Magnitude of the Burden—Causes of Death Magnitude of the Burden—Causes of Death in the United Statesin the United States

0

100

200

300

400

500

600

700

800

900

1,000

Deat

hs in

199

6 (th

ousa

nds)

CVD Cancer Accidents HIV/AIDS

959.2

544.7

93.832.7

American Heart Association. 1999 Heart and Stroke Statistical Update. 1998.

Economic Direct and Indirect Cost of CVD in the Economic Direct and Indirect Cost of CVD in the United StatesUnited States

Hospital/nursing home

Physicians/other professionalsDrugs

Home health/other medical durables

Lost productivity/morbidity

Lost productivity/mortality

American Heart Association. 1999 Heart and Stroke Statistical Update. 1998.

Total direct andindirect costs:$286.5 billion

5-Year Expected Total Cost per Case5-Year Expected Total Cost per Case

Wittels EH et al. Am J Cardiol 1990;65:432–440.

Average Cost(1986 $)

CHD events

Acute myocardial infarction 51,211

Angina pectoris 24,980

Unstable angina pectoris 40,581

Sudden death 9,078

Procedures

Angioplasty 26,916

Bypass surgery 32,465

Preventive Medicine CostsPreventive Medicine Costs

Cost of preventive measuresTreatmentTestingComplications of preventive measures

Treating cases that arise anyway

Treating diseases discovered

Treating other illnesses in population living longer

Pay “up-front” for benefit later

False positiveTreating those who will not develop disease

Cost-Effectiveness AnalysisCost-Effectiveness Analysis

Purpose: Consider both the effectiveness and cost of an intervention

Cost = Cost of medical intervention + cost of illness

Effectiveness = quality adjusted life year saved

CE = Cost-effectiveness ratio

CE2-1 =Cost2 – Cost1

QALY2 – QALY1

Whose Costs Matter?Whose Costs Matter?

Patient:The costs the patient bears directly (depends on co-payment)

Insurance:Costs the insurance bears directly

Societal:Includes all costs and avoids double counting

Measuring CostsMeasuring Costs

Direct Costs: Direct medical costs related to the diagnosis and treatment of the disease

+ disease-specific costs that may be induced or averted

Indirect Costs: Lost earnings

Other Costs: Prolonged life increased cancer, nursing home patients

Premature events, disability payments, reduced productivity

Cost-Effectiveness: Cost-Effectiveness: Quality Adjusted Life YearsQuality Adjusted Life Years

Mild hypertension male age 40 $23,300

Estrogen therapy postmenopausal Sx $32,900

Neonatal intensive care $38,800

School tuberculosis testing $53,300

Hospital hemodialysis $65,900

General Guidelines Incremental Cost-General Guidelines Incremental Cost-Effectiveness (QALY)Effectiveness (QALY)

Goldman L et al. Circulation 1992;85:1960–1968.

0–$20,000 Very attractive

$20,000–$40,000 Currently funded– Hemodialysis– Rx mild hypertension

$60,000–$100,000 > Currently accepted

$100,000+ Unattractive

Cholesterol Lowering:Cholesterol Lowering:Cost-EffectivenessCost-Effectiveness

Goldman L et al. JAMA 1991;265:1145–1151.

Treatment Sex Age CHDChol mg/dl

Cost/LifeYr

Lovastatin M 35-54 + >250 <0

Lovastatin W 45-54 + >250 3,500

Lovastatin M 45-54 - >300 110,000

Lovastatin W 45-54 - >300 320,000

Cost Effectiveness of Simvastatin Cost Effectiveness of Simvastatin Treatment for 5 Years in 59-Year-Old Treatment for 5 Years in 59-Year-Old Patients with CHD and a Pretreatment Patients with CHD and a Pretreatment Total Cholesterol Level of 261 mg/dlTotal Cholesterol Level of 261 mg/dl

Direct CostsDirect +

Indirect Costs

Variable Men Women Men Women

Costs ($)

Intervention 2,242 2,410 2,242 2,410

Associated morbidity –718 –725 –1,783 –1,601

Net 1,524 1,685 459 809

Years of life gained 0.28 0.16 0.28 0.16

Cost per year ($) 5,400 10,500 1,600 5,100

Johannesson M et al. N Engl J Med 1997;336:332–336.Copyright ©1997 Massachusetts Medical Society.

Cost Per Year of Life Gained in Patients Cost Per Year of Life Gained in Patients with CHD Who Received Simvastatin with CHD Who Received Simvastatin Treatment for 5 YearsTreatment for 5 Years

TC before treatment (mg/dl)

Age 35 Age 59 Age 70

Men Women Men Women Men Women

Direct costs

213 11,400 27,400 7,000 16,400 6,200 13,300

261 8,800 18,800 5,500 10,300 4,700 8,500

309 6,700 13,200 4,200 7,100 3,800 6,200

Direct + indirect costs

213 Savings Savings 2,100 8,600 6,200 13,300

261 Savings Savings 1,600 4,900 4,700 8,500

309 Savings Savings 1,200 3,200 3,800 6,200

Johannesson M et al. N Engl J Med 1997;336:332–336.Copyright ©1997 Massachusetts Medical Society.

WOSCOPS Placebo Group 5-Year Total WOSCOPS Placebo Group 5-Year Total Event RatesEvent Rates

West of Scotland Coronary Prevention Group. Lancet 1996;348:1339–1342.

Men 45–54 Men 55–64

Minor ECG 11.9 21.2

Smoking 10.1 14.4

HDL-C <40 mg/dl 8.1 14.1

HTN 8.0 12.3

Family CHD 7.5 13.2

High cholesterol 3.5 5.3

New Tests for Risk AssessmentNew Tests for Risk Assessment

I. Lipoprotein assessment

Lipoprotein(a)*Apoproteins: apo B-100,* A-I, CIII-BLDL particle size Apo E genotype

*Frequently used at Baylor Lipid Metabolism and Atherosclerosis Clinic

Lp(a) in Atherogenesis: Another Culprit?Lp(a) in Atherogenesis: Another Culprit?

Identical to LDL particle except for addition of apo(a)

Plasma concentration predictive of atherosclerotic disease in many, although not all, epidemiologic studies

Accumulates in atherosclerotic plaque

Binds apo B–containing lipoproteins and proteoglycans

Taken up by foam cell precursors

May interfere with thrombolysis

Maher VMG et al. JAMA 1995;274:1771-1774.Stein JH et al. Arch Intern Med 1997;157:1170-1176.

Effects of Lipid-Modulating Drugs on Lp(a)Effects of Lipid-Modulating Drugs on Lp(a)

Niacin and estrogen reduce Lp(a) levels

Apheresis reduces Lp(a) levels

No benefit from statins

No consistent benefit with fibrates, although studies are variable

Apo E GenotypeApo E Genotype

Apo E mediates the metabolism of chylomicrons, chylomicron remnants, VLDL, IDL, and a subclass of HDL particles.1

The 3 alleles of the apo E gene are associated with variations in LDL-C level, which is higher with 4 and lower with 2 compared with 3.2

LDL-C response to diet is reportedly greater in patients with 4,3 response to statins greater with 2 or 3.

1Mahley RW. Science 1988;240:622-630.2Davignon J et al. Arteriosclerosis 1988;8:1-21.3Mänttäri M et al. Metabolism 1991;40:217-221.

Intensity Intensity of lipid-lowering therapy of lipid-lowering therapy is dependent upon theis dependent upon the absolute risk absolute risk

for CHD eventsfor CHD events

NCEP Risk Factors in Primary PreventionNCEP Risk Factors in Primary Prevention

Positive Risk Factors Age

Male 45 yearsFemale 55 years or premature menopause without ERT

Family history of premature CHD Current cigarette smoking Hypertension (140/90 mm Hg or on antihypertensive

medication) Low HDL-C (<35 mg/dl) Diabetes mellitus

Negative Risk Factor High HDL-C (60 mg/dl)

National Cholesterol Education Program.Circulation 1994;89:1329-445.

New Tests for Risk AssessmentNew Tests for Risk Assessment

II. Nonlipid risk factors

Homocysteine*FibrinogenPlasminogen activator inhibitorC-reactive proteinCell adhesion molecules

*Frequently used at Baylor Lipid Metabolism and Atherosclerosis Clinic

Homocysteine as a CVD Risk FactorHomocysteine as a CVD Risk Factor

High plasma homocysteine may be directly related to atherosclerosis development.

High plasma homocysteine may be related to CVD risk by Enhancing inflammatory processes Increasing risk for thrombosis

Decreased folic acid or B12 and B6 may be the primary cause of increased CVD risk.

There may be no causal association between elevated homocysteine and CVD risk.

Kuller LH et al. Circulation 1998;98:196-199.

Plasma HomocysteinePlasma Homocysteineand Mortality in CHD Patientsand Mortality in CHD Patients

Prospective evaluation of 587 CHD patients, followed up for 4.6 years

Fasting plasma homocysteine measured at baseline

Strong, graded relationship between homocysteine levels and all-cause mortality

Nygard O et al. N Engl J Med 1997;337:230–236.

Nygard O et al. N Engl J Med 1997;337:230–236.

Plasma HomocysteinePlasma Homocysteineand Mortality in CHD Patientsand Mortality in CHD Patients

Homocysteine Level (µmol/L) Mortality Ratio

9–14.9 1.9

15–19.9 2.8

20 4.5

Homocysteine in Risk Assessment Homocysteine in Risk Assessment and Risk Reductionand Risk Reduction

Mechanisms of atherogenesis from homocysteine are not known, but endothelial injury and/or potentiation of lipoprotein oxidation are possible.

Laboratory testing of homocysteine levels needs to be better standardized

Treatment with high-dose folic acid (1–2 mg/d) and/or pyridoxine (250 mg/d) can lower homocysteine levels; empiric B12 frequently added

Elevated Plasma FibrinogenElevated Plasma FibrinogenA Major and Independent Risk FactorA Major and Independent Risk Factor

Epidemiological studies

Cross-sectional analyses

Clinical cohort studies

There is a sizeable body of evidence identifying fibrinogen as a major, independent risk factor

Ernst E, et al. Eur Heart J. 1995;16(supplA):47-53.

Fibrinogen and AtherosclerosisFibrinogen and Atherosclerosis

0%

20%

40%

60%

80%

100%

Lower Middle Upper

Present

Absent

Pres

ence

or A

bsen

ce o

f P

laqu

e

Levenson J, et al. Arterioscler Thromb Vasc Biol. 1995;15:1263-1268.

n=652 men

Effects of Lipid-LoweringEffects of Lipid-LoweringAgents on FibrinogenAgents on Fibrinogen

No consistent benefit seen with statins

Fibrates have shown benefit in most studies

Levels reduced with apheresis

Nicotinic acid has shown a modest reduction in some but not all studies

Circulating Adhesion Molecules in the Circulating Adhesion Molecules in the Atherosclerosis Risk in Communities Atherosclerosis Risk in Communities (ARIC) Study(ARIC) Study

Biracial population of 15,792 adults, aged 45–64, in 4 U.S. communities

Incident CHD: fatal or nonfatal MI, surgical revascularization (n=204)

Carotid artery atherosclerosis: B-mode ultrasound assessment of far wall IMT >1.0 mm (n=272)

Controls: IMT <0.68 mm (n=312) stratified by gender and age

Hwang S-J et al. Circulation 1997;96:4219–4225.

Circulating Adhesion Molecules in the Circulating Adhesion Molecules in the Atherosclerosis Risk in Communities (ARIC) Atherosclerosis Risk in Communities (ARIC) StudyStudy

*Adjusted for race, age, gender, BMI, HTN, DM, TC, HDL-C, TG, cigarettes, VWF, fibrinogen, and WBC

Hwang S-J et al. Circulation 1997;96:4219–4225.

Quartile Odds ratio* 95% CI

2nd 1.37 0.69–2.73

3rd 1.46 0.75–2.84

4th 5.53 2.51–12.21

Relative Risks for First MI for Baseline Relative Risks for First MI for Baseline sICAM-1 >260 ng/dlsICAM-1 >260 ng/dl

0

1

2

3

0–1 1–2 4–82–4Years of Study Follow-Up

Rela

tive

Risk

Ridker PM et al. Lancet 1998;351:88-92.Reprinted with permission from Elsevier Science.

New Tests for Risk AssessmentNew Tests for Risk Assessment

III. Noninvasive imaging of early atherosclerosis

Carotid ultrasound—IMT

Ultrafast CT—calcium score

Magnetic resonance imaging

IV. Noninvasive assessment of endothelial function

Brachial forearm flow reserve

Predictive Value of CAC ScorePredictive Value of CAC Score

CAC score Sensitivity Specificity PPV NPV OR

100 0.89 0.77 0.055 0.998 25.8

160 0.89 0.82 0.071 0.998 35.4

680 0.50 0.95 0.140 0.992 20.0

Arad Y et al. Circulation 1996;93:1951–1953.

Limited Predictivity of Coronary Calcium Limited Predictivity of Coronary Calcium Score for Coronary Events: ROC Curve AreasScore for Coronary Events: ROC Curve Areas

Detrano RC et al. Circulation 1999;99:2633-2638.

MI or coronary

death P*

MI, coronary death, or

revascularization P*

Calcium score 0.640.05 .07 0.650.04 .06

Framingham model 0.690.05 .20 0.670.04 .10

Data-derived model 0.680.05 .09 0.690.04 .06

Data-derived model plus calcium score

0.710.04 0.720.03

*Comparison with highest area in preceding column.

CT Monitoring of Effect of Therapy on CT Monitoring of Effect of Therapy on Plaque VolumePlaque Volume

0

200

400

600

800

1000

1200

1400

1600

1800

InitialFinal

No Statin Rx Statin Rx; LDL-C 120 mg/dl

Statin Rx; LDL-C <120 mg/dl

Calci

um-V

olum

e Sc

ore

p<0.001

p=0.005

p=NS

Callister TQ et al. N Engl J Med 1998;339:1972-1978.Copyright ©1998 Massachusetts Medical Society.

New Tools to Improve CHD Risk New Tools to Improve CHD Risk Stratification in Primary Prevention: Stratification in Primary Prevention: Framingham CHD Prediction EquationFramingham CHD Prediction Equation

Incorporates the following risk factors into a summary CHD risk score: Age, sex, LDL-C, HTN, smoking, diabetes

Calculates 10-year absolute CHD risk

Allows targeting of high-risk primary-prevention patients

Wilson PWF et al. Circulation 1998;97:1837–1847.

Improving Cost-Effectiveness of Lipid-Improving Cost-Effectiveness of Lipid-Lowering TreatmentLowering Treatment

Increase treatment effectiveness: Improve compliance Consider agents (e.g., niacin, estrogen) that

improve HDL-C, Lp(a), or dense LDL More aggressive LDL-cholesterol reductions

Improving Cost-Effectiveness of Lipid-Improving Cost-Effectiveness of Lipid-Lowering TreatmentLowering Treatment

Reduce cost of therapy: Maximize diet, exercise, smoking cessation Use less expensive drugs Pill cutters