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Brain Attack!. Secondary Stroke Prevention Gregory T. Gardziola, D.O Director Cerebrovascular Disease Greenville Health Systems Greenville, South Carolina. Stroke is a “Brain Attack.” Stroke happens in the brain not the heart Stroke is an emergency. Call 911 for emergency treatment.

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Brain attack l.jpg
Brain Attack!

Secondary Stroke Prevention

Gregory T. Gardziola, D.O

Director Cerebrovascular Disease

Greenville Health Systems

Greenville, South Carolina

  • Stroke is a “Brain Attack.”

  • Stroke happens in the brain not the heart

  • Stroke is an emergency. Call 911 for emergency treatment.


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What is a Stroke?

  • Ischemic Stroke – Blockage of a blood vessel resulting in death of brain tissue

  • Transient Ischemic Attack – transient blockage of a vessel that results in no permanent damage

  • Hemorrhagic Stroke – blood outside a vessel


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Stroke Subtypes

Lacunar

19%

Thromboembolic

6%

SAH

13%

Cardioembolic

14%

Hemorrhagic 26%

Ischemic 71%

ICH

13%

Unknown

32%

Other 3%

Data from NINCDS Stroke Data Bank: Foulkes et al. Stroke. 1988;19:547.


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The High Socioeconomic Cost of Stroke

Morbidity and Mortality

  • A leading cause of serious, long-term disability1

  • 700,000 new or recurrent strokes occur per year in the US1,2

  • The third leading cause of death in the US, stroke accounted for 167,661 deaths in 20021; second leading cause worldwide3

    Economic Impact

  • Total direct and indirect costs exceed $51 billion annually1

  • Per stroke, the cost of care and treatment exceeds $44,000 and the cost of lost productivity approaches $29,0001,2

1 American Heart Association, Heart Disease and Stroke Statistics – 2003 Update.

2 Broderick J, et al. Stroke. 1998; 29:415-421.


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Risk Factors for Stroke: Non-modifiable

  • Age

  • Gender

  • Race-Ethnicity

  • Genetics


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Stroke Risk Factors

  • Age – doubles per decade over 55 years

  • Sex – 24-30% greater in men

  • Race

    • 2.4 fold increase in African Americans

    • 2.0 fold increase in Hispanics

    • Increase among Chinese

  • Heredity – 1.9 fold increase in first degree relatives


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Inroduction

  • 24-30% greater in men

  • 2.4 fold increase in African Americans

  • 2.0 increase in Hispanics


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ModifiableRiskFactorsForStroke

  • Smoking

  • Diet

  • Alcohol

  • Exercise


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Contribution of Selected Risk Factors to Stroke Incidence

Hypertension 3.0 – 5.0 25 – 56

Cardiac disease 2.0 – 4.0 10 – 20

Atrial fibrillation 5.0 – 18.0 1 – 2

Diabetes mellitus 1.5 – 3.0 4 – 8

Cigarette smoking 1.5 – 3.0 20 – 40

Heavy alcohol use 1.0 – 4.0 5 – 30

Risk Factor RR Prevalence (%)

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.


Hypertension l.jpg
Hypertension

  • Affects 50 million people in the US

  • BP of 140/90 or greater

  • Prehypertension 120-139/80-89

  • Causes shear forces predisposing to atheroma formation and athersosclerosis

  • 38% fewer strokes in patients with 10-12 mmHg SBP decrease and 5-6 mmHG DBP reduction


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Hypertension

PROGRESS Trial

  • 6105 patients, recent stroke or TIA

  • Perindopril +/- indapamide or placebo

  • 28% stroke risk reduction with a mean 9/4 mmHg reduction in the perindopril treated group during 4 years of follow up


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Hypertension

  • HOPE Trial

    • 9297 patients with high cardiovascular risk, 1013 with stroke or TIA

    • Randomized to ramapril 10 mg/day or placebo

    • 32% RRR for stroke with a mean of 3/2 BP reduction over 5 years of followup


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Hypertension

  • LIFE Trial

    • 9193 patients with hypertension and LVH

    • Losartan50-100 mg/day or atenolol

    • All received HCTZ 12.5-25 mg/day

    • 25% hazard reduction in stroke, no difference in mean BP reduction


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Effect of Blood Pressure Control on Incidence of Stroke

6 mm Hg decrease in diastolic blood pressure

40% reduction in incidence of stroke

Antihypertensive stepped-care drug treatment of isolated systolic hypertension

36% reduction in incidence of stroke

Blood pressure reduction in the elderly

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.


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Original ArticleHigh-Dose Atorvastatin after Stroke or Transient Ischemic Attack

The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Investigators

N Engl J Med

Volume 355(6):549-559

August 10, 2006


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Study Overview

  • In this five-year placebo-controlled trial involving patients who had a recent stroke or transient ischemic attack and baseline low-density lipoprotein cholesterol levels of 100 to 190 mg per deciliter (3 to 5 mmol per liter), atorvastatin (80 mg daily) resulted in an absolute reduction in nonfatal or fatal stroke of 2.2 percent and of major cardiovascular events of 3.5 percent


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Baseline Characteristics of the Patients

The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Investigators. N Engl J Med 2006;355:549-559


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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


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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


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Conclusion

  • In patients with recent stroke or TIA and without known coronary heart disease, 80 mg of atorvastatin per day reduced the overall incidence of strokes and of cardiovascular events, despite a small increase in the incidence of hemorrhagic stroke


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Cigarette Smoking

  • Contributes to over 400,000 deaths related to vascular disease

  • Overall stroke risk increase of 50% over nonsmokers

  • Endothelial damage predisposing to atherosclerosis

  • Enhanced platelet aggregation, increased fibrinogen, vasoconstriction


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Benefits of Smoking Cessation

4

3

Estimated Relative Risk of Stroke

2

1

0

0

50

100

150

200

250

Months

Lightwood JM, Glantz SA. Circulation. 1997;96:1089-1096.


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Exercise

  • May decrease stroke risk by lowering blood pressure, increasing HDL cholesterol, promot weight reduction, help manage blood sugars

  • Exercise at least 30 minutes per day

  • Dose response for intensity and duration

  • 63% odds reduction for stroke with regular exercise


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Physical Activity and Ischemic Stroke—Northern Manhattan Stroke Study

1.0

Odds Ratio

0.38

Physical Activity

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.


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Stroke Prevention: How Many Strokes in the United States Can Be Prevented?

Hypertension

246,500

Cholesterol

100,000

Cigarettes

61,500

Atrial fibrillation

47,000

Heavy alcohol use

23,500

0

50,000

100,000

150,000

200,000

250,000

Number of Strokes Prevented

Gorelick, PB. Stroke Prevention. Arch Neurol. 1995;52:347-355.


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Mechanisms of Action of Antiplatelet Agents

Ticlopidine/

Clopidogrel

Aspirin

Dipyridamole

Increases

plasma

adenosine

Inhibits

platelet

phosphodiesterase

Block

ADP

receptors

Inhibits

cyclooxygenase and thromboxane A2

Inhibition of platelet

activation and aggregation



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CAPRIE Study: Efficacy*

Endpoint†

Stroke

Stroke, MI, or

vascular death

RRR

Stroke

Patients

8.0%

7.3%

MI

Patients

–1.0%

–3.7%

PAD

Patients

1.2%

23.8%‡

Total

6.1%

8.7%‡

* Clopidogrel (75 mg qd) vs ASA (325 mg qd).

† 2-year study, N = 19,185, endpoint incidence calculated per year.

‡ P < 0.05

CAPRIE Steering Committee. Lancet. 1996;348:1329.



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ESPS-2: The Second European Stroke Prevention Study

  • Tested efficacy of ASA/ER-DP for secondary stroke prevention

  • Addressed clinical questions

    • Does low-dose ASA prevent stroke?

    • Does ER-DP prevent stroke?

    • Is ASA/ER-DP superior to ASA alone? To ER-DP alone?

    • 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.


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ESPS-2: Endpoints

Primary endpoints

  • Stroke (any type, fatal or nonfatal)

  • Death from any cause

    Selected secondary endpoint

  • Ischemic events (stroke, MI, or sudden death)


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ESPS-2: Treatment Arms

N = 6,602

ASA/ER-DP

25 mg ASA/

200 mg ER-DP

bid

(n = 1,650)

ASA

25 mg bid

(n = 1,649)

ER-DP

200 mg bid

(n = 1,654)

Placebo

(n = 1,649)


Esps 2 effects on stroke relative risk reduction pairwise comparisons l.jpg
ESPS 2: Effects on Stroke—Relative Risk Reduction(Pairwise Comparisons)

37.0%

P < 0.001

40.0%

35.0%

ASA/ER-DP vs. Placebo

30.0%

23.1%

P = 0.006

25.0%

18.1%

P = 0.013

ER-DP vs. Placebo

16.3%

P = 0.039

20.0%

ASA vs. Placebo

15.0%

10.0%

ASA/ER-DP vs. ASA

5.0%

0.0%

ER-DP = Extended-Release Dipyridamole

ASA = Acetylsalicylic Acid

RRR = Relative Risk Reduction

RRR

15 ESPS 2 Group. J Neurol Sci. 1997; 151(suppl):S1-S77.


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Treatment group

Dyspepsia

GI Bleeding

Headache

18.4

16.7

18.1

17.4

4.1

2.1

3.2

2.2

ASA/ER-DP

Placebo

ASA

ER-DP

39.2

32.9

33.8

38.3

*

*Not statistically different from aspirin

ESPS 2: Adverse Events(Percent within each group)

ER-DP = Extended-Release Dipyridamole

ASA = Acetylsalicylic Acid

19Aggrenox® (aspirin/extended-release dipyridamole) 25 mg/200 mg capsules product information, Boehringer Ingelheim Pharmaceuticals, Inc.


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ESPS 2: Safety Severe or Fatal Bleeding

Placebo

7

(0.4%)

ER-DP

6

(0.4%)

ASA

20

(1.2%)

ERDP+ASA

27

(1.6%)

n.s.

ER-DP = Extended-Release Dipyridamole

ASA = Acetylsalicylic Acid

15 ESPS 2 Group. J Neurol Sci. 1997; 151(suppl):S1-S77.



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MATCH

Inclusion Criteria

To be eligible for the study the patient must :

  • 1)Haveexperienced a TIAorIS within the last 3 months

  • (randomization as soon as possible after the qualifying event)

  • and

  • 2) Haveat 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 criteria

Diener H-C et al on behalf of the MATCH Investigators. Cerebrovasc Dis. 2004;17:253-261.PLAVIX backup slide.


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MATCH

Exclusion Criteria

The following patients were excluded from the MATCH trial if they met any of the following criteria:

  • Age < 40 years

  • Severe co-morbid conditions

  • At risk of increased bleeding

  • Scheduled for major surgery or vascular surgery

  • Have a contraindication for ASA or clopidogrel

Diener H-C et al on behalf of the MATCH Investigators. Cerebrovasc Dis. 2004;17:253-261.PLAVIX backup slide.


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MATCHPrimary Endpoint

RRR = 6.4% p=.244


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MATCH

p< 0.001

p <0.001



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Original Article StudyAspirin 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 Med

Volume 359(12):1238-1251

September 18, 2008


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Study Overview Study

  • In this large clinical trial, aspirin plus extended-release dipyridamole was found to have an efficacy similar to that of clopidogrel in the prevention of recurrent stroke

  • However, aspirin plus extended-release dipyridamole resulted in more bleeding, including intracranial bleeding

  • The results will help guide therapy for secondary stroke prevention


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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


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Hazard Ratios for Primary, Secondary, and Key Tertiary Efficacy and Safety Outcomes

Sacco RL et al. N Engl J Med 2008;359:1238-1251


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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


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Conclusion Stroke, According to Prespecified and Post Hoc Baseline Characteristics

  • The trial did not meet the predefined criteria for noninferiority but showed similar rates of recurrent stroke with ASA-ERDP and with clopidogrel

  • There is no evidence that either of the two treatments was superior to the other in the prevention of recurrent stroke


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Original Article Stroke, According to Prespecified and Post Hoc Baseline CharacteristicsThrombolysis 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 Med

Volume 359(13):1317-1329

September 25, 2008


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Study Overview Stroke, According to Prespecified and Post Hoc Baseline Characteristics

  • Intravenous thrombolysis with alteplase improves the outcomes after acute stroke when alteplase is given within 3 hours after the onset of symptoms

  • In this randomized trial involving patients who presented between 3 and 4.5 hours after the onset of stroke, clinical outcomes were modestly better in patients treated with alteplase than in patients given placebo (favorable outcome in 52% vs. 45% of patients)


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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


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Demographic and Baseline Characteristics of the Patients a Study Group, and Included in the Per-Protocol Population

Hacke W et al. N Engl J Med 2008;359:1317-1329


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Major Inclusion and Exclusion Criteria a Study Group, and Included in the Per-Protocol Population

Hacke W et al. N Engl J Med 2008;359:1317-1329


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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


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Conclusion Including Components, in the Intention-to-Treat and Per-Protocol Populations at 90 Days

  • As compared with placebo, intravenous alteplase administered between 3 and 4.5 hours after the onset of symptoms significantly improved clinical outcomes in patients with acute ischemic stroke; alteplase was more frequently associated with symptomatic intracranial hemorrhage


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In Summary Including Components, in the Intention-to-Treat and Per-Protocol Populations at 90 Days

  • Stroke is a heterogenous disorder with multiple risk factors

  • Risk factor modification can have significant impact on stroke risk reduction. This can be prescriptive or lifestyle changes or a combination

  • Stroke identification is important if we wish to treat stroke acutely


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Thank You Including Components, in the Intention-to-Treat and Per-Protocol Populations at 90 Days