Stroke prevention a reality in this millennium

STROKE PREVENTION- A STROKE PREVENTION- A REALITY IN THIS MILLENNIUMREALITY IN THIS MILLENNIUM

Prof. A.V. SRINIVASAN,MD, DM, Ph.D, F.A.A.N, F.I.A.N.

Emeritus Professor

The Tamilnadu Dr. M.G.R. Medical University

Former Head

Institute of Neurology, Madras Medical College

Prof. A.V. SRINIVASAN,MD, DM, Ph.D, F.A.A.N, F.I.A.N.

Emeritus Professor

The Tamilnadu Dr. M.G.R. Medical University

Former Head

Institute of Neurology, Madras Medical College

21-08-10

Cerebrovascular Cerebrovascular PreventionPrevention

Is survival a mere Is survival a mere stroke stroke of Luck?of Luck?

“My Opinions are founded on knowledge but modified by experience”

INTRODUCTIONINTRODUCTION

Perceptual Sense Perceptual Sense (Observation)(Observation) Word Sense Word Sense (Recording)(Recording) Common Sense Common Sense (Thinking)(Thinking)

Will lead you to get - Will lead you to get - Clinical SenseClinical Sense

“ He who cannot forgive others destroys the bridge over which he himself must pass” - Annoy

Cerebrovascular disease – Cerebrovascular disease – Mind boggling factsMind boggling facts

CVD is the most disabling of all neurologic diseases. 50% of survivors have a residual neurologic deficit.

Greater than 25% require chronic care.

World wide incidence: 2/1000 population/annum1

Incidence in people aged 45 – 84 years: about 4/10001

Incidence in India: was 36/100,000 for the year 1998-19993 in a study in Calcutta

Incidence of mortality due to stroke (India: WHO study): 73/100,000 per year2

1.A practical approach to management of stroke patients; 1996; 360-3842. Epidemology of cerebrovascular disorders in India; 1999; 4-19

3. Neuroepidemiology 2001;20:201-207

If you think you can or you can’t You are always right

• CVD 6.7 %

• MI 2.5 %

• Death 7.2 %

• CVD, MI, Vascular death 8.6 %

• CVD, MI, Death 10.3 %

Annual risk CVD, MI, vascular death Annual risk CVD, MI, vascular death following TIA, minor CVDfollowing TIA, minor CVD

Annual risk CVD, MI, vascular death Annual risk CVD, MI, vascular death following TIA, minor CVDfollowing TIA, minor CVD

Experience can be defined as yesterday’s answer to today’s problems

Common Stroke MimicsCommon Stroke Mimics HypoglycemiaHypoglycemia Post ictal statePost ictal state Drug overdoseDrug overdose Concussion with neck injuryConcussion with neck injury Migrainous accompanimentMigrainous accompaniment Encephalopathies with focal signsEncephalopathies with focal signs HyponatremiaHyponatremia Subdural hematoma, EmpyemaSubdural hematoma, Empyema Focal Encephalitis: HerpesFocal Encephalitis: Herpes

Being ignorant is not so much a shame as being unwilling to learn

Drugs used for stroke Drugs used for stroke prevention…prevention…

ACE inhibitors ACE inhibitors

Lipid lowering agentLipid lowering agent

Anti-plateletsAnti-platelets

Prevention of Prevention of Cerebrovascular Events Cerebrovascular Events with Perindopril: with Perindopril:

New Evidence New Evidence

Why ACE inhibitors in stroke Why ACE inhibitors in stroke prevention ?prevention ?

Blood pressure lowering effectBlood pressure lowering effect Prevention of endothelial dysfunctionPrevention of endothelial dysfunction Prevention of progression of atherosclerosisPrevention of progression of atherosclerosis Favourable alteration of the fibrinolytic balanceFavourable alteration of the fibrinolytic balance Prevention of cardiac remodellingPrevention of cardiac remodelling

Clinical evidence…Clinical evidence…

Objective of PROGRESSObjective of PROGRESSWhether in patients with…Whether in patients with…

StrokeStrokeStrokeStroke OROR TIATIATIATIA

Perindopril Perindopril ++ Indapamide IndapamidePerindopril Perindopril ++ Indapamide Indapamide

Risk of stroke & vascular eventsRisk of stroke & vascular eventsRisk of stroke & vascular eventsRisk of stroke & vascular events

WHO – ISH initiated the studyWHO – ISH initiated the studyWHO – ISH initiated the studyWHO – ISH initiated the studyPROGRESS collaborative group. Lancet 2001;358:1033-41.

Evidence of Evidence of

Stroke / TIAStroke / TIA

> 2 weeks and < 5 years of event> 2 weeks and < 5 years of event

Evidence of Evidence of

Stroke / TIAStroke / TIA

> 2 weeks and < 5 years of event> 2 weeks and < 5 years of event

Patient selection criteriaPatient selection criteria

……but without a definite indication / but without a definite indication / contraindication to treatment with an ACE inhibitorcontraindication to treatment with an ACE inhibitor

PROGRESS collaborative group. Lancet 2001;358:1033-41.

NormotensiveNormotensive

Patient selection criteriaPatient selection criteria

OldOld

YoungYoung

DiabeticDiabetic Non-diabeticNon-diabetic

HypertensiveHypertensive

Included


Baseline characteristicsBaseline characteristicsCharacteristicCharacteristic

Mean age (yrs)Mean age (yrs)Females (%)Females (%)Stroke historyStroke history Ischaemic stroke (%)Ischaemic stroke (%) Haemorrhagic stroke (%)Haemorrhagic stroke (%) TIA (%)TIA (%) Duration since event (months)Duration since event (months)Diabetes (%)Diabetes (%)CAD (%)CAD (%)Mean BP (mmHg)Mean BP (mmHg)Hypertension (%)Hypertension (%)Antihypertensive therapy (%)Antihypertensive therapy (%)

64643030

71711111222288

13131616

147/86147/8648485050

Perindopril Perindopril ++ indapamide indapamideN = 3051N = 3051

64643030

71711111222288

12121616

147/86147/8648485151

PlaceboPlaceboN = 3054N = 3054


Total strokeTotal strokeR

isk

redu

ctio

n (%

)R

isk

redu

ctio

n (%

)

00 11 22 33 44 YearsYears

Placebo groupPlacebo group

Active groupActive group

28% 28% risk risk

reductionreduction

28% 28% risk risk

reductionreduction

38%38%


Stroke subtype Stroke subtype (1)(1)

Risk reduction (%)Risk reduction (%)

Fatal / Fatal / disabling strokedisabling stroke

Non fatal / Non fatal / disabling strokedisabling stroke

33332424


Stroke subtype Stroke subtype (2)(2)


Ischaemic Ischaemic

strokestroke

Haemorrhagic Haemorrhagic strokestroke

5050

2424


Hypertensives / normotensivesHypertensives / normotensives


StrokeStroke

HypertensivesHypertensives

3232

2727

NormotensivesNormotensives


Treatment acceptabilityTreatment acceptability

Active group

Placebo

Cau

ses

of w

ithd

raw

al (

%)

All causes Voluntary Cough Hypotension

232321

82

0.4 0.9

82


PROGRESS results showed…PROGRESS results showed…

Perindopril Perindopril ++ indapamide substantially indapamide substantially reduced risk of secondary stroke and other reduced risk of secondary stroke and other vascular eventsvascular eventsIrrespective of Irrespective of AgeAge Blood pressure levelBlood pressure level Other diseasesOther diseases Background medicationBackground medication


Summarise…Summarise…

ACE inhibitors are beneficial in the prevention ACE inhibitors are beneficial in the prevention of strokeof stroke

All stroke patients, hypertensive as well as All stroke patients, hypertensive as well as normotensives should receive an ACE inhibitornormotensives should receive an ACE inhibitor

All CAD patients, diabetic patients, who are at-All CAD patients, diabetic patients, who are at-risk of developing stroke should receive an risk of developing stroke should receive an ACE inhibitorACE inhibitor

Which ACE inhibitor ?Which ACE inhibitor ?

Which ACE inhibitor ?Which ACE inhibitor ?

Perindopril-Perindopril-based therapybased therapy

TreatmentTreatment

23 to prevent23 to prevent1 stroke in 5 years1 stroke in 5 years

67 to prevent67 to prevent1 stroke in 5 years1 stroke in 5 years

Number-needed-to-treatNumber-needed-to-treat

JNC – 7 reference only to perindoprilJNC – 7 reference only to perindopril

Stroke 2002;33:862-875. JNC-7, JAMA May 2003 – Vol.289; No.19: 2560-2571.JAMA May 2003 – Vol.289; No.19: 2560-2571.

Ramipril-based Ramipril-based therapytherapy

Statins: Stroke Statins: Stroke Prevention and Prevention and

Survival BenefitsSurvival Benefits

Primary Prevention of Ischemic StrokePrimary Prevention of Ischemic StrokeA Guideline From the American Heart A Guideline From the American Heart

Association/American StrokeAssociation/American StrokeAssociation Stroke CouncilAssociation Stroke Council

It is recommended that patients with It is recommended that patients with known CAD and high-risk hypertensive known CAD and high-risk hypertensive patients even with normal LDL cholesterol patients even with normal LDL cholesterol levels be treated with lifestyle measures levels be treated with lifestyle measures and a statin (Class I, Level of Evidence A).and a statin (Class I, Level of Evidence A).

Stroke 2006;37;1583-1633

JUPITER & STROKEJUPITER & STROKE

JUPITER is the first large-scale, prospective JUPITER is the first large-scale, prospective study to examine the role of statin therapy in study to examine the role of statin therapy in individuals with low to normal LDL-C levels, but individuals with low to normal LDL-C levels, but with increased cardiovascular risk identified by with increased cardiovascular risk identified by elevated CRPelevated CRP

Nearly half of all cardiovascular events occur in Nearly half of all cardiovascular events occur in patients who are apparently healthy and who patients who are apparently healthy and who have low or normal levels of LDL-Chave low or normal levels of LDL-C

hsCRP predicts cardiovascular disease hsCRP predicts cardiovascular disease independent of LDL-C levelsindependent of LDL-C levels

Rosuvastatin 20 mg (N=8901)Rosuvastatin 20 mg (N=8901)

JUPITERJUPITERMulti-National Randomized Double Blind Placebo Multi-National Randomized Double Blind Placebo

Controlled Trial of Controlled Trial of Rosuvastatin in the Prevention of Cardiovascular Rosuvastatin in the Prevention of Cardiovascular

EventsEventsAmong Individuals With Low LDL and Elevated Among Individuals With Low LDL and Elevated

hsCRPhsCRP

4-week 4-week run-inrun-in

Ridker et al, Circulation 2003;108:2292-2297.

No Prior CVD or DMNo Prior CVD or DMMen Men >>50, Women 50, Women >>6060

LDL <130 mg/dL hsCRP >2 mg/L

JUPITERTrial Design

Placebo (N=8901)Placebo (N=8901)

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica, Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands, Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,

United Kingdom, Uruguay, United States, Venezuela

JUPITER: ResultsJUPITER: Results

48%

Reduction

Circulation 2010;121:143-150

33

64

0

10

20

30

40

50

60

70

Rosuvastatin Placebo

No. of patients with any stroke

n=8901 n=8901

*

* p< 0.002 vs. placebo


48%

Reduction

Circulation 2010;121:143-150

30

58

0

10

20

30

40

50

60


No. of patients with non-fatal stroke

n=8901 n=8901

*



50%

Reduction

Circulation 2010;121:143-150

No. of patients with fatal stroke

n=8901 n=8901

3

6

0

1

2

3

4

5

6



48%

Reduction

Circulation 2010;121:143-150

No. of patients with ischemic stroke

n=8901 n=8901

*


23

47

05

101520253035404550


51%

Primary Prevention of Primary Prevention of Stroke: Stroke:

What do the previous What do the previous statins trials suggest? statins trials suggest?

WOSCOPS STUDY:

Statin: Pravastatin 40 mg

n=6595

Results: Stroke 11%

AFCAPS/TexCAPS STUDY:

Statin: Lovastatin 10-40 mg

n=6605

Results: Stroke 18%

Circulation 2010;121:143-150

MEGA STUDY:

Statin: Pravastatin 10-20 mg

n=7730

Results: Stroke 17%

JUPITER STUDY:

Statin: Rosuvastatin 20 mg

n=17802

Results: Stroke 48%

A meta-analysis of A meta-analysis of WOSCOPS+AFCAPS/TexCAPS+MEGAWOSCOPS+AFCAPS/TexCAPS+MEGA

•Stroke reduction by 14% Stroke reduction by 14% (statistically non-significant)(statistically non-significant)

A meta-analysis of these 3 trials along with A meta-analysis of these 3 trials along with JUPITERJUPITER

•Stroke reduction by 25% Stroke reduction by 25% (statistically significant)(statistically significant)

Analysis of JUPITER only:Analysis of JUPITER only:Stroke reduction by 48% (statistically non-Stroke reduction by 48% (statistically non-significant)significant)

SummarySummary

Stroke is one of the leading cause of death Stroke is one of the leading cause of death worldwide.worldwide.

Guidelines recommends the use of statins Guidelines recommends the use of statins for primary as well as secondary for primary as well as secondary prevention of stroke.prevention of stroke.

JUPITER trial has established that JUPITER trial has established that rosuvastatin is the most effective statin in rosuvastatin is the most effective statin in preventing stroke in high risk population. preventing stroke in high risk population.

Symptomatic Carotid Symptomatic Carotid Endarterectomy ASA 2006 Endarterectomy ASA 2006

Secondary Stroke RecsSecondary Stroke Recs

• Ipsilateral severe (70% to 99%) carotid stenosis, CEA is recommended (Class I, Evidence A).

• Ipsilateral moderate (50% to 69%) carotid stenosis, CEA is recommended depending on age, gender, comorbidities, and the severity of symptoms (Class I, Evidence A).

• Stenosis <50%, there is no indication for CEA (Class III, Evidence A).

Urgent EndarterectomyUrgent Endarterectomy

Surgery within 2 weeks is suggested rather than delaying surgery (Class IIa, Evidence B).

Rothwell PM. Lancet 2004;363(9413):915-24

Carotid Angioplasty and StentingCarotid Angioplasty and StentingASA 2006 Secondary Stroke ASA 2006 Secondary Stroke

RecsRecs• CAS may be considered (Class IIb, Evidence B). - Stenosis (>70%) difficult to access surgically - Medical conditions that greatly increase the

risk for surgery, or - When other circumstances exist such as radiation-induced stenosis or restenosis after CEA.

• CAS is reasonable when performed by operators with morbidity and mortality rates of 4% to 6% (Class IIa, Evidence B).

Atrial FibrillationAtrial FibrillationASA 2006 RecommendationsASA 2006 Recommendations

• For patients with ischemic stroke or TIA with persistent or paroxysmal (intermittent) AF, anticoagulation with adjusted-dose warfarin (target INR 2.5, range 2.0 to 3.0) is recommended (Class I, Evidence A).

• For patients unable to take oral anticoagulants, aspirin 325 mg per day is recommended (Class I, Evidence A).

Stroke Prevention: Stroke Prevention: Non-cardioembolic Non-cardioembolic

ASA 2006 RecommendationsASA 2006 Recommendations

For patients with noncardioembolic ischemic stroke or TIA, antiplatelet agents are recommended rather than oral anticoagulation to reduce the risk of recurrent stroke and other cardiovascular events (Class I, Evidence A).

Stroke Prevention: Non-Stroke Prevention: Non-cardioembolic cardioembolic

ASA 2006 RecommendationsASA 2006 Recommendations

• Acceptable options for initial therapy (Class IIa, Evidence A).

- aspirin (50-325 mg qd) - the combination of aspirin and extended- release dipyridamole (25/200 mg bid) - clopidogrel (75 mg qd)

Antiplatelet TherapyAntiplatelet TherapyASA 2006 RecommendationsASA 2006 Recommendations

• Compared to aspirin alone, both the combination of aspirin and extended-release dipyridamole and clopidogrel are safe.

• The combination of aspirin and extended-release dipyridamole is suggested instead of aspirin alone (Class IIa, Level A).

• Clopidogrel is suggested instead of aspirin alone based on direct comparison trials (Class IIb, Level B).

Secondary Stroke PreventionSecondary Stroke PreventionASA 2006 RecommendationsASA 2006 Recommendations

• Insufficient data are available to make evidence-based recommendations regarding choices between antiplatelet options other than aspirin. Selection of an antiplatelet agent should be individualized based on patient risk factor profiles, tolerance, and other clinical characteristics.


• The addition of aspirin to clopidogrel increases the risk of hemorrhage and is not routinely recommended for stroke or TIA patients (Class III, Evidence A).

• For patients allergic to aspirin, clopidogrel is recommended (Class IIa, Evidence B).

MATCH: Safety OutcomesMATCH: Safety Outcomes

• Excess life-threatening bleeding events with combination versus clopidogrel monotherapy:

96 (2.6%) vs. 49 (1.3%); p<0.0001

• Excess minor bleeds with combination therapy versus clopidogrel alone:

120 (3.2%) vs. 39 (1.0%); p<0.0001

Diener H-C et al. Lancet 2004;364:331-7


• For patients who have an ischemic cerebrovascular event while taking aspirin, there is no reliable evidence that increasing the dose of aspirin provides additional benefit. Although alternative antiplatelet agents are often considered for these patients, no single agent or combination has been specifically evaluated in patients who have had an event while receiving aspirin.

Stroke and Pregnancy Stroke and Pregnancy ASA 2006 Secondary Stroke RecsASA 2006 Secondary Stroke Recs

• High-risk thromboembolic conditions consider: - adjusted-dose UFH throughout pregnancy, - adjusted-dose LMWH with Factor Xa monitoring - UFH or LMWH until week 13, followed by warfarin until mid-3rd trimester, then UFH or LMWH in last trimester (Class IIb, Evidence C).

• Lower risk conditions - UFH or LMWH in the first trimester followed

by - low-dose aspirin for the remainder of the pregnancy (Class IIb, Evidence C).

Postmenopausal Hormones Postmenopausal Hormones ASA 2006 Secondary Stroke Recs ASA 2006 Secondary Stroke Recs

For women with ischemic stroke or TIA, postmenopausal hormone therapy (with estrogen with or without a progestin) is not recommended (Class III, Evidence A).

Women’s Health InitiativeWomen’s Health Initiative • 16,608 postmenopausal women, 50-79 years, with an intact uterus at baseline were recruited by 40 U.S. clinical centers for the period 1993-1998.

• Received conjugated equine estrogens, 0.625 mg/d, plus medroxyprogesterone acetate, 2.5 mg/d, in 1 tablet (n = 8506) or placebo (n = 8102).

• After a mean of 5.2 years of follow-up, the trial was stopped because of high rates of invasive breast cancer and the global index statistic supported risks exceeding benefits.

Rossouw et al. JAMA 2002;288(3):321-33

Other CircumstancesOther CircumstancesASA 2006 Secondary Stroke RecsASA 2006 Secondary Stroke Recs

• Dissections

• PFO and hyperhomocysteinemia

• Hypercoagulable states

• Sickle cell disease

• Cerebral venous thrombosis

• Anticoagulation after cerebral hemorrhage

Level A RecommendationsLevel A Recommendations

• Antihypertensive treatment

• Glucose control to reduce microvascular complications of diabetes

• Statins to reduce LDL to <100 or <70 for high-risk patients (sympt CHD or athero)

• CEA for sympt 50-99%

• NO CEA for <50% sympt stenosis

• Warfarin at INR 2.5 for Afib. (ASA if unable)

• Antiplatelet for noncardioembolic

• NO combination clopidogrel and ASA

Carotid Angioplasty and StentingCarotid Angioplasty and StentingASA 2006 Secondary Stroke RecsASA 2006 Secondary Stroke Recs

• CAS may be considered (Class IIb, Evidence B). - Stenosis (>70%) difficult to access surgically - Medical conditions that greatly increase the

risk for surgery, or - When other circumstances exist such as radiation-induced stenosis or restenosis after CEA.

• CAS is reasonable when performed by operators with morbidity and mortality rates of 4% to 6% (Class IIa, Evidence B).

Other CircumstancesOther CircumstancesASA 2006 Secondary Stroke RecsASA 2006 Secondary Stroke Recs

• Dissections

• PFO and hyperhomocysteinemia

• Hypercoagulable states

• Sickle cell disease

• Cerebral venous thrombosis

• Anticoagulation after cerebral hemorrhage

Level A RecommendationsLevel A Recommendations• Antihypertensive treatment

• Glucose control to reduce microvascular complications of diabetes

• Statins to reduce LDL to <100 or <70 for high-risk patients (sympt CHD or athero)

• CEA for sympt 50-99%

• NO CEA for <50% sympt stenosis

• Warfarin at INR 2.5 for Afib. (ASA if unable)

• Antiplatelet for noncardioembolic

• NO combination clopidogrel and ASA

PROGNOSTIC PEARLSPROGNOSTIC PEARLS

Flaccid Paralysis for more than 96 hrsFlaccid Paralysis for more than 96 hrs When tendon reflexes recover without return of voluntary When tendon reflexes recover without return of voluntary

movement – prognosis poormovement – prognosis poor Recovery of sensory less in usual to a degree. Postion Recovery of sensory less in usual to a degree. Postion

sense recovers but not pain and temperature sense recovers but not pain and temperature Recovery from Dysphasia is never complete Recovery from Dysphasia is never complete Dysarthria usual improves and Dysphagia never improvesDysarthria usual improves and Dysphagia never improves Diplopia due to brain stem is usually permanentDiplopia due to brain stem is usually permanent Conjugate gaze – recoversConjugate gaze – recovers Vertigo improves but hearing loss is permanentVertigo improves but hearing loss is permanent Pseudobulbar palsy permanentPseudobulbar palsy permanent

“By Nature All Men/ Women are alike butby Education widely different”

CVD – Prevention or Cure?CVD – Prevention or Cure?

While number of curative While number of curative methods are available, methods are available, preventive therapy is preventive therapy is

undoubtedly the main strategy undoubtedly the main strategy in the management of CVDin the management of CVD

Lijec Vjesn. 2003 Nov-Dec;125(11-12):322-8

The sign wasn’t placed there

By the Big Printer in the sky

Dedicated to my family for Dedicated to my family for making everything worthwhile making everything worthwhile

READ not to contradict or confute

Nor to Believe and Take for Granted

but TO WEIGH AND CONSIDER

THANK YOUMy sincere thanks to Serdia pharmaceuticalsMy sincere thanks to Serdia pharmaceuticals

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Stroke prevention a reality in this millennium

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