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Markers for coronary artery disease and their treatment Robert Baldor, MD FAAFP Professor, Family Medicine &Community Health University of Massachusetts Medical School 2

At the end of this session, you will: Appreciate the importance of new and established risk factors for CVD Consider the best means for evaluating and addressing treatment and prevention of these risk factors 3

Traditional Risk Factors (JNC/7) 1. Age (>55 men; >65 women) 2. FH premature CVD (men < 55; women < 65) 3. Tobacco Abuse 4. Physical Inactivity 5. Obesity (BMI > 30 kg/m 2 6. Diabetes 7. Microalbuninuria (GFR < 60ml/min) 8. Hypertension 9. Dyslipidemia 4

Therapeutic Life Changes Diet of 5 servings of fruits and vegetables daily Weight management Increased physical activity to at least 120 minutes/week 5

Foods to lower BP High Potassium Banana/Oranges Cantaloupe/Honeydew Raisins/dates/apricots Avocado/artichoke Squash/beans/chickpeas Potato/broccoli Tomato sauce High Magnesium Nuts/seeds Halibut Whole grains/bran Beans/lentils Soybeans Spinach/dark green vegetables 6

Traditional Risk Factors (JNC/7) 1. Age (>55 men; >65 women) 2. FH premature CVD (men < 55; women < 65) 3. Diabetes 4. Tobacco Abuse 5. Physical Inactivity 6. Obesity (BMI > 30 kg/m 2 7. Hypertension 7

Hypertension targeted... < 140/90 mmHg targeted treatment goal < 130/80 for diabetes and chronic kidney disease 8

Traditional Risk Factors (JNC/7) 1. Age (>55 men; >65 women) 2. FH premature CVD (men < 55; women < 65) 3. Diabetes 4. Microalbuninuria (GFR < 60ml/min) 5. Tobacco Abuse 6. Physical Inactivity 7. Obesity (BMI > 30 kg/m 2 8. Hypertension 9. Dyslipidemia 9

LDL-C: Primary Target of Therapy Risk CategoryLDL Goal Consider Drug Therapy 0-1 Risk Factor <160 mg/dL >190 mg/dL mg/dL (optional) 1.Cigarette smoking 2.Hypertension 3.Low HDL cholesterol (<40 mg/dL) 4.Family history of premature CHD male 1 st degree relative <55 years female 1 st degree relative <65 years 5.Age (men  45 years; women  55 years) 10

LDL-C: Primary Target of Therapy Risk CategoryLDL GoalConsider Drug Therapy 0-1 Risk Factor <160 mg/dL >190 mg/dL mg/dL (optional) > 2 Risk Factors (10 yr risk <20%) <130 mg/dL 10 yr risk 10-20%: >130 mg/dL 10 yr risk 160 mg/dL 11

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LDL-C: Primary Target of Therapy Risk CategoryLDL GoalConsider Drug Therapy 0-1 Risk Factor <160 mg/dL >190 mg/dL mg/dL (optional) 2+ Risk Factors (10 yr risk <20%) <130 mg/dL 10 yr risk 10-20%: >130 mg/dL 10 yr risk 160 mg/dL 9% Risk 14

LDL-C: Primary Target of Therapy Risk CategoryLDL GoalConsider Drug Therapy 0-1 Risk Factor <160 mg/dL >190 mg/dL mg/dL (optional) 2+ Risk Factors (10 yr risk <20%) <130 mg/dL 10 yr risk 10-20%: >130 mg/dL 10 yr risk 160 mg/dL CHD or CHD Risk Equivalents (10-year risk >20%) <100 mg/dL >130 mg/dL mg/dL (optional) Equivalents = DM, PAD, AAA, symptomatic carotid AD > 100 mg/dL ! 15

Very high-risk patients …. A recent heart attack or Cardiovascular disease with either: Diabetes A severe or poorly controlled risk factors (such as continued smoking) Metabolic syndrome 16

LDL-C: Primary Target of Therapy Risk CategoryLDL GoalConsider Drug Therapy 0-1 Risk Factor <160 mg/dL >190 mg/dL mg/dL (optional) 2+ Risk Factors (10 yr risk <20%) <130 mg/dL 10 yr risk 10-20%: >130 mg/dL 10 yr risk 160 mg/dL CHD or CHD Risk Equivalents (10-year risk >20%) <100 mg/dL 130 mg/dL very high-risk<70 mg/dL > 100 mg/dL 17

Treat metabolic syndrome Intensify physical activity & weight loss Treat hypertension ASA daily Treat elevated triglycerides or low HDL 18

DM really CVD equivalent? Recent systematic review 45,000 pts followed over 13.4 yrs DM alone is a weak predictor DM but no prior MI had a 43% ↓ risk of CHD event vs. pts w/prior MI but no DM Diabet Med. 2009;26:

Other factors? 50% of MI’s & strokes occur in individuals with LDL levels below recommended levels 20

Emerging factors? Factors must be easily measured Modifying treatments available Is there evidence that the factors causes CVD (risk mediator) or is it noted because CVD is present (risk marker)? 21

Emerging Risk Factors 1. Lipoprotein (a) 2. Homocysteine 3. Prothrombotic factors 4. Proinflammatory factors 5. Subclinical atherosclerosis 6. Impaired fasting glucose 22

1. Lipoprotein(a) LDL like compound Similar to plasminogen, with thrombotic properties 40% cholesterol 23

Lp(a) levels Desirable < 20 mg/dL Borderline High risk V. high risk > 50 24

Associated with ↑Lp(a) Inflammation Genetic predisposition Metabolic syndrome 25

Lowering Lp(a) ? High-dose extended-release niacin 3gm/d above recommended max dose Estrogens (HRT) - but HRT associated increased CVD risk! 26

2. Homocysteine Metabolism By-product requires folic acid, B12 and pyridoxine(B6) No known biologic function Increases CVD risk 27

Associated with ↑ Homocysteine Renal failure Hypothyroidism Folate/B 6 /B 12 deficiency Methotrexate Genetic predisposition MTHFR mutation Bile acid sequestrants 28

Associated with ↓ Homocysteine Folate/B 6 /B 12 supplements Genetic predisposition 29

Marker? Meta-analysis OF 8 RCTs 24,210 pts with > 1 yr follow-up MI and stroke were primary outcomes No CVD benefit from lowering homocysteine with B vitamins Cochrane Database Syst Rev 2009;4:CD

3.Prothrombotic factor (fibrinogen) An acute phase reactant Levels > 350 mg/dl considered elevated The conversion of fibrinogen to fibrin is the final step in the clotting cascade No treatment has been shown to lower levels enough to reduce risk 31

Associated with ↑ Fibrinogen Inflammation Smoking Increased age Obesity Diabetes Menopause Oral contraceptives/estrogens 32

Associated with ↓ Fibrinogen Fibrates (not clinically significant) Niacin (not clinically significant) Smoking cessation Exercise Alcohol (in moderation) 33

4. Proinflammatory factors (hsCRP) high-sensitivity C-reactive protein An acute phase reactant Elevated with inflammation Associated with an increased risk of CAD, independent of other factors, except LDL 34

hs-CRP Low risk < 1 mg/L Mod risk (1-3) High risk (>3 mg/L) Need a least 2 measurements If > 10mg/dL – repeat in 2 weeks to ensure that reading is not due to acute inflammatory reaction 35

Associated with ↑hsCRP HTN Obesity Tobacco use Metabolic syndrome Diabetes mellitus Low HDL/High TG Oral estrogen/progesterone Chronic infections (gastritis, gingivitis) Chronic inflammation (rheumatoid arthritis) 36

Associated with ↓hsCRP Moderate alcohol consumption Increased activity/exercise Weight loss 37

Reducing hs-CRP Statins Ezetimibide (Zetia) Fibrates Niacin Colesevelam (Welchol) Thiazolidinediones ASA 38

Risk mediator or a risk marker? evidence that changes in CRP level lead to primary prevention of CHD events is inconclusive…. Ann Intern Med 2009;151:

5. Sub-clinical atherosclerosis Coronary Artery Calcium (CAC) score ideal CAC score is zero Coronary CT (EBCT) to quantify coronary artery calcification The amount of calcium detected correlates with the presence of atherosclerotic plaque 40

CAC value? CAC score of 0 does not exclude risk Sensitivity of 80%-92% Specificity of 40%-51% Unclear value - studies have shown variability in repeated measures of CAC over time 41

? Apolipoprotein B (apo B) The major atherogenic apolipoprotein apo B predicts severity of CHD events High correlation with non-HDL cholesterol ATP III cites this as the basis for non-HDL cholesterol as a secondary treatment target 42

Non-HDL Cholesterol ? Non-HDL-C = VLDL + LDL (Total C – HDL C) VLDL- C: atherogenic remnant lipoproteins Secondary target when triglycerides  200 mg/dL Goal: LDL goal + 30 mg/dL 43

Triglycerides ? Normal <150 mg/dL Borderline high150–199 mg/dL High200–499 mg/dL Very high  500 mg/dL 44

High Triglycerides Obesity Physical inactivity Tobacco abuse Excess alcohol intake High carbohydrate diet (>60% of energy intake) DM, CRF, Nephrotic syndrome 45

Non-HDL C: Secondary Target Achieve LDL goal before treating non-HDL Therapeutic approaches to elevated non-HDL Intensify therapeutic lifestyle changes Intensify LDL-lowering drug therapy Nicotinic acid or fibrate therapy to lower VLDL 46

Elevated Triglycerides (>500 mg/dL) Goal of therapy: prevent acute pancreatitis Dietary consultation Fibrate or nicotinic acid Fish oil supplements 1 gm omega 3 fatty acids daily 47

Low HDL Cholesterol (<40 mg/dL) High triglycerides Overweight and obesity Physical inactivity Type 2 diabetes Tobacco abuse High carbohydrate intake (>60% energy) 48

Low HDL Cholesterol Achieve LDL goal Weight reduction & ↑ physical activity Consider nicotinic acid or fibrates for high risk patients 49

Statin side effects Check LFTs at onset and 12 weeks after starting or after any dose increase Check annually or if symptoms No evidence for harm from mildly elevated ALT/AST (< 3x normal) 0.69 cases of hepatitis/million statin prescriptions 50

10% can’t tolerate statins Cholestyramine (Questran) bile acid sequestrant – inhibits chol absorption modest ↓ LDL and CHD deaths Fibrates [gemfibrozil (Lopid)/fenofibrate (Tricor)] reduce nonfatal MIs, not overall mortality Ezetimibe (Zetia) – blocks absorption ↓plaque, but no data on improved CHD endpoints Red yeast rice (naturally occurring lovastatin) ↓ LDL 51

JAMA November 2009 Lipid assessment in vascular disease can be simplified by measurement of either total and HDL cholesterol levels or apolipoproteins without the need to fast and without regard to triglyceride 52

AIM Question Statins for Primary Prevention A meta-analysis ( 11 trials; 65,000 high-risk pts w/o CVD disease; 4 yrs statin ) LDL levels lower w/statin (94 vs134 mg/dL) No difference in all-cause mortality JUPITER trial reviewed ( claimed 54% CD relative risk reduction ) felt to be a flawed trial! Stopped too early CV mortality data were lacking Most researchers w/financial ties to industry 53

AIM Editors conclusions…. The meta-analysis "makes it clear that in the short-term, for true primary prevention, the benefit, if any, is very small.“ "The results of the Jupiter trial do not support the use of statin treatment for primary prevention." Arch Intern Med 170:12;

What about ASA? Calculate CVD risk > 10% likelihood of a CHD event over next 10 years- prescribe 6-10% risk – consider < 6% - risk outweights benefits 55

So what do you do? ATP III update recommends more aggressive lipid lowering in those with ‘emerging’ risk factors for CVD Calculate individual risk using the Framingham tool – then decide about treatment…. 56

Drug ClassDaily DosesLipid EffectsSide EffectsContraindications HMG CoA reductase inhibitors (statins) Lovastatin (20-80 mg), Pravastatin (20-40 mg), Simvastatin (20-80 mg), Fluvastatin (20-80 mg), Atorvastatin (10-80 mg), Cerivastatin ( mg) LDL-C ↓ 18-55% HDL-C ↑ 5-15% TG ↓ 7-30% Myopathy ↑ liver enzymes Absolute: Active or chronic liver disease Bile acid Sequestrants Cholestyramine (4-16 g) Colestipol (5-20 g) Colesevelam ( g) LDL-C ↓ 15-30% HDL-C ↑ 3-5% TG No change GI distress Constipation ↓ absorption of other drugs Absolute: dysbeta- lipoproteinemia; TG >400 mg/dL Relative: TG >200 mg/dL Nicotinic acid Immediate release (crystalline) (1.5-3 gm), Extended release (Niaspan ®) (1-2 g), Sustained release (1-2 g) LDL-C ↓ 5-25% HDL-C ↑ 15-35% TG ↓ 20-50% Flushing Hyperglycemia Hyperuricemia Upper GI distress Hepatotoxicity Absolute: -Chronic liver disease; -Severe gout Relative: -Diabetes -Hyperuricemia -Peptic ulcer disease Fibric acids Gemfibrozil (600 mg BID) Fenofibrate (200 mg) Clofibrate (1000 mg BID) LDL-C ↓ 5-20% HDL-C ↑ 10-20% TG ↓ 20-50% Dyspepsia Gallstones Myopathy Absolute: · Severe renal disease · Severe hepatic disease 57

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