Brain Attack! Stroke is a “Brain Attack.” Stroke happens in the brain not the heart Stroke is an emergency. Call 911 for emergency treatment. Secondary

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


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


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


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



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


Incidence of Adverse Events and Elevated Laboratory Values


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)


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.


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


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


Hazard Ratios for the Primary Outcome of First Recurrence of Stroke, According to Prespecified and Post Hoc Baseline Characteristics


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


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


Major Inclusion and Exclusion Criteria


Odds Ratios for Primary End Point and Secondary End Point, Including Components, in the Intention-to-Treat and Per-Protocol Populations at 90 Days


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

Documents

Brain Attack! Stroke is a “Brain Attack.” Stroke happens in the brain not the heart Stroke is an emergency. Call 911 for emergency treatment. Secondary