et al. J Hypertension 2006;24:1413-17

To lower or not lower BP in acute stroke

An old debate!

QuickTime™ and a TIFF (Uncompressed) decompressor are needed to see this picture.

Arch Neurology 1985;42:999-1002

Guidelines for management

Guidelines are expert-based, not evidence-based  Reduce BP Encephalopathy, heart failure/ischaemia, aortic dissection Other hypertensive stroke patients   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 trials

Class Intervention ACE-i ACE-I ARA ARA (ß-RA CCB (CCB CCB CCB Diur.

NO NO NO SANS Perindopril Lisinopril Candesartan Losartan Atenolol/prop Nicardipine Nimodipine Nimodipine Nimodipine Bendroflu.

GTN GTN GTN Phenylephrine N/C Inclusion Outcome Trial 24/1 38/1 339/+ 24/1 358/1 16/1 295/+ 19/?

90/1 40/1 37/1 90/1 18/1 15/1 S170-250; 7d 1d IS, S>200; 3d M110-145 2d IS; S>170; 3d IS; 1d IS; ?d

1d 4d 5d S100-230; 4d S140-220 D/P mismatch TCD BP Vasc. event BP, SPECT CBF Disability CBF (SPECT) Dyker Eveson ACCESS Nazir BEST) Lisk ADL (BI)INWEST) Dose Fagan iv/po BP Uzuner Potter BP, platelets BP, dose Rashid BP, xenon CBF Lesion vol.

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

ACCESS

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

CCBs:

CCB in acute ischaemic stroke: No effect on outcome Horn & Limburg.

Cochrane Library

2002

Multimodality of drugs

BP modifying drugs have other actions: ACE-I ARA ß-RA CCB NO SANS Neuroprotection, block tissue effects, (antiplatelet) Neuroprotection, block tissue effects Antiplatelet, negative inotrope Antiplatelet, negative inotrope, ‘cerebral steal’ Neuroprotection, cerebral vasodilator, anti-platelet, (antileucocyte) Inotrope, chronotrope, vasoconstrictor, platelet agonist Bath P. Stroke 2003;34:1334-5

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: Administration in presence of dysphagia CCBs, ß-RA ?

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

There are several large ongoing trials of antihypertensive agents in acute stroke: Rx Continue vs. stop N aim 2900 2500 GTN (Telmi sartan 5000 20000 Cande sartan ‘Usual’ 2500 400 3000 C aim 100+ 200+ 200+ 640 100+ 70 N now 530 290 680 20133 C now 26 34 36 644 Inclusion IS/PICH + HT IS/PICH + HT IS/PICH + HT IS + 120-180 886 300+ ?

79 IS/PICH + HT PICH + HT PICH + HT Outcome Trial mRS mRS COSSACS ENOS mRS stroke ENOS PRoFESS) mRS stroke mRS mRS SCAST INTERACT-p INTERACT

NO path

Rashid et al. J

Stroke Cerebrovasc

Dis 2003;12:82-7

Nitric oxide (NOx) levels in acute stroke

90 80

  NOx levels low in stroke Low levels associated with a poor outcome

70 60 50

 Supplementing NO might improve outcome?

30 20 10 0 120 Home (n=153) Dead or institution (n=97) 100

60 40 20 0 Control (n=38) Ischaemic stroke (n=228) Brain bleed (n=49)

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?

Willmot et al.

Nitric Oxide

2005;12:141-9

Cerebral autoregulation

Cerebral perfusion normally maintained independently of BP Curve right-shifted in chronic high BP

80 CBF 60 40

Autoregulation lost following stroke Local perfusion becomes dependent on BP

20 0 BP 50 220

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

Glyceryl trinitrate (GTN): left infarct

BP lowered by 10% with GTN; CBF measured using xenon CT CBF: Perfusion did not fall N=18 Willmot et al.

Hypertension

2006;epub

GTN: left haemorrhage

And the same in primary intracerebral haemorrhage N=18 Willmot et al.

Hypertension

2006;epub

Transdermal glyceryl trinitrate (NO donor) on BP in acute stroke

GTN lowers BP in acute stroke (measured using ambulatory BP measuring [ABPM]) N=37 Bath et al. Cerebrovasc Dis 2001;11:265-72

  

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

Subjects Mean BP (mmHg) MCA velocity (m/s) Pulsatility index Augmentation index

Control

30 110.5

26.3

1.42

132.7

GTN

60 104.3

24.6

1.41

115.7

<0.001

NS NS <0.001

GTN: Lowered BP Did not alter middle cerebral artery blood flow velocity Reduced augmentation index, i.e. increases aortic compliance N=90 Rashid et al. J Stroke Cerebrovasc Dis 2003;13:143-51

GTN on blood pressure

GTN lowered systolic BP (systematic review):  Top: Measured over 24 hours (ABPM)  Bottom: Measures 2 hours after placement of GTN QuickTime™ and a TIFF (Uncompressed) decompressor are needed to see this picture.

Gray et al. J Stroke Cerebrovasc Dis 2006;15:245-9

       

Efficacy of Nitric Oxide in Stroke (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 / 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: 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 size

Assumptions:  Alpha   Power Control rate for mRS>2   GTN rate for mRS>2 Absolute treatment effect  Losses to follow-up  5000 patients  Analysis by intention-to-treat 5% 90% 50% 45% 5% 5% www.enos.ac.uk/

Canada (USA) (Portugal) UK Belgium (Spain) Poland Italy (Russia) (Greece) (Thailand) China/ Hong Kong (Mexico) (Colombia) (Brazil) (Nigeria) (Egypt) (South Africa) (India) Sri Lanka Singapore (Malaysia) Philippines Australia New Zealand

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

ENOS: Baseline

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

ENOS: Stroke type

Non-stroke 1% Awaiting CT 2% PICH 14% No CT 1% No lesion 21% HTI 3%

Non-adjudicated information from investigator: Ischaemic 82% Haemorrhage 14%

Infarct 58%

N=646 www.enos.ac.uk/

ENOS: Outcomes, day 7

% Death Recurrence Infarction Haemorrhage Unknown Deterioration SNSS (/58) (at baseline GTN/no GTN 2.5

1.9

1.1

0.5

0.3

7.7

45 38 Continue/stop 0.7

2.4 1.7

0.3

6.1

46 39) N=646/293 www.enos.ac.uk/

ENOS: Rankin, day 90

Planned

GTN/no GTN 8.7

20.6

Current

22.7

mRS >2 = 50%

16.2

14.7

7 10.1

mRS >2 = 48%

Stop/continue 9.3

Current

22.9

N=573/258

0% 22.5

15.1

14 7 9.3

mRS >2 = 45%

20% 0 1 40% 2 3 4 60% 5 80% 100% Death

www.enos.ac.uk/

Systolic BP (mmHg)

175 170 165 160 155 150 145 140 0 1 P=0.002 N=168 2 3 4 5 Days since randomisation Stop Continue 6 7 World Congress of Neurology 2005

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

National Coordinating Centre: Local centres:  Beijing, Tiantan   Hong Kong Wenzhou Number Age Male (%) Scandinavian Stroke Scale (/57) Intracerebral haemorrhage (%) mRS (mean) Tiantan, Beijing Patients 16 4 67 China 87 64 71 35 49 2.4

Rest 615 70 55 35 11 2.7

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!