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Markers for coronary artery disease and their treatment

Robert Baldor, MD FAAFPProfessor, Family Medicine &Community HealthUniversity of Massachusetts Medical School

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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

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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/m2

6. Diabetes

7. Microalbuninuria (GFR < 60ml/min)

8. Hypertension

9. Dyslipidemia

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Therapeutic Life Changes

Diet of 5 servings of fruits and vegetables daily

Weight management Increased physical activity to at least 120

minutes/week

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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

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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/m2

7. Hypertension

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Hypertension targeted ...

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

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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/m2

8. Hypertension

9. Dyslipidemia

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LDL-C: Primary Target of Therapy

Risk Category LDL Goal Consider Drug Therapy

0-1 Risk Factor <160 mg/dL >190 mg/dL 160-189 mg/dL (optional)

1. Cigarette smoking2. Hypertension3. Low HDL cholesterol (<40 mg/dL)4. Family history of premature CHD

male 1st degree relative <55 yearsfemale 1st degree relative <65 years

5. Age (men 45 years; women 55 years)

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LDL-C: Primary Target of Therapy

Risk Category LDL Goal Consider Drug Therapy

0-1 Risk Factor<160 mg/dL

>190 mg/dL160-189 mg/dL (optional)

> 2 Risk Factors (10 yr risk <20%)

<130 mg/dL 10 yr risk 10-20%: >130 mg/dL 10 yr risk <10%: >160 mg/dL

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http://hp2010.nhlbihin.net/ATPIII/calculator.asp?usertype=prof 12

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LDL-C: Primary Target of Therapy

Risk Category LDL Goal Consider Drug Therapy

0-1 Risk Factor<160 mg/dL

>190 mg/dL160-189 mg/dL (optional)

2+ Risk Factors (10 yr risk <20%)

<130 mg/dL10 yr risk 10-20%: >130 mg/dL10 yr risk <10%: >160 mg/dL

9% Risk

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LDL-C: Primary Target of Therapy

Risk Category LDL Goal Consider Drug Therapy

0-1 Risk Factor<160 mg/dL

>190 mg/dL160-189 mg/dL (optional)

2+ Risk Factors (10 yr risk <20%)

<130 mg/dL10 yr risk 10-20%: >130 mg/dL10 yr risk <10%: >160 mg/dL

CHD or CHD Risk Equivalents (10-year risk >20%)

<100 mg/dL >130 mg/dL 100-129 mg/dL (optional)

Equivalents = DM, PAD, AAA, symptomatic carotid AD

> 100 mg/dL !

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Very high-risk patients….

A recent heart attack orCardiovascular disease with either:

DiabetesA severe or poorly controlled risk factors

(such as continued smoking)Metabolic syndrome

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LDL-C: Primary Target of Therapy

Risk Category LDL Goal Consider Drug Therapy

0-1 Risk Factor<160 mg/dL

>190 mg/dL160-189 mg/dL (optional)

2+ Risk Factors (10 yr risk <20%)

<130 mg/dL10 yr risk 10-20%: >130 mg/dL10 yr risk <10%: >160 mg/dL

CHD or CHD Risk Equivalents (10-year risk >20%)

<100 mg/dL130 mg/dL 100-129

very high-risk <70 mg/dL

> 100 mg/dL

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Treat metabolic syndrome

Intensify physical activity & weight lossTreat hypertensionASA dailyTreat elevated triglycerides or low HDL

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DM really CVD equivalent?

Recent systematic review45,000 pts followed over 13.4 yrs

DM alone is a weak predictorDM but no prior MI had a 43% ↓ risk of

CHD event vs. pts w/prior MI but no DM

Diabet Med. 2009;26:142-148

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Other factors?

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

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Emerging factors?

Factors must be easily measuredModifying treatments available

Is there evidence that the factors causes CVD (risk mediator) or is it noted because CVD is present (risk marker)?

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Emerging Risk Factors

1. Lipoprotein (a)

2. Homocysteine

3. Prothrombotic factors

4. Proinflammatory factors

5. Subclinical atherosclerosis

6. Impaired fasting glucose

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1. Lipoprotein(a)

LDL like compoundSimilar to plasminogen, with thrombotic

properties40% cholesterol

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Lp(a) levels

Desirable < 20 mg/dLBorderline 20-30High risk 31-50V. high risk > 50

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Associated with ↑Lp(a)

InflammationGenetic predispositionMetabolic syndrome

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Lowering Lp(a) ?

High-dose extended-release niacin 3gm/d above recommended max dose

Estrogens (HRT) - but HRT associated increased CVD risk!

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2. Homocysteine

Metabolism By-product requires folic acid, B12 and pyridoxine(B6)

No known biologic functionIncreases CVD risk

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Associated with ↑ Homocysteine

Renal failureHypothyroidismFolate/B6/B12 deficiencyMethotrexateGenetic predisposition

MTHFR mutationBile acid sequestrants

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Associated with ↓ Homocysteine

Folate/B6/B12 supplementsGenetic predisposition

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Marker?

Meta-analysis OF 8 RCTs24,210 pts with > 1 yr follow-upMI and stroke were primary outcomes

No CVD benefit from lowering homocysteine with B vitamins

Cochrane Database Syst Rev 2009;4:CD006612

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3.Prothrombotic factor (fibrinogen)

An acute phase reactant Levels > 350 mg/dl considered elevatedThe conversion of fibrinogen to fibrin is

the final step in the clotting cascadeNo treatment has been shown to lower

levels enough to reduce risk

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Associated with ↑ Fibrinogen

InflammationSmokingIncreased ageObesityDiabetesMenopauseOral contraceptives/estrogens

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Associated with ↓ Fibrinogen

Fibrates (not clinically significant)Niacin (not clinically significant)Smoking cessationExerciseAlcohol (in moderation)

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4. Proinflammatory factors (hsCRP)

high-sensitivity C-reactive proteinAn acute phase reactantElevated with inflammationAssociated with an increased risk of

CAD, independent of other factors, except LDL

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hs-CRP

Low risk < 1 mg/LMod risk (1-3)High risk (>3 mg/L)

Need a least 2 measurementsIf > 10mg/dL – repeat in 2 weeks to

ensure that reading is not due to acute inflammatory reaction

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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)

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Associated with ↓hsCRP

Moderate alcohol consumptionIncreased activity/exerciseWeight loss

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Reducing hs-CRP

StatinsEzetimibide (Zetia)FibratesNiacinColesevelam (Welchol)ThiazolidinedionesASA

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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;151:496-507.

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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

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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

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? Apolipoprotein B (apo B)

The major atherogenic apolipoproteinapo B predicts severity of CHD eventsHigh correlation with non-HDL cholesterol

ATP III cites this as the basis for non-HDL cholesterol as a secondary treatment target

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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

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Triglycerides ?

Normal <150 mg/dLBorderline high 150–199 mg/dLHigh 200–499 mg/dLVery high 500 mg/dL

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High Triglycerides

ObesityPhysical inactivityTobacco abuseExcess alcohol intakeHigh carbohydrate diet (>60% of

energy intake)DM, CRF, Nephrotic syndrome

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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

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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

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Low HDL Cholesterol (<40 mg/dL)

High triglycerides Overweight and obesity Physical inactivity Type 2 diabetes Tobacco abuse High carbohydrate intake (>60% energy)

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Low HDL Cholesterol

Achieve LDL goal Weight reduction & ↑ physical activityConsider nicotinic acid or fibrates for high

risk patients

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Statin side effects

Check LFTs at onset and 12 weeks after starting or after any dose increaseCheck annually or if symptoms

No evidence for harm from mildly elevated ALT/AST (< 3x normal)

0.69 cases of hepatitis/million statin prescriptions

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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

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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

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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 earlyCV mortality data were lackingMost researchers w/financial ties to industry

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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; 2010

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What about ASA?

Calculate CVD risk> 10% likelihood of a CHD event over next

10 years- prescribe6-10% risk – consider< 6% - risk outweights benefits

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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….

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