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