Update on the Primary Prevention of Ischemic Stroke AHA/ASA Guidelines

Jennifer M. Ferguson, MD

Objectives
1. The attendee should be able to identify the risk factors for ischemic stroke. 2. The attendee should be able to understand the current treatment guidelines for the modifiable risk factors: Hypertension, Diabetes, Dyslipidemia, Smoking, and Atrial Fibrillation. 3. The attendee should be able to understand the impact of lifestyle modification, diet, nutrition and weight control in the prevention of ischemic stroke.

Ischemic Stroke Causes

Large artery atherosclerosis 13% Small artery occlusion 23% Cardioembolism 27% Undetermined or Cryptogenic 35% Other 2%

Subtypes of brain ischemia

Thrombosis Embolism Hypoperfusion

Characteristics of Ischemic Stroke Subtypes

Thrombosis
Local obstruction of an artery (arteriosclerosis, dissection, fibromuscular dysplasia) Large or small vessel disease Symptoms often fluctuate, remit or progress in a stuttering fashion Particles of debris from another source (heart, aorta, large vessels) which blocks arterial access Symptoms abrupt and maximal at onset More global circulatory problem (brain or other organs) Reduced arterial blood flow Symptoms typically diffuse and nonfocal with bilateral neuro signs common

Embolism

Hypoperfusion

Framingham Stroke Profile

Assesses risk at primary care level Utilizes nine factors in the risk profile
Sex ,age, SBP, antihypertensive treatment, diabetes, smoking, cardiovascular disease, afib, and LVH

Calculates absolute stroke risk over a given period of time Its the best we have for now

Nonmodifiable Risk Factors

Age Gender Race/Ethnicity Family history Genetic factors Low birth weight

Modifiable Risk Factors

Hypertension Diabetes Dyslipidemia AFib Smoking Obesity Physical inactivity Diet

Potentially Modifiable Risk Factors

Metabolic Syndrome Drug and Alcohol Abuse Sleep Apnea Elevated Lp-PLA2 Elevated Lpa Inflammation Infection Migraine headaches Hypercoaguable disorders Oral Contraceptives Elevated homocysteine

Hypertension
Single most important treatable risk factor Reduction in BP associated with a 30-40% decrease in stroke incidence Treatment must be individualized
Goal is < 140/90mmHg ACE-I, ARB and diuretic classes are good starters Tighter control with DM or CKD Goal is < 130/80mmHg ACE-I and/or ARB class of drugs best for DM/CKD

Approximately 60% of all strokes in men and women of all ages attributed to hypertension

Considerations for individualizing antihypertensive therapy

Indication Compelling indications (major improvement in outcome independent of blood pressure) Systolic heart failure Post-myocardial infarction Proteinuric chronic renal failure High coronary disease risk Diabetes mellitus (no proteinuria) Angina pectoris Atrial fibrillation rate control Atrial flutter rate control Likely to have a favorable effect on symptoms in comorbid conditions Benign prostatic hypertrophy Essential tremor Hyperthyroidism Migraine Osteoporosis Perioperative hypertension Raynaud's syndrome Alpha blocker Beta blocker (noncardioselective) Beta blocker Beta blocker, calcium channel blocker Thiazide diuretic Beta blocker Dihydropyridine calcium channel blocker ACE inhibitor or ARB, beta blocker, diuretic, aldosterone antagonist* ACE inhibitor, beta blocker, aldosterone antagonist ACE inhibitor and/or ARB Diuretic (ALLHAT), perhaps ACE inhibitor (HOPE) Diuretic (ALLHAT), perhaps ACE inhibitor (HOPE) Beta blocker, calcium channel blocker Beta blocker, nondihydropyridine calcium channel blocker Beta blocker, nondihydropyridine calcium channel blocker Antihypertensive drugs

Considerations for individualizing antihypertensive therapy

Contraindications
Angioedema Bronchospastic disease Depression Liver disease Pregnancy Second or third degree heart block May have adverse effect on comorbid conditions Depression Gout Hyperkalemia Hyponatremia Renovascular disease Beta blocker, central alpha agonist Diuretic Aldosterone antagonist, ACE inhibitor, ARB Thiazide diuretic ACE inhibitor or ARB ACE inhibitor Beta blocker Reserpine Methyldopa ACE inhibitor, ARB (includes women likely to become pregnant) Beta blocker, nondihydropyridine calcium channel blocker

A survival benefit from an aldosterone antagonist has only been demonstrated in patients with advanced heart
failure; in patients with less severe disease, an aldosterone antagonist is primarily given for hypokalemia Adapted from The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, JAMA 2003; 289:2560.

Diabetes
15-33% of patients with ischemic stroke ADA recommends all patients be treated with and ACE-I or ARB Goal is to treat HTN, dyslipidemia, microalbuminuria and hypoglycemia using multifactorial approach including diet, exercise, oral hypoglycemics and insulin Tight control reduces microvascular complications

Definitions and Goals

Normal=FBS 60-100mg/dl IFG=100-126mg/dl (glucose intolerance) Diabetes=FBS greater than 126mg/dl or a random BS greater than 200mg/dl HgA1c less than 7%

Treatment Outcomes
HgA1c less than 7% reduces the risk of microvascular and possible macrovascular complications UK Prospective Diabetes Study showed that a reduction in A1c by 1% reduced ischemic stroke risk by 15% ACE-I/ARBs affect progression of diabetic nephropathy and reduce albuminuria DCCT revealed that tight control of BS in Type I and Type II DM reduced microvascular complications Fatal and nonfatal CV events were reduced in Type I DM Jury is still out on Type II DM (ACCORD Study) where intensive control of blood sugar in Type II diabetics (with a high risk of CAD) had a higher rate of mortality

Oral agents and Insulin for treatment of diabetes

Insulins
Class of Agents Agents Glipizide Glyburide Glimepiride Metglitinides Biguanides Thiazolidinediones -glucosidase inhibitors Nateglinide Repaglinide Metformin Pioglitazone Rosiglitazone Acarbose Miglitol Trade Name Mechanism of Action Glucotrol Diabeta, Insulin secretagogues Glynase, Micronase Amaryl Postprandial insulin Starlix secretagogues Prandin Glucophage Actos Avandia Precose Glyset Insulin sensitizer (liver) Insulin sensitizer (skeletal muscle) Delay glucose absorption by antagonizing enzymes

Generic Trade name Lispro Aspart Humalog Novolog

Onset of Peak of Duration Action Action of Action

Sulfonylureas

515min

12h

35h

Rapid acting Regular Intermediate acting Long acting Mixed NPH HumulinR Novolin R 3060min 24h Novolin N Humulin N 13h 68h

57h

1318h

Ultralente Glargine Lantus Novolin 70/30

24h 814h 1830h Within 4h Peakless >24h

Dyslipidemia
Clearly an established risk factor for CAD but not so for first or recurrent stroke Risk reduction in statin trials may be for nonfatal stroke (risk was reduced 21-29% for first or recurrent stroke) Patients with ischemic stroke secondary to atherosclerosis are good candidates for a statin Goal LDL < 100mg/dl Patients with low HDL and ischemic stroke may be good candidates for niacin or gemfibrozil

Treatment Options
Lovastatin Pravastatin Simvastatin Fluvastatin Atorvastatin Rosuvastatin

Statins

Gemfibrozil Fenofibrate Nicotinic Acid Bile acid sequestrants

Cholestyramine Cholestipol Colesevelam Ezetimibe

Cholesterol absorption inhibitors Neomycin Probucol

Adult treatment panel III classification of LDL, total, and HDL cholesterol
LDL cholesterol, mg/dL (mmol/L)
<100 (2.58) 100 to 129 (2.58 to 3.33) 130 to 159 (3.36 to 4.11) 160 to 189 (4.13 to 4.88) 190 (4.91) <200 (5.17) 200 to 239 (5.17 to 6.18) 240 (6.20) <40 (1.03) 60 (1.55) Optimal Near or above optimal Borderline high High Very high Desirable Borderline High High Low High

Total cholesterol, mg/dL (mmol/L)

HDL cholesterol, mg/dL (mmol/L)

Adapted from Adult Treatment Panel III at http://www.nhlbi.nih.gov/.

Atrial Fibrillation (AF)

Valvular Nonvalvular Persistent and paroxysmal AF are strong predictors of first and second stroke AF accounts for 20% of ischemic strokes

CHADS2 score
CHF HTN Age DM Secondary prevention in pts with prior ischemic stroke or TIA or systemic embolic event The CHADS2 score estimates the risk of stroke in warfarin versus no warfarin treatment groups in patients with nonvalvular AF. Warfarin treatment group results were statistically significant in primary prevention of ischemic stroke.

Lifestyle Modification and Impact on Reduction of Ischemic Stroke

Obesity/Weight Loss Smoking Cessation Alcohol Abuse Exercise Diet and Nutrition

Obesity/Weight Loss
Definitions BMI is a measure of body fat based on height and weight Obese

Physicans Health Study conclusive for increased risk of ischemic stroke in men with obesity (data not conclusive for women)

Waist circumference > 40 inches in males, > 35 inches in females, BMI >30kg/m2 Goal BMI <24.9kg/m2, normal (18.524.9kg/m2), overweight (25-29.9kg/m2)

Metabolic Syndrome
Current ATP III criteria define the metabolic syndrome as the presence of any three of the following five traits: Abdominal obesity, defined as a waist circumference in men >102 cm (40 in) and in women >88 cm (35 in) Serum triglycerides 150 mg/dL (1.7 mmol/L) or drug treatment for elevated triglycerides Serum HDL cholesterol <40 mg/dL (1 mmol/L) in men and <50 mg/dL (1.3 mmol/L) in women or drug treatment for low HDL-C Blood pressure 130/85 mmHg or drug treatment for elevated blood pressure Fasting plasma glucose (FPG) 100 mg/dL (5.6 mmol/L) or drug treatment for elevated blood glucose.

Smoking
Believed to increase stroke by generation of thrombus in previously narrowed arteries (increases atherosclerosis) Multiple studies show increase in ischemic and hemorrhagic stroke (2-fold) Framingham revealed that heavy smokers (>40 cigs/day) had two times the risk of stroke vs light smokers (<10 cigs/day) Risk of stroke was significantly reduced in 2 years post cessation and reached nonsmoker level by 5 years Cessation therapy is behavioral or medication based

Pharmacotherapy Non-nicotine based Therapy

Bupropion HCl/Wellbutrin
May be used in combination with patch for greater efficacy Provides therapy for co-morbid depression (anti-smoking effect independent of this) Use relatively contraindicated in smokers with a history of seizures, head trauma, heavy alcohol abuse, or anorexia Multiple drug-drug interactions, esp. with anti-HIV meds 300 mg/day (in 2 divided doses to minimize side effects) Start two weeks prior to anticipated quit date and continue for 7 to 12 weeks Optimal duration of treatment not well defined One 0.5 mg tablet daily for three days, one 0.5 mg tablet twice daily for the next four days, one 1 mg tablet twice daily starting at day seven.

Varenicline/Chantix

Pharmacotherapy Nicotine based Therapy

Nicotine polacrilex (gum or lozenge)
Accessible over-the-counter over- theMay satisfy oral behavior Requires multiple dosing, thus, compliance may be affected Start on quit date <25 cigarettes/day use: 2 mg tab. 25 cigarettes/day use: 4 mgtab. cigarettes/day mgtab. 1 to 2 tab/hour for 6 weeks, taper over 6 weeks Easy dosing (QD) may improve compliance Over-the-counter Over- theLocal skin irritation in up to 50 % of users Insomnia with 24-hour 24Nicoderm CQ: 21 mg/d for 6 wks, then 14 mg/d for 2 wks, then 7 mg/d for 2 wks Nicotrol: Use single dose patch for 16 hours/day for 6 weeks (no tapering recommended) Nicotrol: tapering Higher/quicker nicotine levels Initial adverse effects (nasal and throat irritation, sneezing, rhinorrhea, coughing, and eye rhinorrhea, irritation) 1 to 2 doses per hour for 3 months. Most pts require from 7 to 40 sprays over 24 hours. 40 Substitutes for behavioral aspects of smoking. Low nicotine levels similar to those achieved with gum 10 mg cartriges used over 20 minutes. Six to 16 cartriges per day.

Nicotine patch

Nicotine nasal spray

Nicotine inhaler

ETOH
Light to moderate alcohol (<2 drinks/d for men and <1 drink/d for non-pregnant women) may be protective for ischemic stroke but may increase the risk for hemorrhagic stroke Heavy alcohol use ( >5 drinks/day) increases all stroke risk by 69% 1 drink=12oz beer, 4oz wine or 1.5oz liquor

Exercise/Diet/Nutrition
CDC and NIH recommend 30 minutes of vigorous activity (brisk walking) 4-6X/week DASH diet (Dietary Approaches to Stop HTN) designed to reduce blood pressure, cholesterol and improve insulin sensitivity DASH diet associated with lower rate of stroke and MI in healthy women Supplements and Dietary fat (Vit E, C, Fish Oils, and Fat intake) are controversial in stroke prevention Reduced sodium (<2.3g/d) and increased potassium (>4.7g/d) in patients with HTN without CKD reduces risk

Summary
700,000 Strokes/year in USA 80% of all strokes are ischemic, 20% are hemorrhagic The main subtypes of ischemic stroke are due to thrombus, embolus, or hypoperfusion Major modifiable risk factors
HTN Diabetes Dyslipidemia Afib Smoking Alcohol Obesity/Metabolic Syndrome Sedentary Lifestyle

Treatment and control of risk factors by the primary care physician will reduce the overall incidence of ischemic stroke

Stroke Work-up
MEDICAL TEST
STARE INTO THE CAT'S EYES FOR 10 SECONDS ...

Stroke Work-up
NOW STARE IN THE PUPPY'S EYES FOR 10 SECONDS ...

Your CAT SCAN and LAB TESTS are COMPLETE!

Stroke Work-up

Sorry, couldnt resist!