11

Prevention and Management Prevention and Management

of hypertensive strokeof hypertensive stroke

Dr. LO, ManDr. LO, Man--waiwai

MBChB (CUHK)MBChB (CUHK)

MRCP (UK)MRCP (UK)

MPH (CUHK)MPH (CUHK)

FHKCPFHKCP

FHKAM (Medicine)FHKAM (Medicine)

Specialist in NeurologySpecialist in Neurology

Dept. of MedicineDept. of Medicine

Queen Elizabeth HospitalQueen Elizabeth Hospital

4 Dec 20064 Dec 2006

ContentContent

�� How does HT cause stroke?How does HT cause stroke?

�� What are the clinical and radiological What are the clinical and radiological manifestations for HTmanifestations for HT--related stroke?related stroke?

�� How should we lower BP in acute stroke?How should we lower BP in acute stroke?

�� What is the current concepts in antiWhat is the current concepts in anti--hypertensive therapy for prevention of hypertensive therapy for prevention of first and recurrent stroke?first and recurrent stroke?

22

How does HT cause stroke?How does HT cause stroke?

LipohyalinosisLipohyalinosis

Fibrinoiddegeneration

AtherosclerosisAtherosclerosis

33

44

55

Cortical infarction

MCA territory infarction

66

ACA territory infarction

PCA territory infarction

77

ACA

MCA

PCA

Lacunar Infarct

88

Lacunar Infarct

Binswanger’s disease

99

BinswangerBinswanger’’ss diseasedisease

�� SubcorticalSubcortical arterioscleroticarteriosclerotic

encephalopathyencephalopathy

�� Chronic small vessel diseaseChronic small vessel disease

�� Vascular parkinsonismVascular parkinsonism

�� Lower half parkinsonismLower half parkinsonism

BinswangerBinswanger’’ss diseasedisease

�� ApathyApathy

�� Gait Gait apraxiaapraxia

�� Small step gaitSmall step gait

�� HyperreflexiaHyperreflexia

�� Extensor plantar reflexesExtensor plantar reflexes

�� SubcorticalSubcortical dementia dementia –– cognitive slowingcognitive slowing

1010

Cardioembolicstroke

hypertensive hemorrhage

1111

Basal ganglia haemorrhage

Pontinehaemorrhage

1212

Cerebellar haemorrhage

SubarachnoidSubarachnoid haemorrhagehaemorrhage

1313

SAH

AntiplateletAntiplatelet agentsagents

Aspirin

� small benefit in reducing the death and recurrent stroke rate

� net decrease of 9deaths or occurrences of further stroke per 1000 patients (level Ia)

1414

IV IV thrombolysisthrombolysis

FDA approval 1996FDA approval 1996iv tPA iv tPA <3 hr<3 hr improved outcome at 3 monthsimproved outcome at 3 months

NINDSNINDS

TPATPA--treated group treated group were at least were at least 30%30%more likely to have more likely to have minimal or no minimal or no disability at 3 disability at 3 monthsmonths

Benefit were Benefit were consistent consistent regardless of age, regardless of age, stroke subtype or stroke subtype or prior use of aspirinprior use of aspirin �

1515

6.4% tPA vs. 0.6% in placebo (within 36hrs)

Mortality rate in both treatment group was similar at 3mo & at 1 year

1616

IntraIntra--arterial arterial

thrombolysisthrombolysis

MERCI balloon guide MERCI balloon guide

cathetercatheterFDA August 11, 2004 FDA August 11, 2004

1st medical 1st medical device device specifically specifically

indicated to indicated to --

retrieve blood clots from the retrieve blood clots from the

brain in ischemic stroke for brain in ischemic stroke for --

patients who fail or are patients who fail or are

ineligible for iv tPAineligible for iv tPA

1717

BP lowering BP lowering in acute phasein acute phase

IschaemicIschaemic penumbrapenumbra

1818

IschaemicIschaemic penumbrapenumbra

Cerebral Cerebral autoregulationautoregulation

1919

Cerebral Cerebral autoregulationautoregulation

Normotensive patient

Hypertensive patient

CBF

Mean arterial BP

BP management in acute BP management in acute

ischaemicischaemic strokestroke

�� CBF is pressure dependent in CBF is pressure dependent in ischaemicischaemic

brain regionsbrain regions

�� Further reduction Further reduction

�� irreversibly injure theirreversibly injure the ischaemicischaemic

penumbra penumbra

�� increase stroke volumeincrease stroke volume

2020

BP management in BP management in

acute acute ischaemicischaemic strokestroke

�� Transient HT Transient HT –– common after acute common after acute ischaemicischaemic strokestroke

�� Causes: Causes: �� anxietyanxiety

�� painpain

�� neuroendocrineneuroendocrine factorsfactors

�� stroke locationstroke location

�� compensatory response to brain hypoxia or compensatory response to brain hypoxia or increased ICPincreased ICP

BP management in acute BP management in acute

ischaemicischaemic strokestroke

�� Manage stress responses, pain, nausea and Manage stress responses, pain, nausea and vomiting, bladder distension or other sources of vomiting, bladder distension or other sources of anxietyanxiety

�� Early BP elevations often decline spontaneously Early BP elevations often decline spontaneously during the first minutes to hours during the first minutes to hours

�� May not require pharmacologic RxMay not require pharmacologic Rx

2121

Blood pressure decreaseBlood pressure decrease during the during the acute acute

phasephase of ischemic stroke is associated with of ischemic stroke is associated with

brain injury and poor stroke outcomebrain injury and poor stroke outcome

Castillo J, Castillo J, LeiraLeira R, Garcia MM, Serena J, Blanco M, R, Garcia MM, Serena J, Blanco M, DavalosDavalos A.A.

Stroke. 2004 Feb;35(2):520Stroke. 2004 Feb;35(2):520--6. 6. EpubEpub 2004 Jan 15. 2004 Jan 15.

Power Grade 3/5

Power Grade 1/5

Anti-HT Drugfor BP 180/90

2222

““Stroke in evolutionStroke in evolution””??

NonNon--specificspecific

�� Failure of collateral circulationFailure of collateral circulation

�� Systemic hypotensionSystemic hypotension

�� Cardiac Cardiac arrthymiaarrthymia

�� EmbolizationEmbolization or propagation of thrombusor propagation of thrombus

�� Progressive occlusion of vessel lumenProgressive occlusion of vessel lumen

�� Psychological depressionPsychological depression

�� SepsisSepsis

�� SeizuresSeizures

Any conditions deserve Any conditions deserve

BP lowering?BP lowering?

� AMI

� Aortic dissection

� Hypertensive encephalopathy

� Severe left heart failure

� Post-thrombolysis

2323

Consensus for BP Consensus for BP MxMx(not eligible for (not eligible for thrombolysisthrombolysis))

Sodium Sodium nitroprussidenitroprusside 0.5 0.5 µµm/kg per min IV m/kg per min IV

with continuous BP monitoring with continuous BP monitoring

(target 10%(target 10%––15% reduction)15% reduction)

DBP >140 mm Hg DBP >140 mm Hg

LabetalolLabetalol OR OR nicardipinenicardipine

(target 10%(target 10%––15% reduction) 15% reduction)

SBP >220 mm Hg SBP >220 mm Hg

or or

DBP 121DBP 121––140 mm Hg 140 mm Hg

Observe BPObserve BP

unless end organ involvementunless end organ involvement

SBP <220 mm Hg SBP <220 mm Hg

or or

DBP <120 mm Hg DBP <120 mm Hg

Guidelines for the Early Management of Patients With Ischemic StGuidelines for the Early Management of Patients With Ischemic Stroke roke

Stroke.Stroke. 2003;34:1056 2003;34:1056

Resume previous antiResume previous anti--HT Rx?HT Rx?

Those already taking antiThose already taking anti--HT Rx:HT Rx:

�� Resume drugs to avoid Resume drugs to avoid rebound HTrebound HT

� Maintain::

SBP 180–220 mm Hg

DBP < 120 mm Hg

2424

LabetololLabetolol

�� Selective Selective αα11 antagonist antagonist

�� ßß11 & & ßß22 antagonistantagonist

�� Decrease systemic vascular Decrease systemic vascular

resistance through resistance through αα blockadeblockade

�� BetaBeta--blocking reflex tachycardia blocking reflex tachycardia

induced by vasodilatationinduced by vasodilatation

LabetololLabetolol

Does not affect cerebral blood flowDoes not affect cerebral blood flow

Dosing regimen 10Dosing regimen 10--20mg iv (over 120mg iv (over 1--2 min) 2 min)

every 15every 15--20min 20min

DoubingDoubing of each subsequent dose is of each subsequent dose is

recommendedrecommended

2525

Sublingual Sublingual NifedipineNifedipine

�� Should be avoidedShould be avoided

�� Cause precipitous reduction in BPCause precipitous reduction in BP

AdalatAdalat 5mg S.L. stat5mg S.L. statX

Bring home message:Bring home message:

DonDon’’t lower BP in acute t lower BP in acute ischaemicischaemic stroke if stroke if

SBP <220 mm Hg

or

DBP <120 mm Hg

2626

Managing HT in ICHManaging HT in ICH

�� limited observational data limited observational data

�� no data from randomized clinical trialsno data from randomized clinical trials

�� left with consensus opinion and our best left with consensus opinion and our best judgementjudgement

�� balancing the two competing issues: balancing the two competing issues: �� RebleedingRebleeding

�� Secondary brain injurySecondary brain injury

�� BP lowering to limit BP lowering to limit hematomahematoma expansion, nonexpansion, non--nervous system organ injurynervous system organ injury

Keep cerebral perfusion Keep cerebral perfusion

pressure > 70mmHgpressure > 70mmHgIf ICP monitoring is presentIf ICP monitoring is present

Observe Observe SBP <180SBP <180 mm Hgmm Hg

DBP <105 mm HgDBP <105 mm Hg

IV IV labetalollabetalol, , esmololesmolol, ,

enalaprilenalaprilSBP 180 to 230 mm HgSBP 180 to 230 mm Hg

DBP 105 to 140 mm HgDBP 105 to 140 mm Hg

or MAP 130 mm Hg or MAP 130 mm Hg

on 2 readings 20 minutes aparton 2 readings 20 minutes apart

NitroprussideNitroprussideSBP >230 mm HgSBP >230 mm Hg

DBP >140 mm HgDBP >140 mm Hg

on 2 readings 5 minutes aparton 2 readings 5 minutes apart

AHA Scientific StatementAHA Scientific Statement

Guidelines for the Management of Guidelines for the Management of

Spontaneous ICHSpontaneous ICHStroke.Stroke. 1999;30:9051999;30:905--915 915

2727

Primary preventionPrimary prevention

2828

Risk factors for strokeRisk factors for stroke

NonNon--modifiablemodifiable

�� NonNon--white ethnicitywhite ethnicity

�� Male sexMale sex

�� Older ageOlder age

�� Positive family history Positive family history

ModifiableModifiable

�� HTHT

�� SmokingSmoking

�� Excessive alcohol intake Excessive alcohol intake (>60g/d)(>60g/d)

�� ObesityObesity

�� DyslipidaemiaDyslipidaemia

�� DMDM

�� Carotid artery diseaseCarotid artery disease

�� AFAF

�� CHFCHF

Blood Pressure and Stroke: An Overview of Published ReviewsBlood Pressure and Stroke: An Overview of Published ReviewsCarlene M.M. Carlene M.M. LawesLawes, Derrick A. Bennett, , Derrick A. Bennett, ValeryValery L. L. FeiginFeigin, and Anthony Rodgers, and Anthony Rodgers

Stroke 2004 35: 776 Stroke 2004 35: 776 -- 785785

2929

BP level & risk of vascular BP level & risk of vascular

diseasedisease

�� JNC VIIJNC VII

�� Risk begins at 115/75 Risk begins at 115/75 mmHgmmHg

�� No limits below this No limits below this pointpoint

�� No JNo J--curve responsecurve response

Stage 2 HT

Stage 1 HT

Prehypertension

Normal

120120

140140

160160

8080 1001009090

SBPSBP

DBPDBP

Classification of BP by JNC 7Classification of BP by JNC 7

3030

Which drug should we use?Which drug should we use?

Any class effect?Any class effect?

Blood Pressure Lowering Treatment Trialists' Collaboration. Effects of different blood-pressure-lowering regimens on major cardiovascular events: results of prospectively-designed overviews of randomized trials.

Lancet. 2003;362:1527-1535.

Comparison with placeboComparison with placebo

3131

Blood Pressure Lowering Treatment Trialists' Collaboration. Effects of different blood-pressure-lowering regimens on major cardiovascular events: results of prospectively-designed overviews of randomized trials.

Lancet. 2003;362:1527-1535.

Direct comparison between Direct comparison between antianti--HT regimenHT regimen

Size does matterSize does matter

Size (intensity)Size (intensity)

of BP of BP ��

Type of Type of

antianti--HT RxHT Rx

3232

Compelling reasons & Compelling reasons &

recommendationsrecommendations

����������������Recurrent Recurrent CVACVA

����������������CRFCRF

����������������������������������������DMDM

��������������������������������High CHD High CHD riskrisk

������������������������PostPost--MIMI

����������������������������������������CHFCHF

AldosteroneAldosteroneAntagonistAntagonist

CCBCCBARBARBACEIACEIBB--blockerblockerDiureticDiuretic

3333

Stage 2 HT

Stage 1 HT

Prehypertension

Normal120120

140140

160160

8080 1001009090

SBPSBP

DBPDBP

Lifestyle modification��������

Compelling indications? treatY

Stage 2 HT

Stage 1 HT

Prehypertension

Normal120120

140140

160160

8080 1001009090

SBPSBP

DBPDBP

Lifestyle modification��������

Treat with Treat with

thiazidethiazideACEI, ARB, BB, CCB,ACEI, ARB, BB, CCB,

or combinationor combination

��������

3434

Stage 2 HT

Stage 1 HT

Prehypertension

Normal120120

140140

160160

8080 1001009090

SBPSBP

DBPDBP

Lifestyle modification��������

2 drugs combinations2 drugs combinations

ThiazideThiazide + ACEI/ARB/BB/CCB+ ACEI/ARB/BB/CCB

Central Central PontinePontine

MyelinolysisMyelinolysis

3535

What are the risk factors for What are the risk factors for

thiazidethiazide induced induced hyponatremiahyponatremia??

�� AgeAge

�� Low body Low body

massmass

�� HypokalemiaHypokalemia

Risk factors for Risk factors for thiazidethiazide--induced induced hyponatraemiahyponatraemia..

K.M. Chow, C.C. K.M. Chow, C.C. SzetoSzeto, T.Y., T.Y.--H. Wong, C.B. Leung P.K.H. Wong, C.B. Leung P.K.--T. Li T. Li

Q J Med 2003; 96: 911Q J Med 2003; 96: 911--917917

Stroke prevention in DiabeticsStroke prevention in Diabetics

�� 40 40 –– 60% adult with type 2 DM have HT60% adult with type 2 DM have HT

�� Any difference in BP management for Any difference in BP management for this special group of patients to prevent this special group of patients to prevent stroke?stroke?

3636

UKPDS UKPDS Event Rates for Select Event Rates for Select Endpoints With Endpoints With

Tight Tight vsvs Less Tight Blood Pressure ControlLess Tight Blood Pressure Control

0

10

20

30

40

50

60

70

80

Any DM-related endpoint

DM-

related deathStroke Microvascular

complications

Events per 1000 patient yrs P=0.005

P=0.02 P=0.01 P=0.009

Less tight (n=390) mean achieved BP 154/87 mmHg

Tight (n=758) mean achieved BP 144/82 mmHg

UKPDS Group. BMJ. 1998;317:703–713.

-33

-25

-21

-16

-12

-50

-40

-30

-20

-10

0

Microalbuminuria at 12 yrs Microvascular complications

Retinopathy Myocardial Infarction

Any DM endpoint

% relative risk reduction

P=0.03

P<0.01

P<0.01

P=0.05

P=0.02

UKPDS Group. Lancet. 1998;352:837-853.

UKPDS Relative Risk Reduction for UKPDS Relative Risk Reduction for Intensive Intensive vsvs Less Intensive Less Intensive Glucose ControlGlucose Control

Over 10 years, HbA1c was 7.0% (6.2-8.2) in the intensive group (n=2,729) compared with 7.9% (6.9-8.8) in the conventional group (n=1,138).

3737

UKPDS Findings:UKPDS Findings:Tight BP Control vs. Intensive Glucose ControlTight BP Control vs. Intensive Glucose Control

�� Tight vs. Less tightTight vs. Less tight BP control BP control reduces risk ofreduces risk of

�� Any diabetesAny diabetes--related endpoint related endpoint 24% 24% P=0.005P=0.005

�� MicrovascularMicrovascular complicationscomplications 37% 37% P=0.009P=0.009

�� Stroke Stroke 44% 44% P=0.01P=0.01

�� Intensive vs. Conventional Intensive vs. Conventional glucose controlglucose control policy policy reduces risk of reduces risk of

�� Any diabetesAny diabetes--related endpoint related endpoint 12% 12% P=0.03P=0.03

�� MicrovascularMicrovascular complications complications 25% 25% P<0.01P<0.01

�� Myocardial infarctionMyocardial infarction 16% 16% P=0.05P=0.05

UKPDS Group. BMJ. 1998;317:703–712.UKPDS Group. Lancet. 1998;352:837-853.

““Is ACEI/ARB better for diabetics ?Is ACEI/ARB better for diabetics ?””

Angiotensinogen

⇑⇑⇑⇑ Angiotensin I

⇑⇑⇑⇑ Angiotensin II

AT1 AT2 ATn

Bradykinin

Inactivepeptides

Non-renin(eg tPA)

Non-ACE(eg chymase) ACE

Renin

3838

ABCD, CAPPP, FACET ABCD, CAPPP, FACET

and UKPDS Metaand UKPDS Meta--AnalysisAnalysis

�� Is ACEI superior to other agents in the prevention of Is ACEI superior to other agents in the prevention of

cardiovascular events in cardiovascular events in hypertensive type 2 hypertensive type 2

diabetics?diabetics?

Pahor M, et al. Diabetes Care. 2000;23:888-892.

atenololcaptoprilcaptopril758758UKPDSUKPDS

amlodipinefosinoprilfosinopril380380FACETFACET

Diuretic or BBcaptoprilcaptopril572572CAPPPCAPPP

nisoldipineenalaprilenalapril470470ABCDABCD

OthersOthersACEIACEISizeSize

Relative Risk Reduction With Relative Risk Reduction With ACEIsACEIsin ABCD, CAPPP and FACETin ABCD, CAPPP and FACET

-24-24-24-24

-43-43-43-43

-63-63-63-63

-51-51-51-51

-70-70-70-70

-60-60-60-60

-50-50-50-50

-40-40-40-40

-30-30-30-30

-20-20-20-20

-10-10-10-10

0000

% relative risk reduction

Pahor M, et al. Diabetes Care. 2000;23:888-892.

AMI CVS Event StrokeAll-cause Mortality

P<0.001

P<0.001

P=0.01

NS

3939

0

5

10

15

20

25Placebo Ramipril

Combined primary endpoint*

Myocardial infarction

Stroke Cardiovascular death

RR=25%P<0.001

RR=22%P=0.01

RR=33%P=0.007

RR=37%P<0.001

Events per patient group (%)

*The occurrence of myocardial infarction, stroke or cardiovascular death

HOPE Study Investigators. Lancet. 2000;355:253-259.

MICROMICRO--HOPEHOPE substudiessubstudies of DM patientsof DM patients

RamiprilRamipril (n = 3,577)(n = 3,577)

LIFE Study LIFE Study Diabetes SubgroupDiabetes Subgroup

((LorsartanLorsartan))

Lindholm LH, et al. Lancet. 2002;359:1004-1010.

0.5 1 1.5Favors atenolol

Adjusted hazard ratio (95% CI)

No. of events

Favors losartan

P value

Composite

CV Death

Stroke

Myocardialinfarction

Total Mortality

242

99

116

91

167

0.031

0.028

NS

NS

0.002

Endpoints

21%

4040

ImplicationsImplications

� Tight control of HT with ACEI or ARB treatment reduces the risk of stroke in persons with DM

� Glycemic control reduces microvascularcomplications, but evidence showing a reduction in stroke risk with tight glycemic control is lacking

ASA/AHA 2006 recommendationASA/AHA 2006 recommendation

Primary stroke prevention for Primary stroke prevention for

DiabeticsDiabetics

�� Tight BP controlTight BP control

�� Keep BP < 130/ 80 Keep BP < 130/ 80

mmHgmmHg

�� Consider ACEI/ Consider ACEI/

ARBARB

4141

Case Case scenerioscenerio

Chan Tai ManChan Tai Man M/52M/52

BP 145/ 85 p70BP 145/ 85 p70 HstixHstix 2hr pp 16.32hr pp 16.3

HypertensionHypertension

StrokeStroke

StrokeStroke

x

x

PrimaryPrimaryPreventionPrevention

SecondarySecondaryPreventionPrevention

4242

ACEI for 2ACEI for 2ndnd stroke prevention? stroke prevention?

�� HOPE HOPE �� RamiprilRamipril vs. Placebo vs. Placebo

�� for 1013 patients with for 1013 patients with HxHx of stroke/TIAof stroke/TIA

�� 24% RR (95% CI, 5 24% RR (95% CI, 5 –– 40) stroke, MI or vascular 40) stroke, MI or vascular death; (n =1013)death; (n =1013)

�� BP lowering 3/2mm Hg (Office BP)BP lowering 3/2mm Hg (Office BP)

�� HOPE HOPE substudysubstudy (Ambulatory BP)(Ambulatory BP)�� 10/4 mmHg reduction over 24hr10/4 mmHg reduction over 24hr�� 17/8 mmHg reduction during nighttime17/8 mmHg reduction during nighttime�� �� BP lowering effect leading to stroke risk reduction?BP lowering effect leading to stroke risk reduction?

Comparative Effects of Ramipril on Ambulatory and Office Blood PressuresPer Svensson; Ulf de Faire; Peter Sleight; Salim Yusuf; Jan Östergren

Hypertension. 2001;38:e28

PROGRESS PROGRESS ((perindoprilperindopril))�� N = 6105N = 6105�� HxHx of stroke or TIAof stroke or TIA�� ACEI, ACEI + ACEI, ACEI + indapamideindapamide

�� Recurrent CVA:Recurrent CVA:�� 43% RRR (95% CI 30 43% RRR (95% CI 30 –– 54); 12/5 mmHg 54); 12/5 mmHg ��

�� Recurrent major CVS events:Recurrent major CVS events:�� 40% RRR (95% CI 29 40% RRR (95% CI 29 –– 49)49)

�� No benefit when ACEI was given aloneNo benefit when ACEI was given alone�� Benefit also shown in Benefit also shown in normotensivenormotensive patientspatients

PROGRESS Collaborative Group. Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6105 individuals with previous stroke or transient ischaemic attack.

Lancet. 2001;358:1033- 1041.

4343

AHA/ ASA Guideline 2006AHA/ ASA Guideline 2006Secondary Prevention of StrokeSecondary Prevention of Stroke

�� How much?How much?�� Benefit seen in reduction of ~10/5 mmHgBenefit seen in reduction of ~10/5 mmHg�� Normal BP < 120/80 mmHg by JNCNormal BP < 120/80 mmHg by JNC--77

All patients with All patients with ischaemicischaemic strokestroke

or TIAor TIAAntiAnti--HT RxHT Rx

4444

AHA/ ASA Guideline 2006AHA/ ASA Guideline 2006Secondary Prevention of StrokeSecondary Prevention of Stroke

�� Which drug?Which drug?

�� Optimal regimen Optimal regimen ––uncertainuncertain

�� Available data support:Available data support:�� Diuretic Diuretic

�� Diuretic + ACEI Diuretic + ACEI

�� Individualized with Individualized with patient characteristicspatient characteristics

Key messageKey message

�� Benefit for HT Rx is clearBenefit for HT Rx is clear

�� Choice of agent must be individualizedChoice of agent must be individualized

�� Reduction of BP is generally more Reduction of BP is generally more important than specific agentimportant than specific agent

�� ““Size does matter!Size does matter!””