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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
PROGRESS collaborative group. Lancet 2001;358:1033-41.
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
PROGRESS collaborative group. Lancet 2001;358:1033-41.
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%
PROGRESS collaborative group. Lancet 2001;358:1033-41.
Stroke subtype Stroke subtype (1)(1)
Risk reduction (%)Risk reduction (%)
Fatal / Fatal / disabling strokedisabling stroke
Non fatal / Non fatal / disabling strokedisabling stroke
33332424
PROGRESS collaborative group. Lancet 2001;358:1033-41.
Stroke subtype Stroke subtype (2)(2)
Risk reduction (%)Risk reduction (%)
Ischaemic Ischaemic
strokestroke
Haemorrhagic Haemorrhagic strokestroke
5050
2424
PROGRESS collaborative group. Lancet 2001;358:1033-41.
Hypertensives / normotensivesHypertensives / normotensives
Risk reduction (%)Risk reduction (%)
StrokeStroke
HypertensivesHypertensives
3232
2727
NormotensivesNormotensives
PROGRESS collaborative group. Lancet 2001;358:1033-41.
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 collaborative group. Lancet 2001;358:1033-41.
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
PROGRESS collaborative group. Lancet 2001;358:1033-41.
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
JUPITER: ResultsJUPITER: Results
48%
Reduction
Circulation 2010;121:143-150
30
58
0
10
20
30
40
50
60
Rosuvastatin Placebo
No. of patients with non-fatal stroke
n=8901 n=8901
*
* p< 0.003 vs. placebo
JUPITER: ResultsJUPITER: Results
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
Rosuvastatin Placebo
JUPITER: ResultsJUPITER: Results
48%
Reduction
Circulation 2010;121:143-150
No. of patients with ischemic stroke
n=8901 n=8901
*
* p< 0.004 vs. placebo
23
47
05
101520253035404550
Rosuvastatin Placebo
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.
Secondary Stroke PreventionSecondary Stroke PreventionASA 2006 RecommendationsASA 2006 Recommendations
• 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
Secondary Stroke PreventionSecondary Stroke PreventionASA 2006 RecommendationsASA 2006 Recommendations
• 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