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Brain Attack!

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!

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  1. 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.

  2. 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

  3. 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.

  4. 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.

  5. Risk Factors for Stroke: Non-modifiable • Age • Gender • Race-Ethnicity • Genetics

  6. 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

  7. Inroduction • 24-30% greater in men • 2.4 fold increase in African Americans • 2.0 increase in Hispanics

  8. ModifiableRiskFactorsForStroke • Smoking • Diet • Alcohol • Exercise

  9. 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.

  10. 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

  11. 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

  12. 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

  13. 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

  14. 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.

  15. 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

  16. 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

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

  18. 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

  19. 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

  20. 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

  21. 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

  22. 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.

  23. 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

  24. 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.

  25. 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.

  26. 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

  27. CAPRIE

  28. 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.

  29. ESPS 2

  30. 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.

  31. 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)

  32. 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)

  33. 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.

  34. 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.

  35. 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.

  36. MATCH

  37. 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.

  38. 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.

  39. MATCHPrimary Endpoint RRR = 6.4% p=.244

  40. MATCH p< 0.001 p <0.001

  41. Clopidogrel in Unstable Angina to Prevent Recurrent Events Study CURE

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