Brain Attack!Brain Attack! Stroke is a “Brain Attack.”Stroke is a “Brain Attack.”
Stroke happens in the brain not Stroke happens in the brain not the heartthe heart
Stroke is an emergency. Call Stroke is an emergency. Call 911 for emergency treatment.911 for emergency treatment.
Secondary Stroke Prevention
Gregory T. Gardziola, D.O
Director Cerebrovascular Disease
Greenville Health Systems
Greenville, South Carolina
What is a Stroke?What is a Stroke?
Ischemic Stroke – Blockage of a blood Ischemic Stroke – Blockage of a blood vessel resulting in death of brain tissuevessel resulting in death of brain tissue
Transient Ischemic Attack – transient Transient Ischemic Attack – transient blockage of a vessel that results in no blockage of a vessel that results in no permanent damagepermanent damage
Hemorrhagic Stroke – blood outside a Hemorrhagic Stroke – blood outside a vesselvessel
Stroke SubtypesStroke Subtypes
ICH13%
SAH13%
Lacunar19%
Thromboembolic6%
Cardioembolic14%
Other 3%
Unknown32%
Ischemic 71%
Hemorrhagic 26%
Data from NINCDS Stroke Data Bank: Foulkes et al. Stroke. 1988;19:547.
The High Socioeconomic Cost The High Socioeconomic Cost of Strokeof Stroke
Morbidity and MortalityMorbidity and Mortality A leading cause of serious, long-term disabilityA leading cause of serious, long-term disability11
700,000 new or recurrent strokes occur per year 700,000 new or recurrent strokes occur per year in the USin the US1,21,2
The third leading cause of death in the USThe third leading cause of death in the US, stroke , stroke accounted for 167,661 deaths in 2002accounted for 167,661 deaths in 200211; second ; second leading cause worldwideleading cause worldwide33
Economic ImpactEconomic Impact Total direct and indirect costs exceed $51 billion Total direct and indirect costs exceed $51 billion
annuallyannually11
Per stroke, the cost of care and treatment exceeds Per stroke, the cost of care and treatment exceeds $44,000 and the cost of lost productivity $44,000 and the cost of lost productivity approaches $29,000approaches $29,0001,21,2
1 American Heart Association, Heart Disease and Stroke Statistics – 2003 Update.2 Broderick J, et al. Stroke. 1998; 29:415-421.
Risk Factors for Stroke: Risk Factors for Stroke: Non-modifiableNon-modifiable
AgeAge
GenderGender
Race-EthnicityRace-Ethnicity
GeneticsGenetics
Stroke Risk FactorsStroke Risk Factors
Age – doubles per decade over 55 yearsAge – doubles per decade over 55 years Sex – 24-30% greater in menSex – 24-30% greater in men Race Race
2.4 fold increase in African Americans2.4 fold increase in African Americans 2.0 fold increase in Hispanics2.0 fold increase in Hispanics Increase among ChineseIncrease among Chinese
Heredity – 1.9 fold increase in first Heredity – 1.9 fold increase in first degree relativesdegree relatives
InroductionInroduction
24-30% greater in men24-30% greater in men 2.4 fold increase in African Americans2.4 fold increase in African Americans 2.0 increase in Hispanics2.0 increase in Hispanics
ModifiableModifiable RiskRisk FactorsFactors ForFor StrokeStroke
SmokingSmoking
DietDiet
AlcoholAlcohol
ExerciseExercise
Contribution of Selected Risk Contribution of Selected Risk Factors Factors
to Stroke Incidence to Stroke Incidence
HypertensionHypertension 3.0 3.0 – – 5.05.0 25 – 56 25 – 56Cardiac diseaseCardiac disease 2.0 2.0 – – 4.04.0 10 – 20 10 – 20Atrial fibrillationAtrial fibrillation 5.0 5.0 – – 18.018.0 1 – 2 1 – 2Diabetes mellitusDiabetes mellitus 1.5 1.5 – – 3.03.0 4 – 8 4 – 8Cigarette smokingCigarette smoking 1.5 1.5 – – 3.03.0 20 – 40 20 – 40Heavy alcohol useHeavy alcohol use 1.0 1.0 – – 4.04.0 5 – 30 5 – 30
Adapted from Sacco. In: Gorelick and Alter (eds). Handbook of Neuroepidemiology. New York: Marcel Dekker, Inc; 1994:87, with data from Feinberg. Curr Opin Neurol. 1996;9:46; Gorelick. Stroke. 1994;25:222.
Risk Factor RR Prevalence (%)
HypertensionHypertension
Affects 50 million people in the USAffects 50 million people in the US BP of 140/90 or greaterBP of 140/90 or greater Prehypertension 120-139/80-89Prehypertension 120-139/80-89 Causes shear forces predisposing to Causes shear forces predisposing to
atheroma formation and athersosclerosisatheroma formation and athersosclerosis 38% fewer strokes in patients with 10-12 38% fewer strokes in patients with 10-12
mmHg SBP decrease and 5-6 mmHG DBP mmHg SBP decrease and 5-6 mmHG DBP reductionreduction
HypertensionHypertension
PROGRESS TrialPROGRESS Trial 6105 patients, recent stroke or TIA6105 patients, recent stroke or TIA Perindopril +/- indapamide or placeboPerindopril +/- indapamide or placebo 28% stroke risk reduction with a mean 9/4 28% stroke risk reduction with a mean 9/4
mmHg reduction in the perindopril treated mmHg reduction in the perindopril treated group during 4 years of follow up group during 4 years of follow up
HypertensionHypertension
HOPE TrialHOPE Trial 9297 patients with high cardiovascular risk, 9297 patients with high cardiovascular risk,
1013 with stroke or TIA1013 with stroke or TIA Randomized to ramapril 10 mg/day or Randomized to ramapril 10 mg/day or
placeboplacebo 32% RRR for stroke with a mean of 3/2 BP 32% RRR for stroke with a mean of 3/2 BP
reduction over 5 years of followupreduction over 5 years of followup
HypertensionHypertension
LIFE TrialLIFE Trial 9193 patients with hypertension and LVH9193 patients with hypertension and LVH Losartan50-100 mg/day or atenolol Losartan50-100 mg/day or atenolol All received HCTZ 12.5-25 mg/dayAll received HCTZ 12.5-25 mg/day 25% hazard reduction in stroke, no difference 25% hazard reduction in stroke, no difference
in mean BP reductionin mean BP reduction
Effect of Blood Pressure Effect of Blood Pressure Control on Incidence of Control on Incidence of
StrokeStroke
6 mm Hg decrease in diastolic blood pressure
Antihypertensive stepped-care drug treatment of isolated systolic hypertension
Blood pressure reduction in the elderly
40% reduction in incidence of stroke
36% reduction in incidence of stroke
47% reduction in incidence of stroke
Adapted from: MacMahon S. Clin Exp Hyperten[A]. 1989;A11.Adapted from: SHEP Cooperative Research Group. JAMA. 1991;265.
Original Article High-Dose Atorvastatin after Stroke or Transient
Ischemic Attack
The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Investigators
N Engl J MedVolume 355(6):549-559
August 10, 2006
Study OverviewStudy Overview In this five-year placebo-controlled trial In this five-year placebo-controlled trial
involving patients who had a recent stroke involving patients who had a recent stroke or transient ischemic attack and baseline or transient ischemic attack and baseline low-density lipoprotein cholesterol levels of low-density lipoprotein cholesterol levels of 100 to 190 mg per deciliter (3 to 5 mmol 100 to 190 mg per deciliter (3 to 5 mmol per liter), atorvastatin (80 mg daily) per liter), atorvastatin (80 mg daily) resulted in an absolute reduction in nonfatal resulted in an absolute reduction in nonfatal or fatal stroke of 2.2 percent and of major or fatal stroke of 2.2 percent and of major cardiovascular events of 3.5 percentcardiovascular events of 3.5 percent
Baseline Characteristics of the Patients
The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Investigators. N Engl J Med 2006;355:549-559
Kaplan-Meier Curves for Stroke and TIA
The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Investigators. N Engl J Med 2006;355:549-559
Incidence of Adverse Events and Elevated Laboratory Values
The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Investigators. N Engl J Med 2006;355:549-559
ConclusionConclusion
In patients with recent stroke or TIA In patients with recent stroke or TIA and without known coronary heart and without known coronary heart disease, 80 mg of atorvastatin per day disease, 80 mg of atorvastatin per day reduced the overall incidence of strokes reduced the overall incidence of strokes and of cardiovascular events, despite a and of cardiovascular events, despite a small increase in the incidence of small increase in the incidence of hemorrhagic strokehemorrhagic stroke
Cigarette SmokingCigarette Smoking
Contributes to over 400,000 deaths Contributes to over 400,000 deaths related to vascular diseaserelated to vascular disease
Overall stroke risk increase of 50% over Overall stroke risk increase of 50% over nonsmokersnonsmokers
Endothelial damage predisposing to Endothelial damage predisposing to atherosclerosisatherosclerosis
Enhanced platelet aggregation, increased Enhanced platelet aggregation, increased fibrinogen, vasoconstrictionfibrinogen, vasoconstriction
Lightwood JM, Glantz SA. Circulation. 1997;96:1089-1096.
Benefits of Smoking Benefits of Smoking CessationCessation
150 200 2500 50 100
0
1
2
3
4
Est
imat
ed R
elat
ive
Ris
k o
f S
tro
ke
Months
ExerciseExercise
May decrease stroke risk by lowering May decrease stroke risk by lowering blood pressure, increasing HDL blood pressure, increasing HDL cholesterol, promot weight reduction, cholesterol, promot weight reduction, help manage blood sugarshelp manage blood sugars
Exercise at least 30 minutes per dayExercise at least 30 minutes per day Dose response for intensity and durationDose response for intensity and duration 63% odds reduction for stroke with 63% odds reduction for stroke with
regular exerciseregular exercise
Matching for Age, Gender, and Race and Adjusting for HTN, DM, PVD, Smoking, Cardiac Disease, Obesity, Heavy Alcohol, Activities Limited for Medical Reasons, Education
Sacco RL et al. Stroke. 1998;29:380-387.
Physical Activity and Physical Activity and Ischemic Stroke—Ischemic Stroke—
Northern Manhattan Stroke Northern Manhattan Stroke StudyStudy
0
0.2
0.4
0.6
0.8
1
None Any
Od
ds
Rat
io
Physical Activity
0.38
1.0
Gorelick, PB. Stroke Prevention. Arch Neurol. 1995;52:347-355.
Stroke Prevention: Stroke Prevention: How Many Strokes in the How Many Strokes in the
United States Can Be United States Can Be Prevented?Prevented?
0 50,000 100,000 150,000 200,000 250,000
Number of Strokes Prevented
23,500
47,000
61,500
100,000
246,500
Heavy alcohol use
Atrial fibrillation
Cigarettes
Cholesterol
Hypertension
Mechanisms of Action of Mechanisms of Action of Antiplatelet AgentsAntiplatelet Agents
AspirinTiclopidine/Clopidogrel
Dipyridamole
Inhibition of plateletactivation and aggregation
Block ADP
receptors
Inhibitscyclooxygenase and
thromboxane A2
Increasesplasma
adenosine
Inhibits platelet
phosphodiesterase
CAPRIE
CAPRIE Study: Efficacy*CAPRIE Study: Efficacy*
† 2-year study, N = 19,185, endpoint incidence calculated per year.‡ P < 0.05
Endpoint†
Stroke
Stroke, MI, orvascular death
RRRStroke Patients
8.0%
7.3%
MIPatients
–1.0%
–3.7%
PAD Patients
1.2%
23.8%‡
Total
6.1%
8.7%‡
CAPRIE Steering Committee. Lancet. 1996;348:1329.
* Clopidogrel (75 mg qd) vs ASA (325 mg qd).
ESPS 2ESPS 2
ESPS-2: The Second ESPS-2: The Second European Stroke Prevention European Stroke Prevention
Study Study Tested efficacy of ASA/ER-DP for secondary Tested efficacy of ASA/ER-DP for secondary
stroke preventionstroke prevention
Addressed clinical questionsAddressed clinical questions Does low-dose ASA prevent stroke?Does low-dose ASA prevent stroke? Does ER-DP prevent stroke?Does ER-DP prevent stroke? Is ASA/ER-DP superior to ASA alone? To Is ASA/ER-DP superior to ASA alone? To
ER-DP alone?ER-DP alone? Is ASA/ER-DP well tolerated?Is ASA/ER-DP well tolerated?
The ESPS-2 Group. J Neurol Sci. 1997;151:S3. Diener et al. J Neurol Sci. 1996;143:1.
ESPS-2: EndpointsESPS-2: Endpoints
Primary endpointsPrimary endpoints Stroke (any type, fatal or Stroke (any type, fatal or
nonfatal)nonfatal) Death from any causeDeath from any cause
Selected secondary endpointSelected secondary endpoint Ischemic events Ischemic events
(stroke, MI, or sudden death)(stroke, MI, or sudden death)
ESPS-2: Treatment ArmsESPS-2: Treatment Arms
N = 6,602N = 6,602N = 6,602N = 6,602
PlaceboPlacebo
(n = 1,649)
ER-DPER-DP200 mg bid200 mg bid
(n = 1,654)
ASAASA25 mg bid25 mg bid
(n = 1,649)
ASA/ER-DPASA/ER-DP25 mg ASA/25 mg ASA/
200 mg ER-DP 200 mg ER-DP bidbid
(n = 1,650)
ESPS 2: Effects on Stroke—ESPS 2: Effects on Stroke—Relative Risk ReductionRelative Risk Reduction
(Pairwise Comparisons)(Pairwise Comparisons)
ER-DP = Extended-Release DipyridamoleASA = Acetylsalicylic Acid
RRR = Relative Risk Reduction
15 ESPS 2 Group. J Neurol Sci. 1997; 151(suppl):S1-S77.
37.0%P < 0.001
16.3%P = 0.039
18.1%P = 0.013
23.1%P = 0.006
0.0%
5.0%
10.0%
15.0%
20.0%
25.0%
30.0%
35.0%
40.0%
RRR
ASA/ER-DP vs. Placebo
ER-DP vs. Placebo
ASA vs. Placebo
ASA/ER-DP vs. ASA
ESPS 2: Adverse EventsESPS 2: Adverse Events(Percent within each group)(Percent within each group)
ER-DP = Extended-Release DipyridamoleASA = Acetylsalicylic Acid
Treatment group Dyspepsia GI Bleeding Headache
ASA/ER-DP
Placebo
ASA
ER-DP
18.4
16.7
18.1
17.4
4.1
2.1
3.2
2.2
39.2
32.9
33.8
38.3
*Not statistically different from aspirin
*
19 Aggrenox® (aspirin/extended-release dipyridamole) 25 mg/200 mg capsules product information, Boehringer Ingelheim Pharmaceuticals, Inc.
ESPS 2: SafetyESPS 2: Safety Severe or Fatal Bleeding Severe or Fatal Bleeding
ASA
20
(1.2%)
ER-DP
6
(0.4%)
ERDP+ASA
27(1.6%)
Placebo
7
(0.4%)
n.s.
ER-DP = Extended-Release DipyridamoleASA = Acetylsalicylic Acid
15 ESPS 2 Group. J Neurol Sci. 1997; 151(suppl):S1-S77.
MATCHMATCH
To be eligible for the study the patient must :
1) Have experienced a TIA or IS within the last 3 months (randomization as soon as possible after the qualifying event)
and
2) Have at least 1 additional vascular risk factor within the previous 3 yrs
• previous IS
• previous MI
• angina pectoris
• symptomatic PAD
• diabetes mellitus
and
3) Meet no exclusion criteriaDiener H-C et al on behalf of the MATCH Investigators. Cerebrovasc Dis. 2004;17:253-261.PLAVIX backup slide.
MATCH
Inclusion CriteriaInclusion Criteria
The following patients were excluded from the The following patients were excluded from the MATCH trial if they met any of the following MATCH trial if they met any of the following criteria:criteria:
Age < 40 yearsAge < 40 years Severe co-morbid conditionsSevere co-morbid conditions At risk of increased bleedingAt risk of increased bleeding Scheduled for major surgery or vascular Scheduled for major surgery or vascular surgerysurgery Have a contraindication for ASA or Have a contraindication for ASA or clopidogrelclopidogrelDiener H-C et al on behalf of the MATCH Investigators. Cerebrovasc Dis. 2004;17:253-261.
PLAVIX backup slide.
MATCH
Exclusion CriteriaExclusion Criteria
MATCHMATCHPrimary EndpointPrimary Endpoint
16.7 15.7
0
5
10
15
20
%
C C+A
Stroke, MI, Vascular Death, Rehospitalization
RRR = 6.4% p=.244
MATCHMATCH
1.3
2.6
0.6
1.9
0
0.5
1
1.5
2
2.5
3
%
Life-threatening Major
Hemorrhage Rates
C
C+A
p< 0.001
p <0.001
Clopidogrel in Clopidogrel in Unstable Angina to Unstable Angina to Prevent Recurrent Prevent Recurrent
Events StudyEvents StudyCURECURE
Original Article Aspirin and Extended-Release Dipyridamole versus
Clopidogrel for Recurrent Stroke
Ralph L. Sacco, M.D., Hans-Christoph Diener, M.D., Ph.D., Salim Yusuf, M.B., B.S., D.Phil., Daniel Cotton, M.S., Stephanie Ôunpuu, Ph.D., William A. Lawton, B.A., Yuko
Palesch, Ph.D., Reneé H. Martin, Ph.D., Gregory W. Albers, M.D., Philip Bath, F.R.C.P., Natan Bornstein, M.D., Bernard P.L. Chan, M.D., Sien-Tsong Chen, M.D.,
Luis Cunha, M.D., Ph.D., Björn Dahlöf, M.D., Ph.D., Jacques De Keyser, M.D., Ph.D., Geoffrey A. Donnan, M.D., Conrado Estol, M.D., Ph.D., Philip Gorelick, M.D., Vivian
Gu, M.D., Karin Hermansson, D.M.Sc., Lutz Hilbrich, M.D., Markku Kaste, M.D., Ph.D., Chuanzhen Lu, M.D., Thomas Machnig, M.D., Prem Pais, M.D., Robin Roberts, M.Tech., Veronika Skvortsova, M.D., Philip Teal, M.D., Danilo Toni, M.D., Cam
VanderMaelen, Ph.D., Thor Voigt, M.D., Michael Weber, M.D., Byung-Woo Yoon, M.D., Ph.D., for the PRoFESS Study Group
N Engl J MedVolume 359(12):1238-1251
September 18, 2008
Study Overview
In this large clinical trial, aspirin plus In this large clinical trial, aspirin plus extended-release dipyridamole was extended-release dipyridamole was found to have an efficacy similar to that found to have an efficacy similar to that of clopidogrel in the prevention of of clopidogrel in the prevention of recurrent strokerecurrent stroke
However, aspirin plus extended-release However, aspirin plus extended-release dipyridamole resulted in more bleeding, dipyridamole resulted in more bleeding, including intracranial bleedingincluding intracranial bleeding
The results will help guide therapy for The results will help guide therapy for secondary stroke preventionsecondary stroke prevention
Kaplan-Meier Estimates of the Cumulative Probability of Primary and Secondary Outcomes, According to Treatment Group
Sacco RL et al. N Engl J Med 2008;359:1238-1251
Hazard Ratios for Primary, Secondary, and Key Tertiary Efficacy and Safety Outcomes
Sacco RL et al. N Engl J Med 2008;359:1238-1251
Hazard Ratios for the Primary Outcome of First Recurrence of Stroke, According to Prespecified and Post Hoc Baseline Characteristics
Sacco RL et al. N Engl J Med 2008;359:1238-1251
Conclusion
The trial did not meet the predefined The trial did not meet the predefined criteria for noninferiority but showed criteria for noninferiority but showed similar rates of recurrent stroke with similar rates of recurrent stroke with ASA-ERDP and with clopidogrelASA-ERDP and with clopidogrel
There is no evidence that either of the There is no evidence that either of the two treatments was superior to the two treatments was superior to the other in the prevention of recurrent other in the prevention of recurrent strokestroke
Original Article Thrombolysis with Alteplase 3 to 4.5 Hours after
Acute Ischemic Stroke
Werner Hacke, M.D., Markku Kaste, M.D., Erich Bluhmki, Ph.D., Miroslav Brozman, M.D., Antoni Dávalos, M.D., Donata Guidetti, M.D., Vincent Larrue, M.D., Kennedy R.
Lees, M.D., Zakaria Medeghri, M.D., Thomas Machnig, M.D., Dietmar Schneider, M.D., Rüdiger von Kummer, M.D., Nils Wahlgren, M.D., Danilo Toni, M.D., for the
ECASS Investigators
N Engl J MedVolume 359(13):1317-1329
September 25, 2008
Study Overview
Intravenous thrombolysis with alteplase Intravenous thrombolysis with alteplase improves the outcomes after acute stroke improves the outcomes after acute stroke when alteplase is given within 3 hours when alteplase is given within 3 hours after the onset of symptomsafter the onset of symptoms
In this randomized trial involving In this randomized trial involving patients who presented between 3 and patients who presented between 3 and 4.5 hours after the onset of stroke, 4.5 hours after the onset of stroke, clinical outcomes were modestly better clinical outcomes were modestly better in patients treated with alteplase than in in patients treated with alteplase than in patients given placebo (favorable patients given placebo (favorable outcome in 52% vs. 45% of patients)outcome in 52% vs. 45% of patients)
Numbers of Patients Who Were Enrolled, Randomly Assigned to a Study Group, and Included in the Per-Protocol Population
Hacke W et al. N Engl J Med 2008;359:1317-1329
Demographic and Baseline Characteristics of the Patients
Hacke W et al. N Engl J Med 2008;359:1317-1329
Major Inclusion and Exclusion Criteria
Hacke W et al. N Engl J Med 2008;359:1317-1329
Odds Ratios for Primary End Point and Secondary End Point, Including Components, in the Intention-to-Treat and Per-Protocol Populations at 90 Days
Hacke W et al. N Engl J Med 2008;359:1317-1329
Conclusion
As compared with placebo, intravenous As compared with placebo, intravenous alteplase administered between 3 and alteplase administered between 3 and 4.5 hours after the onset of symptoms 4.5 hours after the onset of symptoms significantly improved clinical outcomes significantly improved clinical outcomes in patients with acute ischemic stroke; in patients with acute ischemic stroke; alteplase was more frequently alteplase was more frequently associated with symptomatic associated with symptomatic intracranial hemorrhageintracranial hemorrhage
In SummaryIn Summary
Stroke is a heterogenous disorder Stroke is a heterogenous disorder with multiple risk factorswith multiple risk factors
Risk factor modification can have Risk factor modification can have significant impact on stroke risk significant impact on stroke risk reduction. This can be prescriptive or reduction. This can be prescriptive or lifestyle changes or a combinationlifestyle changes or a combination
Stroke identification is important if Stroke identification is important if we wish to treat stroke acutelywe wish to treat stroke acutely
Thank You