Costs and Effectiveness of Cholesterol

Screening in the Elderly

April 1989

NTIS order #PB89-224638
Costs and Effectiveness of Cholesterol Screening in the Elderly

by

Alan M. Garber

Benjamin Littenberg

Harold C. Sex, Jr.

Division of General Internal Medicine

Stanford University School of Medicine

Palo Alto Veterans Administration Hospital

and

Michael E. Gluck

Judith L. Wagner

Brigitte M. Duffy

Health Program

Office of Technology Assessment

Congress of the United States

Washington, DC 20510-8025

April 1989

A paper

in OTA’s Series on

Preventive Health Services Under Medicare

This paper was prepared for desk-top publishing by Karen Davis and Carol Guntow.

The views expressed in this paper do not necessarily represent those of the Technology Assessment

Board, the Technology Assessment Advisory Council, or their individual members.

For sale by the Superintendent of Documents, U.S Government Printing Office

Washington, DC 20402
CONTENTS

Chapter Page

1.

2.

3.

4.

5.

6.

Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...... . 1

Cholesterol and Heart Disease in the Elderly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

Treatment of High Cholesterol in the Elderly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

Costs of Screening and Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

Implications for Medicare . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

Epidemiology of Hypercholesterolemia in the Elderly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

Diseases Associated With Hypercholesterolemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

The Distribution of Serum Cholesterol Levels Among Elderly Americans . . . . . . . . . . . . . . . . . . . . . . . . . . 8

Evidence That Hypercholesterolemia is Associated With Increased

Morbidity and Mortality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

Measuring Cholesterol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

Recommendations for Cholesterol Measurement Among the Elderly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

Cholesterol Measurement Techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

Factors That Influence Cholesterol Measurements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

Reliability of HDL and LDL Measurements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

Costs of Lipoprotein Measurement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

Followup Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23

Importance of the Locale of Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23

Treatment of Hypercholesterolemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25

Dietary Treatment of Hypercholesterolemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25

Drug Treatment of Hypercholesterolemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25

Costs of Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27

Health Outcomes of Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

Implications for Medicare . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35

Implications of Cholesterol Screening in the Elderly for Total

Health Care Expenditures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35

Use of Cholesterol Screening Services . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38

Implementing a Cholesterol Screening Benefit . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38

Costs and Effectiveness of Cholesterol Screening . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39

Appendix

A. Advisory Panel-- Project on Preventive Health Services Under Medicare . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41

B. Acknowledgments . . . . . . . . . . . . . . . . . . . . . . .

C. Expenditure Model for Diagnos

in the Elderly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Acronyms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .42

s and Treatment of Hypercholesterolemia

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .48

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49

ii
——————— .

CONTENTS (cent’d)

Tables

Table Page

1.

2.

3.

4.

5.

6.

7.

8.

9.

Mean Serum Cholesterol Levels of Men and Women, SEM, Age-Adjusted Values

Selected Percentiles, Number of Examined Persons, and Estimated

Population, by Race and Age: United States, 1978-1980 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

Simple Pearson Correlation Coefficients Between Various Plasma Lipids and

Lipoprotein Fractions From Various Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

Selected Charges for Lipoprotein Measurement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23

Costs of Treating Hypercholesterolemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28

Randomized Trials of Cholesterol Reduction and Mortality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30

Estimated Total Health Care Costs of Full Compliance With National

Cholesterol Education Program Protocol in the Elderly Population in 1995 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36

Total Number of Lipoprotein Measurement Services Allowed Under Medicare

in 1986 by Type of Procedure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38

NCEP Risk Factors for Coronary Heart Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43

Assumptions for Cholesterol Expenditure Model . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44

Figures

Figure Page

1.

2.

3.

Relation Between Plasma Cholesterol Level and Relative Risk of Coronary

Heart Disease in Three Prospective Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

Age-Adjusted 6-Year CHD and Total Mortality per 1,000 Men Screened for

MRFIT According to Serum Cholesterol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

Protocol for Cholesterol Screening in the Elderly . . . . . . . . . . . . . . . . . . . . . . . . . . . .............,...........................45

. . .

111
1. SUMMARY

Cardiovascular disease is the most common cause of death among elderly (i.e., age

65 or older) Americans. In the general population, an elevated serum cholesterol level is

associated with an increased risk of contracting and dying from cardiovascular disease.

This paper reviews the evidence that elevation of serum cholesterol (hypercholesterolemia) is an independent risk factor for

cardiovascular disease in the elderly and that

the detection and treatment of hypercholesterolemia in an elderly individual who

does not have clinically apparent heart disease

will diminish overall morbidity or mortality.

It also estimates health care expenditures associated with screening and treatment of hypercholesterolemia in the elderly.

Cholesterol and Heart Disease in

the Elderly

Cholesterol is a fat, or lipid, that circulates in the bloodstream bound to proteins in

complexes called lipoproteins. Cholesterolcontaining lipoproteins are generally grouped

into four categories, each containing different

proportions of cholesterol, other lipids, and

proteins. Low-density lipoproteins (LDLs)

are 50 to 60 percent cholesterol; high-density

lipoproteins (HDLs) are only 18 to 25 percent

cholesterol; very low-density lipoproteins

(VLDLs) contain between 20 and 30 percent

cholesterol; and chylomicrons are only about

2 percent cholesterol ( 15). The serum

cholesterol is the total amount of cholesterol

circulating in all molecular forms.

Prolonged hyperlipoproteinemia or hyperlipidemia (elevated levels of lipids in the

blood) has long been thought to contribute to

the risk of heart disease. Hypercholesterolemia--long believed to be the most important form of hyperlipidemia--has been

shown to be a major risk factor for coronary

heart disease (CHD) in middle-aged men.

However, epidemiologic studies suggest that

the cholesterol level does not have the same

significance as a risk factor for cardiac disease in the elderly as in middle-aged and

younger populations. Relatively few studies

have addressed whether the cholesterol level

at age 65 or older predicts CHD risk; the

results of these are conflicting and vary with

gender. Almost all studies of elderly men

failed to find an association between

cholesterol level and CHD incidence or

mortality (4,5,8,22,44,115,126). The single

exception was conducted on a population with

a very low CHD mortality rate (13). In

elderly women, cholesterol level was found to

predict CHD or CHD mortalit y

(13,51,1 15, 126). Although it is not certain

why cholesterol might be a better predictor of

CHD or CHD mortality in elderly women

than in elderly men, women begin to develop

symptoms of CHD at more advanced ages

than men, so from the standpoint of cardiac

disease, an elderly woman may bear risks

similar to those of a middle-aged man. It is

possible that future studies, conducted in

populations with lower rates of CHD

mortality, may confirm that cholesterol is a

risk factor in both elderly men and women,

but today the evidence that cholesterol is an

important CHD risk factor at advanced ages

remains equivocal.

Whatever its association with CHD incidence or mortality, the cholesterol level

does not appear to be an independent predictor of overall survival in the elderly. The

few studies that investigated this issue found

either that the cholesterol level does not predict total mortality at all (5,8,13) or that it is

a statistically significant predictor of lower

morality (1 15). Since the cholesterol level is

not associated with mortality in the elderlyj

and since the development of CHD is only
2 ■ Costs and Effectiveness of Cholesterol Screening in the Elderly

weakly associated with the cholesterol level,

the epidemiologic evidence does not confirm

that detecting and treating hypercholesterolemia in the elderly will increase their

longevity.

The HDL level may be a better predictor

of cardiac risk in the elderly (higher levels

indicating lower risk). However, HDL assays

in routine clinical use are not well standardized. Because of the resulting inaccuracies,

the HDL level may not predict cardiac risk as

accurately as the well-standardized HDL assays used in the epidemiologic studies that

have found an association between HDL and

cardiac risk.

Treatment of High Cholesterol In

the Elderly

The effects of cholesterol-lowering treatment in the elderly have not been studied extensively. In middle-aged men without evidence of heart disease, treatment of hypercholesterolemia lowers CHD incidence and

CHD mortality but has not been shown to affect overall survival. In the elderly, the efficacy of cholesterol reduction has not been

tested, and the adverse effects of treatment

may be more frequent and more severe.

Consequently, there is no firm evidence to

suggest that cholesterol screening and subsequent treatment would prolong the lives of

elderly individuals who have no evidence of

heart disease.

Costs of Screening and

Treatment

Recommendations for periodic cholesterol screening have recently been promulgated by the National Heart, Lung, and Blood

Institute’s National Cholesterol Education

Program (NCEP) (l16). These recommendations call for a total cholesterol determination

at least every 5 years beginning at age 20.

They also specify diagnostic followup and

treatment regimens for individuals identified

at screening with high cholesterol levels.

OTA estimated the annual health care expenditures implied by the NCEP protocol if

the protocol were fully implemented in the

elderly population. This model estimates the

national health care expenditures associated

with full compliance with the NCEP screening and treatment regimens.

The estimates of national health expenditures represent total incremental health expenditures associated with cholesterol screening and subsequent treatment of those requiring it in the asymptomatic elderly population

compared to no screening or treatment in that

population. Because many elderly people are

presently screened and treated for high

cholesterol, some of these costs are already

incurred today. A Medicare cholesterol

screening benefit would further increase

cholesterol screening and treatment rates and

the health care costs associated with them.

Expenditures for actual screening are

relatively low compared to the costs of treating hypercholesterolemia; hence, total health

care expenditures associated with the NCEP

protocols are very sensitive to the costs of

medications. Full compliance with NCEP

screening and treatment protocols would

result in treatment, either with diet or

medication, of between 47 and 57 percent of

the elderly population. In 1995, total health

care expenditures associated with the NCEP

protocols for cholesterol screening and treatment of the elderly would be between $2.9

billion and $14.3 billion (in 1988 prices)

depending on the prevalence of certain risk

factors in the elderly and the mix of medications prescribed by physicians treating elderly

patients with hypercholesterolemia.

Whether the elderly would fully comply

with cholesterol screening and treatment

regimens even under full Medicare funding is

questionable, so the actual impact of NCEP

or Medicare coverage on health expenditures

is probably substantially less than the

estimates imply. For example, if only 25

percent of the elderly were to comply with

the screening and treatment protocols

specified by the NCEP, national health care
Costs and Effectiveness of Cholesterol Screening in the Elderly 3

expenditures for cholesterol screening and

treatment of the elderly would range between

$800 million and $3.6 billion in 1995. It is

worth noting, however, that the extent to

which the actual costs of the NCEP protocol

turn out to be lower than the costs estimated

for full compliance is a reflection of the failure of the NCEP to achieve its stated goal of

full participation in cholesterol screening.

Implications for Medicare

Medicare currently pays 80 percent of

allowed charges after the beneficiary has met

an annual deductible. Assuming that Medicare similarly were to pay 80 percent of

screening expenditures, Medicare costs for

screening only (not including treatment)

would be roughly $46 million in 1995. In

addition, Medicare would pay 80 percent of

allowed charges for physician services and

diagnostic procedures necessary for monitoring drug therapy, which would range from

about $250 to $550 annually for each treated

individual. If the entire elderly population were to comply fully with the NCEP

guidelines, Medicare expenditures for testing

and monitoring would range from $1 billion

to $5.4 billion in 1995, depending on the frequency of risk factors and the monitoring required for prescribed medications. With a 25

percent compliance rate in the elderly,

Medicare’s expenditures (net of outpatient

prescription drug benefits) would be reduced

proportionately to between $261 million and

$1.3 billion. Under the recently enacted

Medicare Catastrophic Coverage Act of 1988

(Public Law 100-360), Medicare would also

likely bear some portion of the cost of drugs

used to treat hypercholesterolemia. A1though

some cholesterol-lowering drugs by themselves are unlike] y to cause beneficiaries’

drug expenses to exceed the required deductible, many elderly taking cholesterol-lowering

drugs would qualify for the drug benefit because they use multiple prescription medications.
2. INTRODUCTION

Heart disease is the most common cause

of death among elderly Americans, killing 2.5

percent of American men and 1.9 percent of

American women aged 65 and over in 1984

(121). Prolonged hyperlipidemia, or elevated

levels of lipids (fats) in the blood, 1 has long

been thought to contribute to the risk of

heart disease. Biological, epidemiological,

pathological, and clinical evidence has shown

that the most important form of hyperlipidemia, hypercholesterolemia (elevation of

the blood cholesterol level), is an important

risk factor for coronary heart disease (CHD),

the leading form of heart disease in adults.

hypercholesterolemia is thought to result in

CHD by causing atherosclerosis (the accumulation of fat deposits in blood vessels) in

the arteries supplying blood to the heart.

Atherosclerosis can affect other organs as

well, leading to severe limb pain, gangrene,

kidney failure, and strokes. Interest in

cholesterol screening has sprung from the

hope that the detection and treatment of hypercholesterolemia will help avert the pain,

suffering, and mortality of these diseases.

Several randomized controlled trials conducted in the past decade have shown that

treatment of hypercholesterolemia can

diminish the incidence of CHD and reduce

the number of cardiovascular deaths. At the

same time, inexpensive tests have become

available for measuring the cholesterol level

in blood serum. The trend toward identifying and treating hypercholesterolemia has

culminated in the report of the National

Cholesterol Education Program (NCEP), an

expert consensus group, which has recommended that all Americans 20 years of age

and over be screened for hypercholesterolemia at least once every 5 years. Treat1 Fats present in the b(ood are usual[y combine d

~ith proteins to form 1llipoproteins.ll Because th e

disorders considered in this document are charac -

terized by excess lipoproteins, some authors us e

the term 1lhyper [ipoproteinemiall rather than 1lhy -

per [ i pidemi a. II

ment should be determined according to the

cholesterol level and the presence of other

risk factors (1 16). Public awareness of

cholesterol as a risk factor for cardiac disease

has increased in the wake of concerted educational campaigns of the National Institutes

of Health, the American Heart Association,

and others. Interest in screening for hypercholesterolemia is at an all-time high, at least

among the medical profession (105).

Most of the evidence about cholesterol as

a risk factor and about the treatment of hypercholesterolemia has been obtained from

populations of middle-aged men. The elderly

may be different. Medications often have

more severe and frequent side-effects in the

elderly (95,101). Many of the elderly metabolize some drugs more slowly than younger

people; they may take more medications,

risking adverse drug interactions; and they

are particularly likely to suffer from multiple

illnesses that affect their ability to tolerate

medications. Because of these and other factors, the benefits and risks of cholesterol

reduction in elderly men and women may be

different from those of middle-aged men.

This paper addresses two questions: (1)

will cholesterol screening improve the health

of asymptomatic elderly Americans? and (2)

what are the implications of cholesterol

screening and treatment in the elderly for

health care expenditures? The population

considered in this paper excludes individuals

who have clinical evidence of diabetes mellitus or heart disease. Heart disease includes

the presence of angina pectoris (brie f

episodes of chest pain caused by narrowing or

blockages of the coronary arteries), a previous

myocardial infarction (heart attack), arrhythmia (disturbances of the heart rhythm), congestive heart failure, or hypertension (high

blood pressure). Such individuals, whose

conditions put them at high risk of heart attack and death, should be under the treatment

of physicians and are likely to be taking

5
6 ■ Cost and Effectiveness of Cholesterol Screening in the Elderlv

medications that affect their cholesterol level.

Cholesterol determinations may be important

in these individuals for the purpose of

monitoring rather than the detection of a risk

factor. A discussion of this use of cholesterol

testing is beyond the scope of this paper.

Although this paper emphasizes the effects of cholesterol on mortality, it also discusses its role in causing symptoms and diseases that result in hospitalization. The argument in favor of cholesterol screening rests

upon the following premises: First, the risk

factor it detects is important because it is

common. Second, the cholesterol test identifies a group of individuals at excess risk of a

serious disease. Third, treatment of hypercholesterolemia is more effective in reducing

overall mortality and morbidity if initiated

before it causes symptoms. After critically

examining these premises, the paper turns to

evidence about the current utilization of

cholesterol assays among Medicare recipients

to discover whether liberalized reimbursement

policies would increase participation in

cholesterol screening programs. Finally, it

addresses the implications of such changes for

national health care expenditures.
——. — -

3. EPIDEMIOLOGY OF hypercholesterolemia IN THE ELDERLY

hypercholesterolemia (elevation of the

blood cholesterol level) is a health problem

because it predisposes to diseases that cause

significant morbidity and mortality.

Diseases Associated With

hypercholesterolemia

Stroke

Stroke refers to brain injury that results

from inadequate blood flow to the brain.

Common causes include congenital abnormalities of cerebral arteries and hypertensive damage to cerebral blood vessels. In

addition, atherosclerosis can cause stroke in

three ways: atherosclerotic deposits can block

arteries carrying blood to the brain; fragments

of the deposits in the major arteries to the

brain or elsewhere can dislodge and block

smaller arteries; or atherosclerotic deposits

can develop in small vessels in the brain

causing hemorrhage and stroke. The role of

atherosclerosis in the sequence of events leading to a stroke has led many to suspect that

hypercholesterolemia might be a risk factor

for this syndrome.

Stroke is important because it is a common cause of death and because nonfatal

stroke can lead to severe disability and institutionalization. More than 2.6 percent of

all men and 2.2 percent of all women aged 65

and over were admitted to hospitals in 1984

with a diagnosis of cerebrovascular disease.

The number of stroke deaths per 100,000 men

and women aged 65 and over was 447.7 and

495.1, respectively, in 1984 (121). Stroke is

the second most common cause of death in

Americans aged 85 and over, and the third

most common cause in 65 to 84 year-olds.

Peripheral Vascular Disease

Peripheral vascular disease (PVD) refers

to obstructive disease of blood vessels of the

extremities. Although some authors include

disease of the veins and lymphatic vessels in

the definition of PVD, this paper will discuss

only disease of the arteries, which is more

likely than venous or lymphatic disease to be

related to hypercholesterolemia. Most PVD is

thought to be due to atherosclerotic occlusion

of the arteries supplying blood to the lower

extremities.

PVD can affect any large artery of the

extremities. The most common syndromes

are intermittent claudication, a sever e

exercise-related pain in the calves or buttocks; coldness and numbness in an extremity;

impotence; and loss of strength in an affected

leg. Severe PVD can lead to skin ulceration,

gangrene, and loss of the extremity.

The prevalence of symptomatic PVD is

uncertain. Since many individuals with

severe PVD have concomitant diabetes and/or

coronary heart disease (CHD), it has been

difficult to discern the independent effect of

PVD on mortality. However, it can produce

severe disability since even minimal walking

may precipitate severe claudication pain.

Coronary Heart Disease

Ischemic or coronary heart disease refers

to the clinical syndromes that result from impaired blood flow to the myocardium (heart

muscle), Ischemia, or inadequate blood flow,

reflects an imbalance between blood supply

and demand and is usually associated with

obstructive deposits of cholesterol- rich

material in the coronary arteries (coronary

atherosclerosis). CHD includes angina pectoris, a characteristic chest pain syndrome;

myocardial infarction (heart attack); sudden

death, or death occurring within an hour of

the onset of symptoms and in the absence of

a known cause; l and coronary insufficiency,

or unstable angina, a syndrome of prolonged

chest pain associated with electrocardio-

] Some authors use a longer time [ imit for sudde n

death, inc~uding a [ 1 deaths that occur wi thin 2 4

hours of the onset of symptoms in the definition .

7
8 ■ Costs and Effectiveness of Cholesterol Screening in the Elderly

graphic abnormalities, but lacking the chemical or electrocardiographic evidence of

definite myocardial infarction.

CHD is the most common cause of death

among adult Americans, and it is a very common disease. Most symptomatic CHD occurs

in the elderly; more than 17 percent of men

and 11 percent of women aged 65 and over

who are not in nursing homes or other institutions report that they suffer from ischemic heart disease (120). In 1984, 8.4 percent of all men and 6.9 percent of all women

aged 65 and over were admitted to a hospital

because of heart disease (121). Most of these

admissions were due to CHD or consequences

of CHD, such as congestive heart failure.

These admissions accounted for more than 7.6

million and 10 million days of hospital care

for men and women, respectively (121). The

National Vital Statistics system reported that

in 1985 heart disease killed more than 1 percent of all Americans who were between the

ages of 65 and 74, 2.7 percent of 75 to 84

year-olds, and 7.3 percent of Americans aged

85 and over (122).

The Distribution of Serum

Cholesterol Levels Among

Elderly Americans

According to a recent consensus statement from the National Heart, Lung, and

Blood Institute (NHLBI) and other experts,

serum cholesterol levels of 240 milligrams per

deciliter of blood serum (mg/dl) and above

are “high-risk” even in the absence of other

cardiac risk factors. In the presence of other

risk factors, a cholesterol level of 200 mg/dl

or more should lead to further evaluation

(1 16). As table 1 demonstrates, most adult

Americans have cholesterol levels that exceed

the “desirable” level of 200 mg/dl or less.

If the 240 mg/dl cutoff is used, about 30

percent of men and 50 percent of women

aged 65 to 74 are at high risk. Even at the

higher cutoff of 260 mg/dl for high risk proposed by an earlier NHLBI--sponsored consensus conference (11 4), 18 percent of men

and 34 percent of women aged 65 to 74 fall

into the high-risk category (121). If a “highrisk” cholesterol level mandates treatment, a

vast number of elderly Americans will need

to undergo therapy.

Evidence That

hypercholesterolemia Is

Associated With Increased

Morbidity and Mortality

Although hypercholesterolemia may contribute to other illnesses, its most important

impact is on CHD. Many studies of middleaged and younger men have demonstrated

that the cholesterol level predicts CHD incidence, CHD mortality, and mortality from

all causes (39). The evidence comes from international comparisons of CHD incidence

and death rates (66), as well as epidemiologic

and clinical studies. This section describes

the evidence that the cholesterol level is a

predictor of the incidence of stroke ,

peripheral vascular disease, and CHD, and of

mortality from CHD and from all causes.

Serum Cholesterol as a Predictor

of Stroke Incidence

Because there are substantial similarities

between the pathology of atherosclerosis of

the coronary arteries and the lesions responsible for stroke, many authors have suggested

that hypercholesterolemia may be an independent predictor of morbidity from stroke.

Three main lines of evidence are available to

test this hypothesis. First, several authors

have compared the cholesterol levels in stroke

victims to those without strokes. A binational cooperative study compared stroke

victims to controls in Japan and Minnesota

(14) and found no difference in the cholesterol levels of the cases and controls within

each country. A report on stroke in adults

less than 50 years old (35) found no difference between the cholesterol levels of the

victims and local population averages.

More direct evidence comes from longitudinal studies that have examined cholesterol

as a predictor of stroke. The Honolulu Heart
—.—

Costs and Effectiveness of Cholesterol Screening in the Elderly 9

Table 1.-- Mean Serum Cholesterol Levels of Men and Women, SEM, Age-Adjusted Values,

Selected Percentiles, Number of Examined Persons, and Estimated Population,

by Race and Age: United States, 1978-1980

Number of Estimated

persons population Percentilea

Age examined i n thousands Mean SEM 5th IOth 15th 25th 50th 75th 85th 90th 95th

All races:

20-74 5604

20-24 676

25-34 1067

35-44 745

45-54 690

55-64 1227

65-74 1199

White:

20-74 4883

20-24 581

25-34 901

35-44 653

45-54 617

55-64 1086

65-74 1045

Black:

20-74 607

20-24 79

25-34 139

35-44 70

45-54 62

55-64 129

65-74 128

Age-adjusted values:

All races, 20-74 MA

White, 20-74 MA

Black, 20-74 MA

63611

9331

15895

11367

11114

9607

6297

55808

8052

13864

9808

9865

8642

5576

6102

1043

1546

1112

1044

801

555

MA

MA

MA

—

69994

9994

16856

12284

11918

10743

8198

60785

8408

14494

10584

10369

9601

7329

7579

1304

1953

1415

1215

959

733

MA

MA

MA

All races: b

20-74 6260

20-24 738

25-34 1170

35-44 844

45-54 763

55-64 1329

65-74 1416

White:

20-74 5418

20-24 624

25-34 1000

35-44 726

45-54 647

55-64 1176

65-74 1245

Black:

20-74 729

20-24 94

25-34 145

35-44 103

45-54 100

55-64 135

65-74 152

Age-adjusted values:

All races, 20-74 MA

White 20-74 MA

Black 20-74 MA

aSerun cholesterol va[ues are given in mi~ ( igrams per deci L iter. To convert values to mi~limo[es per Liter,

~mu~tip(y by 0.02586.

Inctudes data for races not shorn separately.

ABBREVIATIONS: SEM = standard error of the mean, NA = not appticab~e.

SOURCE: Reproduced from AduLt Treatment Pane(, NationaL Cho[estero( Education Program, NationaL Heart, Lung, and

BLood Institute, Nationa[ Institute of Health, U.S. Department of Health and Human Services, “Report of the

National Cho[estero[ Education Program Expert Pane( on Detection, Evacuation, and Treatment of High BLood

Choiestero( in Adu(ts,” Arch. Intern Med. 148:36-69, 1988.

211

180

199

217

227

229

221

211

180

199

217

227

230

222

208

171

199

218

229

223

217

211

211

209

215

184

192

207

232

249

246

216

184

192

207

232

249

246

212

185

191

206

230

251

243

215

215

214

Men

1.2 144 156

1.7 129 136

1.5 141 152

2.0 153 166

1.8 159 176

1.8 164 176

1.8 153 167

1.2 145 157

1.8 131 138

1.7 144 153

1.8 153 166

1.8 160 177

2.0 164 178

2.0 153 167

2.5 133 146

3.7b

b 128

4.1b

129 136

8.3b

b 156

7.1b

b 174

4.8b

157 168

4.2 149 163

1.1 MA MA

1.1 MA NA

2.5 MA NA

Women

1.2 143 156

1.9 132 140

1.4 135 145

1.8 147 158

2.2 164 178

2.0 180 193

1.6 173 189

1.3 143 156

2.1 133 140

1.5 135 145

1.9 147 157

2.6 166 179

1.7 180 193

1.7 174 190

3.1 140 154

4.9b

b 136

4.1 129 144

4.5b

143 158

7.2b150 172

8.0b178 185

4.2 173 189

1.2 MA MA

1.2 MA MA

2.7 MA MA

165

145

159

173

182

184

175

166

146

161

173

181

185

175

156

134

144

168

184

172

173

MA

NA

MA

166

145

154

164

188

203

198

166

147

153

164

188

203

199

166

144

156

170

181

198

198

MA

MA

MA

179

155

172

187

197

198

191

179

155

172

187

198

199

191

171

149

163

176

195

183

183

MA

MA

NA

179

157

164

177

199

215

214

179

159

164

177

199

215

214

176

156

167

175

200

211

211

MA

MA

MA

206

176

194

215

223

225

217

207

176

194

214

222

225

217

200

170

192

202

232

218

216

MA

MA

NA

210

180

188

202

228

242

241

210

181

188

203

228

244

242

205

178

190

194

226

233

237

MA

MA

NA

239

202

220

244

255

254

249

239

202

220

244

254

255

250

238

193

226

238

261

254

244

NA

MA

NA

245

204

215

231

257

277

274

246

204

215

231

257

277

275

237

204

212

233

263

280

269

MA

MA

MA

258

215

240

262

271

277

265

258

216

239

260

271

278

266

260

210

248

275

268

271

261

MA

MA

MA

266

216

233

248

275

299

295

267

215

235

248

274

298

296

263

220

226

254

277

318

290

MA

MA

MA

271

227

254

275

283

288

279

271

229

254

272

283

289

281

273

211

259

283

279

299

277

MA

MA

MA

282

230

243

260

290

314

309

282

230

244

250

290

312

309

279

237

235

274

291

336

308

MA

MA

MA

291

246

275

293

303

307

301

291

244

273

291

303

307

301

301

b

301

b

b

312

299

MA

MA

MA

305

250

263

276

306

336

327

305

249

261

277

308

330

328

308

b

267

279

306

345

322

NA

MA

MA
10 ■ Costs and Effectiveness of Cholesterol Screening in the Elderly

Program reported a statistically significant Ushaped association between cholesterol and

subsequent incidence of stroke (97). Stroke

rates were higher at both very low and high

cholesterol levels than for cholesterol levels in

the middle range. However, in a similar

analysis of transient ischemic attacks (a

stroke-like syndrome that resolves within 24

hours), the predictive ability of cholesterol

disappeared when hypertension and cigarette

smoking were considered (98).

Westlund (127) and Balodimos (1 1) each

reported that cholesterol is a significant predictor of stroke when examined alone (i.e., in

a univariate analysis). Another univariate

analysis, a 10-year followup of residents of

Shikoku Island, Japan found no association

between cholesterol and stroke (109). None

of these reports included a multivariate analysis. Only a multivariate analysis, which

measures the independent or separate effects

of each of several risk factors, can distinguish

the effect of cholesterol from the effect of

other risks, such as cigarette smoking, that

are also correlated with the cholesterol level.

Studies that control for the impact of

other potential risk factors suggest that

cholesterol is not independently associated

with the risk of stroke. Two Italian reports

of fatal and nonfatal strokes in men between

40 and 59 years of age found no independent

role for cholesterol as a risk factor (33,86).

A 7-year followup of a cohort of adults 35 to

39 years old in Eastern Finland found hypertension, age, tobacco use, prior stroke, and

diabetes to be independent predictors of

stroke, while the independent association with

cholesterol was not significant (102), A 13-

year study of 50-year-old men found that the

diastolic blood pressure, smoking habits, and

the erythrocyte sedimentation rate were significant predictors (3). Once again, the association with cholesterol was insignificant. An

8-year followup of adults 40 to 69 years of

age in a farming village in Akita, Japan ascribed a similarly insignificant independent

role to cholesterol (111). Finally, the Framingham Heart Study (an ongoing prospective

epidemiologic study of several thousand

adults from Framingham, Massachusetts, that

was begun in the late 1940s) found that the

cholesterol level was not associated with the

risk of stroke except in subjects who also had

other risk factors (65). In multivariate

analyses of the 2-year risk of stroke from

Framingham, the independent effects of the

cholesterol level on the risks of stroke and

transient ischemic attack were not statistically

significant in either men or women with the

exception of women aged 65 to 74.

In summary, case-control studies as well

as multi variate longitudinal analyses have

suggested that the serum cholesterol does not

appear to be independently associated with

the risk of stroke. The apparent relation between cholesterol and stroke is due to the relation between cholesterol and other variables,

particularly smoking and hypertension, that

appear to be much stronger predictors of

stroke risk.

Serum Cholesterol as a Predictor of

Peripheral Vascular Disease Incidence

Just as hypercholesterolemia would be

expected to predispose individuals to stroke,

it also is a potential risk factor for peripheral

artery disease. Few studies have examined

whether there is a significant association between cholesterol level and the incidence of

PVD.

Two studies found that the cholesterol

level was a significant predictor of the subsequent development of PVD in univariate

analyses, but none of these studies controlled

for the effect of other risk factors (1 1, 127),

One report from the Framing ham Study

found that intermittent claudication, a clinical

marker for PVD, was more common in hypercholesterolemic subjects but failed to apply multivariate analysis (45). A recently

reported 25-year evaluation of two rural

Italian communities found that deaths from

PVD were so rare (0,72 percent over 25

years) that no statistical relations to to

cholesterol could be determined (86).
Costs and Effectiveness of Cholesterol Screening in the Elderly ■ 11

Studies could not be located that assessed

whether the serum cholesterol level has an association with PVD that is independent of

such confounding variables as cigarette smoking and the blood pressure level. Because the

serum cholesterol level is associated at the

population level with cigarette smoking, the

association of cholesterol level and PVD independent of those factors is likely to be smaller than the association found in univariate

analyses.

Serum Cholesterol as a Risk Factor for

Coronary Heart Disease Incidence and Death

Numerous multi variate studies of

middle-aged men have shown that, over a

wide range of cholesterol values, the probability that an asymptomatic individual will

subsequently develop angina or suffer a

myocardial infarction or sudden cardiac death

rises in an approximately exponential fashion

with his or her cholesterol level. Thus, the

same increment in cholesterol has a much

more pronounced effect at higher levels than

at lower levels of serum cholesterol. For example, among 361,662 men screened in the

Multiple Risk Factor Intervention Trial

(MRFIT), individuals whose cholesterol exceeded 263, 2 placing them at or above the

90th percentile, had four times the risk of

coronary death of the bottom 20 percent,

whose cholesterol level was less than 182 (85).

In the Whitehall study, the 10-year CHD

mortality ranged from 2.85 percent in the

lowest quintile, to 3.44 percent in the next

lowest quintile, to 5.37 percent in the highest

quintile of cholesterol levels (99). A pattern

of slowly rising risk of CHD at lower

cholesterol levels and rapidly rising risk at

higher levels was observed in the Framingham Study (63), which examined CHD incidence, and in a prospective study of Israeli

z Unless otherwise noted, throughout this docunent

Ilcho[ estero[ II refers to the serun cholesterol ! evel

and is reported i n units of mg/d( . Ch 01 esterol

levels in many countries are reported i n units o f

rmnol/L (S1 units); to convert f ran mg/dl to nwnol/L,

mu( t ip[y by 0.02586 .

Figure 1--- Relation Between Plasma

Cholesterol Level and Relative Risk of

Coronary Heart Disease (CHD) in Three

Prospective Studies

150 200 250

(3.6a) (5. 17) (6.47)

Plasma Cholesterol,

mg/dL (mmol/L)

Key: ● = Framingham Heart

A = Pooling Projec t

300

(7.76)

study

o = Israeli Prospective Stud y

SOURCE : Reproduced w ith permi ss i on from S. M.

Grundy, IIcholesterol and Coronary Heart

Disease, J

’ J. A.M.A. 256:2849-58, 1986.

Copyright 1986, American Medical Assoc i at ion.

civil servants (41), which examined CHD

mortal it y. The relation between cholesterol

level and relative risk of developing CHD in

three prospective studies is illustrated in figure 1 (48). Epidemiologic studies have also

found that the effect of hypercholesterolemia

is highly dependent on the presence of other

risk factors. Cholesterol interacts in a

synergistic fashion with other risk factors to

increase the risk of coronary disease .

Cigarette smoking and hypertension, in particular, produce greater increases in CHD

mortality in people with hypercholesterolemia

than would be predicted on the basis of each

risk factor alone (64,93).

It is not certain that these results apply

to the elderly. The relation betwee n

cholesterol and CHD risk in the elderly will
12 ■ Costs and Effectiveness of Cholesterol Screening in the Elderly

undoubtedly be clarified when more data become available. Relatively few studies have

addressed whether the cholesterol level predicts CHD risk at age 65 or older, although

the Stockholm Prospective Study (22),

Framingham, and a few others included

elderly individuals. Investigators in the

Framingham Study reported several years ago

that total cholesterol is not a significant risk

factor for the development of CHD in the

elderly, despite its clear predictive power in

younger individuals (44). Two later publications based on 30 years of followup from the

Framing ham Heart Study indicated that

cholesterol is a risk factor for CHD in elderly

women, but not elderly men. In a multivariate logistic regression analysis, Framingham investigators reported that the cholesterol

level was not a statistically significant independent predictor of the incidence of CHD

among men aged 65 and over, although it was

a significant predictor for women (1 15).

The second Framingham publication used

Cox-type proportional hazards analysis 3 t o

relate the development of CHD to putative

cardiac risk factors in individuals 65 years of

age and over (5 1 ). For this study, the

cholesterol level was divided into four categories: <200 mg/dl; 200 to 239 mg/dl; 240

mg/dl to the 90th percentile (306 mg/dl for

women and 275 mg/dl for men); and 90th

percentile and above. The risk of CHD was

significantly elevated for those individuals

whose cholesterol was at the 90th percentile

or greater, when men and women were

pooled; the elevated risk for those in the

category between 240 mg/dl and the 90th

percentile reached borderline statistical significance . The association betwee n

cholesterol category and risk of CHD was

much stronger for women than for men.

When men and women were analyzed separately, the risk of developing heart disease

3 Proportional hazards analysis is a biostatistical

method for ana 1 yz i ng the association twtueen r i sk

factors and variation in survival (27) .

was 2.3 times as great for women whose

cholesterol exceeded 305 mg/dl as for women

whose cholesterol level was less than 200

mg/dl. This risk elevation was statistically

significant. There was a trend toward increasing risk of CHD with increasing

cholesterol level for both men and women,

but aside from the single category of women

whose cholesterol levels were in the top 10

percent, the association between cholesterol

level and CHD risk did not achieve statistical

significance. Thus both of these reports from

the Framingham Heart Study suggest that

very high cholesterol levels are associated

with an elevated risk of developing CHD for

elderly women, but not necessarily for the

elderly men.

In the Glostrup prospective epidemiologic

study of 230 men and 210 women aged 70

and above from nine Danish municipalities,

the cholesterol level at age 70 did not predict

the development of cardiovascular disease

(CVD) during the succeeding ten years, when

suspected risk factors that are correlated with

cholesterol-- triglycerides, glucose intolerance

(diabetes), and a prior history of CVD--were

taken into account. CHD was not reported

separately; CVD included CHD as well as

cerebrovascular disease and intermittent

claudication. These results were true for men

and women (4,5). In univariate analyses of

the Busselton (Australia) Study, th e

cholesterol level did not predict the development of CHD in the succeeding 6 years

among men or women who were 60 years of

age or older; multi variate results were not

presented ( 126). A univariate 9-year fol10WUP study of Swedish men found that the

serum cholesterol level did not predict the

subsequent development of CHD among men

who were aged 60 or over at the time the

cholesterol was drawn (22).

The relation between cholesterol and

CHD death rates is similar to the relation

with CHD incidence. In the Glostrup study

of 70 year-olds (5), the serum cholesterol was

not a significant independent predictor of
Costs and Effectiveness of Cholesterol Screening in the Elderly 13

cardiovascular mortality. In the Busselton

study, total cholesterol did not predict CHD

or CVD mortality in men or women aged 60

to 69, or in men aged 70 and above, although

cholesterol was significant at the 5 percent

level in predicting CHD mortality among

women aged 70 and above (126). In the 30-

year followup of the Framingham Study, the

serum cholesterol predicted CHD death rates

in elderly women, but not in elderly men

(1 15).

This review located only one published

study that found cholesterol is a significant

independent predictor of CHD death rates

among both elderly men and women. This

study, in adults between 50 and 79 years of

age in Southern California, reported results of

a Cox-type proportional hazards analysis that

found that total cholesterol was a significant

independent predictor (p<0.01) of CHD mortality among men and women aged 65 to 70.

Among women aged 65 to 79, it was significant at the 5 percent level. The authors

explained the disparity with other studies by

noting that they conducted their investigation

more recently. Because of falling CHD mortality rates, “subjects with high levels of risk

factors [were] no longer weeded out by age

50 or even by age 65. Consequently, the impact of selective mortality may be delayed so

that these risk factors still have expression at

later ages” ( 13). Their hypothesis was supported by the low CHD mortality rate in their

study population compared to other studies

and compared to the general U.S. population

(the risk ratios for men and women were 0,40

and 0.27, respectively). Unpublished observations from the Lipid Research Clinics followup study, a major epidemiologic study

conducted by several collaborating institutions, also suggest that the total cholesterol

level is a significant predictor of CHD incidence and mortality in the elderly (19).

Collectively, these studies demonstrate

that the blood cholesterol level is an independent risk factor for the development of CHD

in middle-aged men and elderly women. Although it is not certain why cholesterol seems

to retain its importance as a risk factor in

elderly women more than in elderly men,

women begin to develop symptoms of CHD at

more advanced ages than men, so from the

standpoint of cardiac disease, an elderly

woman may bear risks similar to those of a

middle-aged man. It is possible that newer

studies will confirm that cholesterol is a risk

factor in elderly men and women, as the

work of Barrett-Connor and colleagues and

the results from the Lipid Research Clinics

followup suggest. However, there is currently little evidence that cholesterol is a CHD

risk factor in men who have reached the age

of 65 without manifesting heart disease.

The Serum Cholesterol Level as a

Risk Factor for All-Cause Mortality

Does the relation between overall

mortality and cholesterol level parallel the relation between CHD risk and cholesterol

level? Univariate analyses have found that,

for individuals whose cholesterol is below the

tenth or twentieth percentile, mortality actually decreases as cholesterol levels increase;

at higher cholesterol levels, further increases

in cholesterol are associated with rising

mortality (see figure 2). The MRFIT study

found that middle-aged men whose cholesterol levels were in the bottom decile had a

significantly increased rate of cancer death

early in the trial (before the intervention

could have been responsible for an increased

cancer risk). Adjusted for age, smoking

status, and randomization group, the MRFIT

participants who died of cancer experienced

much greater falls in serum cholesterol levels

after enrollment than did survivors. Furthermore, the drop in cholesterol was greatest

among the men who died of cancer early in

the trial, which has been interpreted to mean

that cancer causes the serum cholesterol to

fall ( 106), rather than that a falling

cholesterol causes cancer. Other large studies have also found that at very low

cholesterol levels, declines in cholesterol are

associated with increased all-cause mortality.

In the Israeli civil servants study, ageadjusted overall mortality at 15 years was
14 Costs and Effectiveness of Cholesterol Screening in the Elderly

Figure 2--- Age-Adjusted 6-year CHD and

Total Mortality per 1,000 Men Screened for

MRFIT According to Serum Cholesterol

40

30

20

10

Total Mortalit y

A A

SERUM CHOLESTEROL (mmol/L )

Entire cohort of 361,662 men was divided into ap -

proximate twentieths , and each point represents th e

mortality (either CHD or total) and the mea n

cholesterol level in one of those twentieths .

Modified lines are drawn through the points .

ABBREVIATION: CHD = coronary heart disease .

SOURCE: Reproduced with permission from H.J.

!4artin, S.B. Hulley, and U.S. Browner ,

IISerum Cholesterol, Blood Pressure, an d

Plortality: Iir@lications From a Cohort o f

361,662 ken,” Lancet 2:933-936, 1986 .

lowest for individuals in the third decile, corresponding to a serum cholesterol of 177 to

187 mg/dl (41). All-cause mortality in the

bottom decile, corresponding to a cholesterol

level of less than 161 mg/dl, was about the

same as mortality in the seventh decile, corresponding to a cholesterol level of 217 to

227 mg/dl,

Not all studies have found a negative association between cholesterol level and noncardiovascular mortality. The inconsistent

findings of epidemiologic studies have led

some experts to question whether a low

cholesterol level is associated with elevated

cancer mortality (34,107), but most of the

studies were not designed to examine the relation between cardiovascular risk factors and

noncardiovascular mortality. More controversial than the existence of an association

is its interpretation; many cardiovascular experts doubt that a declining cholesterol level

leads to elevated total mortality, while others

(104) believe that a low cholesterol level may

be more than a preclinical marker of cancer.

Whether the low cholesterol level causes cancer or cancer causes the cholesterol level to

fall, the relation with total mortality suggests

that there is little reason to further reduce an

already low cholesterol level in middle-aged

men, while rises in their cholesterol levels

clearly place them at higher risk if their

cholesterol is already elevated.

In the elderly, the total cholesterol level

does not appear to be an independent predictor of survival. The few studies that investigated this issue found either that the cholesterol level does not predict total mortality at

all (5,8,13) or, in the case of the Framingham

Study, that it is a statistically significant predictor of lower mortality for both men and

women (l15). The insignificant or negative

association may reflect the much higher incidence of death from noncardiovascular

causes in old age. For example, among white

males in 1985, the death rate from malignant

neoplasms between the ages of 35 and 44 was

39.5 per 100,000, while the death rate was

1,061 per 100,000 at ages 65 to 74 and 1,820

per 100,000 between ages 75 and 84 (115).

Cancer death rates for white females are

lower than for white males but also rise

dramatically with age. If cancer, occult or

overt, lowers the serum cholesterol, it may

cause the association between cholesterol and

total mortality to weaken or reverse with age.

In the absence of studies that directly assess the effects of cholesterol reduction in the

elderly, further investigation of the reasons

for the lack of association (or negative association) between cholesterol level and total

mortality in the elderly is important. If the

cholesterol level is not associated with

mortality in the elderly, and if the develop-
Costs and Effectiveness of Cholesterol Screening in the Elderly ■ 15

ment of CHD is only weakly associated with

the cholesterol level, the epidemiologic evidence does not confirm that detecting and

treating hypercholesterolemia in the elderly

will increase their longevity.

Do Other Lipoprotein Levels Predict

Mortality and Morbidity in the Elderly?

Cholesterol and triglycerides are the two

major lipids that circulate in blood. Both

circulate as constituents of lipoproteins. Tests

to detect hyperlipoproteinemia include serum

cholesterol and triglyceride levels as well as

measurements of specific lipoprotein classes

(sometimes called “lipoprotein fractions”).

Besides the serum cholesterol level, the

triglyceride level and the levels of two classes

of lipoproteins- -HDL and low-density

lipoprotein (LDL)--are widely used to assess

hyperlipoproteinemia. What is the role of

these tests in the identification of individuals

at high risk of CHD?

Whether the triglyceride level is an independent risk factor for CHD at any age is

controversial. In univariate analyses, the

triglyceride level appears to predict CHD

risk. However, hypertriglyceridemia is associated with cigarette smoking, obesity, diabetes mellitus, and other potential cardiac risk

factors (such as a low HDL level). Among

asymptomatic individuals who are not obese,

who do not have diabetes or a family history

of hyperlipidemia, and who do not have hypercholesterolemia, the triglyceride level does

not appear to be an independent risk factor

for CHD (12,58,59). Perhaps the most important confirmation of the importance of a

risk factor comes from studies that show that

health is improved by eliminating the risk

factor. It appears that no randomized trials

have been conducted of triglyceride reduction

alone, but a randomized trial of gemfibrozil,

a drug that raises HDL levels and lowers total

and LDL cholesterol and triglyceride levels

found that the decline in CHD incidence correlated with changes in HDL, LDL, and total

cholesterol levels, but not with the fall in

triglycerides (84).

Studies

tions have

(sometimes

cholesterol)

developing

of (primarily) nonelderly populashown that the level of HDL

called the “scavenger” or “good”

is inversely related to the risk of

CHD, and that the LDL level is

positively related to CHD risk (128). The

ratio of LDL to HDL and the ratio of HDL

to the serum cholesterol 1evel may also be

reliable predictors of cardiac risk (62). Most

commonly, the HDL and LDL levels are

viewed as adjuncts to the measurement of

serum cholesterol; many experts recommend

first obtaining a serum cholesterol level and

then determining HDL and LDL levels if the

cholesterol is elevated. Usually the LDL is a

calculated value that requires a serum

cholesterol measurement (see below), so the

LDL cannot be substituted for a cholesterol

measurement. The serum cholesterol level is

highly correlated with the LDL but not with

the HDL level (table 2), so high-risk individuals who have a low HDL level in association

with a low serum cholesterol may not be

detected if LDL and HDL measurement

(referred to as fractionation) is limited to hypercholesterolemic subjects (54,58,75).

Few studies have evaluated the HDL or

LDL levels as risk factors for CHD incidence

in the elderly, and this review did not locate

any studies that reported on the relation between HDL or LDL and either CHD mortality or total mortality in the elderly. Investigators from the Framingham Study reported

that HDL was a much better predictor of

CHD incidence among the elderly than the

total cholesterol level (43). Among men aged

60 to 69, the HDL level was a significant

predictor (p<0.05) of CHD but it was not significant for men aged 70 to 79. Among

women at age 60 to 69 or 70 to 79, the HDL

level was not a significant predictor of CHD

risk. In these analyses, the LDL level was

significant (p<0.05) in predicting the risk of

CHD among men aged 60 to 69 and 70 to 79,

and significant at the 1 percent level in predicting CHD incidence among women aged

60 to 69. Another report from the Framingham Study (44) published the same year

stated that both the HDL and LDL choles-
16 ■ Costs and Effectiveness of Cholesterol Screening in the Elderly

Table 2--- Simple Pearson Correlation Coefficients Between Various Plasma Lipids

and Lipoprotein Fractions From Various Studies

Correlation between :

stud y HDL and TC HDL and LDL LDL and TC

Framingham:

Hen (n=1 ,025) 0.1 0 -0.0 4 0.8 4

Women (n=l,445) 0.07 -0.16 0.88

Ages 49-82 years

Hawaii:

Japanese men (n=2,019) 0.03 -0.01 0.78

Ages 50-72 years

Cooperative Lipoprotein

Phenotyping Study :

a

Men (n=4,898 ) 0.03 to 0.1 8 -0.01 to -0.3 1 0.78 to 0.8 8

Women(n=l,683 ) 0.06 to 0.2 4 -0.09 to -0.1 6 0.88 to 0.8 9

Ages 40-70 year s

MRFIT :

Men (n=301) NA -0.0 8 NA

Ages 35-57 year s

a

The correlation coefficients reported for the Cooperative Lipoprotein Phenotyping Study represent the rang e

for the five geographic sites of the study .

ABBREVIATIONS: HDL = high-density lipoprotein; LDL = low-density lipoprotein; MRFIT = Multiple Risk Facto r

Intervention Trial; TC = total cholesterol; NA = not applicable .

SOURCE: Office of Technology Assessment , 1989; adapted from C.E. Davis, D. Gordon, J. LaRosa et al., ‘iCorre(ations of Plasma High Density Lipoprotein Cholesterol Levels Uith Other Plasma Lipid an d

Lipoprotein Concentrations : The Lipid Research Clinics Program Prevalence Study ,

M Circulatio n

62(supp. IV):IV-24--IV-3O, 1980 .

terol levels were highly significant predictors

of CHD risk among men and women aged 49

to 82 years. This study did not report the

number of participants who were aged 65 and

above, nor did it report results for the elderly

(aged 65 and over) separately. Because the

HDL and LDL levels were not measured as

part of the Framingham Study until 1968, the

results of both of these publications were

based on only about 4 years of followup. A

more recent publication from the Framingham investigators, based on 12 years of fol10WUP, reported that the HDL cholesterol is a

particularly strong indepen-dent predictor of

one form of CHD--myocardial infarction--

among older women, and is of borderline significance for older men (l).

Taken as a whole, the evidence from the

Framingham Study indicates that at least

among some groups of the middle-aged and

the elderly HDL and LDL levels predict CHD

incidence.

Summary

Do the cholesterol level, HDL level, or

LDL level predict the risk of significant cardiac events and death among the asymptomatic elderly? The epidemiologic studies

that included elderly individuals have found,

in some cases, that the total cholesterol level

may predict CHD risk among the elderly, but

the effect is not nearly as striking or as consistent as the relation among the middle-aged.

The relation between cholesterol level and

CHD mortality has not been reported as frequently, and here the relation is even weaker.

Furthermore, some of the studies that report

the relation between cholesterol level and

CHD mortality include individuals who have

already manifested symptoms (such as angina)
Costs and Effectiveness of Cholesterol Screening in the Elderly ■ 17

or signs (such as hypertension) of heart disease, in whom the relation between cholesterol level and CHD death may be stronger.

The HDL and LDL levels may be better predictors of CHD risk in the elderly than the

total cholesterol level. The studies that have

reported on the association between the total

cholesterol level and overall mortality have

found that the cholesterol level either is a

significant negative predictor of mortality in

the elderly (the opposite is observed in

middle-aged and younger individuals), or

does not predict overall mortality rates at all.

Why does the relation between cholesterol and CHD events weaken with age, and

why does the association with total mortality

reverse? One might speculate that individuals

who have hypercholesterolemia and remain

free of CHD when elderly may have a different mix of apolipoproteins, 4 or for some

other reason may tolerate hypercholes -

terolemia better than those who went on to

develop heart disease at earlier ages. Their

selective CHD-free survival may explain why

the individuals who survive to old age with

hypercholesterolemia and no evidence of

CHD subsequently seem to suffer few

deleterious consequences from their hypercholesterolemia . At younger ages, the

cholesterol level does not seem to be associated with non-CHD mortality, except at very

low cholesterol levels, where non-CHD

mortality may rise as the cholesterol level

falls. Several studies have found that the

elevated mortality at low cholesterol levels is

associated with cancer, though this is not a

uniform finding. The role of the serum

cholesterol level at advanced age is of great

concern because of the large potential at

4 Apol ipoproteins are parts of the 1 ipoproteins t o

uh i ch cholesterol binds.

tributable risk of hypercholesterolemia. Attributable risk refers to the expected number

of excess deaths due to the presence of a risk

factor. It is usually distinguished from the

relative risk, or the ratio of the number of

deaths in persons with the risk factor to the

number of deaths in persons without the risk

factor. The attributable risk is superior to

the relative risk as a measure of the impact

of a risk factor on overall survival, since the

relative risk of an uncommon event can be

very high without significantly affecting survival rates, For example, about 2.7 percent

of Americans between the ages of 75 and 84

died of heart disease in 1985 compared to

0.15 percent of 45 to 54 year-olds (122).

Suppose that a risk factor increases the relative risk of CHD death at all ages by 10 percent (i.e., the ratio of the rate of CHD death

among individuals with the risk factor to the

rate in individuals without it is 1.1 ). Then

the attributable risk of the factor is about

0.27 percent among 75 to 84 year-olds (i.e.,

almost 27 additional deaths per 10,000 people

in this age group would occur each year), but

it is only 0.015 percent among 45 to 54 yearolds (i. e., 2 additional deaths per 10,000

people in the age group would occur).

Most of the epidemiologic studies cited

in this paper indirectly measured the impact

of cholesterol on attributable risk, not relative

risk, but they did not find that it had a

statistically significant effect. Because the

estimates were often imprecise, they are consistent with a large impact on attributable

risk of CHD, but they are also consistent

with a small or even negative impact on attributable risk. With prolonged followup of

larger numbers of elderly individuals, the attributable risk of CHD due to elevations in

the cholesterol level may prove to be large,

but existing studies provide weak support for

such a speculation.
—

4. MEASURING CHOLESTEROL

Recommendations for Cholesterol

Measurement Among the Elderly

The National Heart, Lung, and Blood Institute’s National Cholesterol Education Program (NCEP) established an Adult Treatment

Panel composed of outside experts that published guidelines in 1988 for the measurement

and treatment of hypercholesterolemia ( 116).

NCEP categorized cholesterol levels according

to increasing risk of coronary heart disease

(CHD). For serum cholesterol, the panel

considered measurements under 200 mg/dl as

“no r m al, ” between 200 and 239 mg/dl as

“borderline high,” and 240 mg/dl or above as

“high.” Although it did not provide separate

screening guidelines for persons over 65 years

old, the panel recommended that all adults

over the age of 20 should have their total

serum cholesterol measured at least every 5

years. The full set of recommendations developed by this group for diagnosing and

treating hyperlipidemia are summarized in

appendix C.

The conclusions of the Adult Treatment

Panel supersede an earlier National Institutes

of Health Consensus Conference (114) that

concluded, without documentation, that a

cholesterol determination during annual

physician office visits would be cost-effective

for adults.

The American Heart Association (AHA)

publishes general guidelines for the prevention of CHD (6,49). Representatives of

the A HA participated in NCEP. Like the

Adult Treatment Panel, AHA recommends

that healthy people should have routine

measurement of cholesterol and triglycerides

every 5 years until age 60. But for older

patients, these tests are considered optional if

baseline measurements have been wellestablished. Like NCEP, AHA categorizes

cholesterol levels into normal (<200 mg/dl),

borderline high (200 to 239 mg/dl), and high

( > 240 mg/dl) categories and recommends that

physicians take other risk factors for CHD

into account when prescribing treatment for

persons whose lipid levels fall outside the

normal range.

The U.S. Department of Health and Human Services’ Preventive Services Task Force

(a group of experts from outside the government) is currently considering screening for

hyperlipidemia as well as other conditions.

Its recommendations for cholesterol screening

are expected to be released in the summer of

1989.

In Canada, a task force convened by the

Department of National Health and Welfare

to make recommendations on the frequency

and content of the periodic health examination considered cholesterol screening in its

initial report (20). The Canadian Task Force

(CTF) concluded that there was insufficient

medical evidence to warrant routine screening

of cholesterol or triglycerides. However, this

group did suggest that physicians may wish to

measure blood lipids for other reasons, such

as the presence of other CHD risk factors.

CTF has not reevaluated its position since

1979.

Cholesterol Measurement

Techniques

The hundreds of assays that have been

used to measure cholesterol in blood (90, 108)

can be divided into three categories. The

first includes multi-stage techniques based on

the modified Abell-Kendall method, which is

considered the “standard reference method”

(2,31 ). Application of the standard reference

method is more demanding than many

laboratory procedures, requiring relatively

sophisticated facilities and technical skills.

The laboratories of the Lipid Research

Clinics and others that use this method have

made extensive efforts to standardize and improve the quality of testing. These laboratories are thought to supply the most nearly

error-free results in clinical use. The test requires a few milliliters of blood, and labora-
20 Costs and Effectiveness of Cholesterol Screening in the Elderly

tories can generally provide results within 24

to 72 hours of receiving the specimen. These

methods are used by the Centers for Disease

Control (CDC) and Lipids Research Clinics

around the country.

The second kind of assay is based on

automated analyzers. This less exacting procedure is used mainly by general clinical

laboratories, such as those available in most

hospitals and freestanding clinics. Often, the

measurement is performed as part of a panel

of blood chemistry assays. Inaccuracy in

these tests, partly due to variability in technical competence among the thousands of clinical laboratories in the country, is a major

concern (1 17). Although the results of these

assays may be less reliable than those produced by a reference laboratory, they are

convenient because a number of measurements in addition to cholesterol can be performed on the same tube of blood. Results

can be available within minutes.

The third kind of assay, a one-step enzymatic method that has recently become

available, is particularly convenient for both

patients and providers of care. These tests

require only a few drops of blood from a

finger stick and give results in 3 to 8

minutes. The equipment can be operated in a

physician’s office, clinic, or community

screening site by personnel without a special

background in clinical chemistry. These

methods have a low per-screening cost (less

than $3 in one large-scale community screening program (47)). Preliminary reports, generated under ideal circumstances of operator

training and attention to calibration and technique, have found that assays are accurate

(18). It is not known whether this level of

accuracy will be maintained when the technology is used more widely.

Factors That Influence

Cholesterol Measurements

The measured cholesterol level is influenced by long-term or clinically significant

biologic factors, transient or insignificant

biologic factors, and measurement error. The

main determinants of the cholesterol level are

genetic characteristics, diet, exercise, and

lipid-lowering medications. To the extent

that these factors can be altered, the serum

cholesterol level may be lowered and the risk

of adverse outcome may be influenced.

A variety of other factors influence the

measured cholesterol level (73). Patient posture (reclining, sitting, or standing) and

venous stasis (blood pooling in an extremity,

which sometimes occurs during blooddrawing when a tourniquet is applied) can

change the plasma volume enough to alter

reported cholesterol levels by 5 to 12 percent.

The cholesterol level increases slightly at

ovulation and substantially during pregnancy

(75 percent over nonpregnant subjects). Although recent food ingestion, alcohol intake,

and exercise are thought not to influence

cholesterol, there is some evidence that

transient emotional stress may elevate the

level. Medications, especially those used to

treat high blood pressure, can elevate the

cholesterol level (74). Seasonal variation can

be responsible for temporary changes (1 10).

In the placebo group of the Lipid Research

Clinics-Coronary Primary Prevention Trial,

which studied men aged 35 to 59 years whose

plasma cholesterol levels1 exceeded 265 mg/dl

after a brief trial of diet, the measured

cholesterol averaged 7.4 mg/dl higher on December 30 than on June 30 (42). Other

studies (reviewed in Hegsted, 1987) have

found that even when an individual adheres

to a strictly controlled diet, his or her

measured cholesterol varies substantially over

short periods of time. A number of technical

factors can also influence the reported level

of cholesterol after the specimen has been

collected. The cholesterol level obtained in

some assays is affected by hemolysis (mechanical disruption of the blood that can occur when blood is withdrawn from a vein).

1 Plasma cholesterol levels are consistently 3

percent lower than serun cholesterol .
Costs and Effectiveness of Cholesterol Screening in the Elderly ■ 21

The most important source of variability

in the reported cholesterol level is, however,

the clinical laboratory (1 17). Most of the

epidemiologic studies that have contributed to

our knowledge of cholesterol as a risk factor

used meticulously standardized methods that

were periodically tested against a central

reference laboratory. Although laboratory error has diminished over the last 40 years, and

although NCEP has urged clinical laboratories

to redouble their efforts to standardize,

measurements remain imprecise (117). Variation in reported cholesterol levels is partially

the consequence of the varied methods used

to test cholesterol, but substantial variation

occurs even among laboratories using the

same method. The College of American

Pathologists sent a sample specimen whose

cholesterol concentration was determined by

CDC to be 262.6 mg/dl to 5,000 clinical

laboratories. The cholesterol values reported

by the surveyed laboratories ranged from 101

to 524 mg/dl (1 17). Current standards established by NCEP call for a coefficient of variatio n

2 of less than 3 percent. However,

recent studies show the coefficient of variation to be at least 6 percent (1 17).

Errors in the cholesterol level may arise

from bias in a particular laboratory method,

meaning that even when standardized well,

the reading will differ repeatedly from the

true cholesterol level. A study conducted by

Kroll and colleagues (70) compared the performance of the reference standard method to

other assays, including the SMACtm (Technicon Instruments Corp., Tarrytown, NY) and

the acatm (DuPont Co., Medical Products Department, Wilmington DE), the most widely

used methods for cholesterol determinations

in clinical laboratories. For a true cholesterol

value between 170 mg/dl and 260 mg/dl, the

aca method had an upward bias of between

4.0 and 4.8 percent, while the SMAC method

2 The coefficient of variation is the standar d

devi at ion of a probabi [ i ty distributions as a per -

cent age of the mean . This stat i st ic a 1 lows compari son of variation among di stri but ion ui th di fferent means .

had a 2.6 percent upward bias,

3 A mor e

recent report showed that one laboratory,

with careful attention to standardization and

proper performance of the tests, was able to

produce highly accurate and precise results

using three commonly employed assays for

cholesterol (69). The bias and coefficient of

variation in each of these tests were less than

3 percent when compared to the standard

reference method. Laboratories that do not

strictly adhere to quality control measures are

unlikely to achieve results as accurate as those

of either Kroll or Koch. The physician who

orders a serum cholesterol level risks misinterpreting the test result if he or she does

not know the laboratory’s assay method or if

the laboratory fails to standardize properly.

The new one-step enzymatic techniques

have not been tested extensively, but they

appear to be accurate if well-standardized

and properly performed. In preliminary

results, collected under near-ideal conditions,

three of these methods were evaluated when

used by a family medicine physician. The

degree of imprecision was less than the 3

percent coefficient of variation recommended

by NCEP. However, two of the three methods produced cholesterol values that were 2.5

to 8.1 percent higher than the reference

method ( 18). If not properly standardized,

these methods are not likely to perform as

accurately in physicians’ offices, drug stores,

field-screening programs, and other settings.

In order to achieve their goals of biases

of 3 percent or less, and coefficients of variation of 3 percent or less for all assays and

laboratories, NCEP’s Laboratory Standardization Panel has endorsed a campaign to educate physicians and laboratories about the

components of accurate and precise measurement methods. In addition, they have encouraged the use of reference serum samples

produced by CDC and the National Bureau of

3 This bias may be due to a “matrix effect” (92) .

The “matr i x“ is the envi ronment in which the cornpound being measured exists. For cholesterol, the

matrix is usual ly serum ( 11 7).
22 Costs and Effectiveness of Cholesterol Screening in the Elderly

Standards with which laboratories can test

and calibrate their assays. They have also

encouraged participation in proficiency testing programs sponsored by the College of

American Pathologists and the American Association of Bioanalysts (91,117).

Reliability of HDL and LDL

Measurements

Many clinical laboratories can measure

the high-density lipoprotein (HDL) cholesterol level directly. However, direct measurement of the low-density lipoprotein

(LDL) level requires specialized equipment,

so the LDL level is usually calculated from

the total cholesterol, HDL cholesterol, and

triglyceride levels (37).4

When HDL and LDL levels and ratios

based on these levels are used for routine

screening, they are unlikely to predict CHD

risk as accurately as they did in a research

setting. In routine clinical use, HDL assays

are not as reproducible as serum cholesterol

measurements, nor are they standardized as

well as the HDL assays used in epidemiologic

studies. The calculated LDL suffers from the

same flaw because the components of the

formula are often inaccurate. In a recent

survey of chemistry laboratories (23), a standardized specimen whose “true” HDL value

(as measured by CDC) was 34.6 mg/dl was

sent to a large number of laboratories.

Measurements reported by the participants

were grouped according to which of eight

d The l’Friedeua[d formula” for calculating the LDL

(evel is :

LDL = tota 1 cho[estero 1- HDL cho[ esterol -

trig 1 ycerides/5.

Th i s formula i s considered accurate uhen th e

trig lyceride [evel does not exceed 400 mg/dl. A

triglyceride level of 400 mg/dl is very uncomnon i n

the general population , so this formula can usua[[y

be applied . The 95th percentile for seru m

triglyceride levels in American men and women i s

Hell below 400 mg/dl at all ages, at least 6 years

and above (75).

methods the laboratory used. There was significant variation between the methods and

among laboratories using the same method.

The mean for each method ranged from 29.0

to 39.4 mg/dl. The method that produced a

mean value of 39.4 mg/dl had a standard

deviation of 7.9, implying that an HDL level

of 34.6 mg/dl would be reported as 47 mg/dl

or greater 16 percent of the time, denoting a

much lower risk of heart disease than actually

exists.

The variability in measured HDL levels

is reflected in the coefficient of variation of

the test results obtained by different

laboratories. The coefficient of variation for

the serum HDL among laboratories using the

same method ranged from 11.1 to 20.0 percent. The striking variation in reported HDL

levels indicates that routine HDL assays are

imprecise, and are unlikely to predict risk as

well as the meticulously standardized HDL

assays used in epidemiologic studies.

Costs of Lipoprotein

Measurement

The costs of lipoprotein testing depend

on the method used and the combination of

tests performed. Although the incremental

costs of performing these tests are not easily

determined, the charges reported to thirdparty payers provide a useful estimate of the

likely costs of implementing a testing program. Table 3 summarizes the average allowed charges for lipoprotein determination

procedures reported by two payers and a

community-based screening program. Of the

two payers, Blue Shield of California reports

somewhat higher charges than the national

Medicare program. The community-based

screening program in Rochester, New York

used an analyzer representative of the fingerstick method (the Retroflontm manufactured

by Boehringer-Mannheim). This equipment

costs $5,000 for the analyzer and $1.10 per

reagent strip. The organizers of the screening

program estimated the costs to be $2.78 per

determination (47).
Costs and Effectiveness of Cholesterol Screening in the Elderly 23

Table 3--- Selected Charges for Lipoprotein

Measurement

Blu e c ommunity

Shiel d screening

Californi a

a Medicar eb progra m

c

Total cholestero l $14.2 6 $6.3 5 $2.7 8

Lipoprotein cholestero l

fractionation (b y

calculation formula ) 23.8 0 15.8 0 NA

Complete lipid profil e

(HDL, cholesterol ,

and triglycerides ) 39.0 6 NA NA

aBlue Shield average a[(oued charges (R. Schaffarzick, Blue Shield of California, persona( com -

b

munication, Novenber 1988) .

Medicare average alloued charges (M. Newton ,

Health Care Financing Administration, Baltimore ,

MD, personal communication, October 1988) .

c

Estimated cost of cholesterol determination i n

cormnunity screening program using the Retrof(ontm

fingerstick method (P. Green~and, J.C. Levenkron ,

M.G. Radley et al. ,

llFeasibility of Large-Sca(e

Cholesterol Screening : Experience With a Portab(e

Capil(ary-Blood Testing Device,~ Am. J. Pub .

Hea[th 77:73-75, 1987) .

ABBREVIATIONS: HDL = high-density lipoprotein ;

NA = not applicable .

SOURCE: Office of Technology Assessment, 1989 .

Followup Testing

Followup testing for hypercholesterolemia can include repeating the cholesterol

determination and performing assays for

lipoprotein fractions and triglycerides. Although apolipoprotein determinations may

eventually prove to be an important component of the followup testing for individuals

found to have hypercholesterolemia, these

tests are experimental at this time.

NCEP recommends that all subjects with

an initial cholesterol of 200 mg/dl or greater

have one or two repeat determinations. If the

average of the two readings remains over 240

mg/dl, lipoprotein analysis is advised. The

recommended threshold for lipoprotein analy5 A lipoprotein test that analyzes their protei n

composition .

sis is 200 mg/dl in subjects with known CHD

or two risk factors (including male sex).

Further treatment advice is based on the calculated LDL-cholesterol level.

Importance of the Locale of

Testing

A successful screening program depends

upon characteristics of the test procedure, the

population screened, and the efficacy of

treatment. All of these may vary with the

setting for testing. The most obvious problem for cholesterol is accurate testing procedures. Because most current methods require

careful calibration, extra precautions must be

taken to assure valid reporting when assays

are performed away from a highly standardized clinical laboratory. Although newer fingerstick methods show promise for making

accurate cholesterol assays available in the

field, they have not yet been validated.

The completeness of followup testing is

likely to vary with the locale of the original

cholesterol test. An individual who is

screened as part of a mass screening program

or in a nonmedical setting will almost always

need to go to another site for followup testing. This may deter some Medicare recipients from obtaining further tests. Similarly,

when a cholesterol test is ordered or per–

formed in a doctor’s office or hospital clinic,

it will be simpler to institute treatment than

if screening is performed elsewhere.

Finally, the place where testing is performed may influence the feasibility of reimbursement under the Medicare program. A

cholesterol measurement obtained as part of a

battery of tests, in a physician’s office or a

hospital, could be reimbursed like other covered services under Medicare Part A or Part

B. It is likely that the administrative costs

would be large relative to the size of the

reimbursement if cholesterol was measured as

a single test, without any associated services.

Consequently, while screening in shopping

centers and drug stores might be inexpensive,

reimbursement by Medicare or any other

third-party payer is likely to be impractical.
5. TREATMENT OF hypercholesterolemia

Dietary Treatment of

Cholesterolemia

The dietary treatment of hypercholesterolemia has been reviewed elsewhere (72).

Cholesterol-lowering diets involve the reduction of overall fat and cholesterol intake, and

the substitution of polyunsaturated vegetable

oils for saturated fats and complex carbohydrates for sugars (116). Many people

have reduced their cholesterol levels dramatically by diet alone. However, when averaged

across many individuals, the reduction in

serum cholesterol in the randomized trials of

dietary interventions has been modest. In the

Multiple Risk Factor Intervention Trial

(MRFIT), diet reduced the cholesterol level

by an average of about 7 percent.

Dietary treatment, although generally

safer than pharmacologic approaches, is not

entirely without cost. Significant changes in

eating habits may reduce the quality of life.

The monetary and utility costs of dietary

modification have not been well studied.

Other than the potential for loss of pleasure

in eating, however, dietary changes have few

known side effects.

Oat bran is a soluble fiber that reduces

serum cholesterol. With a dietary intake of 1

to 1.5 cups of dry bran per day, serum

cholesterol falls by 13 to 19 percent (7,9,

10,67,89). When used with other soluble

fibers, the sustained reduction in serum

cholesterol can be 20 to 25 percent. At current prices, a 90 gm daily dose of oat bran

costs less than $0.40, if purchased in bulk.

The cost does not include the time or money

required to convert the oat bran to palatable

food, such as bread or muffins.

Certain foods, especially fish containing

omega-3 fatty acids, may have a beneficial

effect on serum cholesterol (46,52,53,112). In

one study of healthy persons, a fish diet

reduced low-density lipoprotein (LDL)

cholesterol and very low-density lipoprotein

(VLDL) cholesterol with variable effects on

high-density lipoprotein (HDL) cholesterol

(124). There have been no reported longterm studies of omega-3 fatty acids in hypercholesterolemic patients (125).

Drug Treatment of

hypercholesterolemia

Bile Acid Sequestrants: Cholestyramine and

Colestipol

The bile acid sequestrants, which interrupt the circulation of bile acids in the body

and cause the liver to synthesize new bile

acids from cholesterol, are commonly used to

reduce the LDL-cholesterol level. These

drugs can reduce total serum cholesterol by

20 percent and LDL-cholesterol by 27 percent if taken in full doses (77), with a proportionate loss in effect when compliance is

imperfect (79).

The bile acid sequestrants are difficult to

take regularly, in part because some people

have difficulty swallowing the slurry in

which they are administered and in part because of minor but unpleasant side effects.

The resin is administered in a liquid suspension and must be drunk quickly to avoid settling. Nausea, abdominal discomfort, and indigestion are common, and constipation occurs in as many as 45 percent of patients

treated with cholestyramine (77). Impaction

of stool may occur and be particularly

troublesome in the elderly. The resins also

bind other drugs in the intestine, decreasing

their absorption. Despite their favorable effects on the LDL cholesterol, bile acid sequestrants can raise the triglyceride level.

Nicotinic Acid

and

Nicotinic acid (niacin) is an inexpensive

effective cholesterol-lowering medication.

25
26 Costs and Effectiveness of Cholesterol Screening in the Elderly

The frequent occurrence of side effects has

limited its acceptance. Nicotinic acid lowers

the levels of plasma triglycerides and LDL

cholesterol and raises HDL cholesterol.

Nicotinic acid reduced total serum cholesterol

by an average of 10 percent in the Coronary

Drug Project (26) but can reduce cholesterol

by as much as 40 percent in combination

with bile acid sequestrants (61).

In the Coronary Drug Project, the incidence of the most common side effects of

nicotinic acid, skin flushing and itching, were

92 and 49 percent, respectively. These

side-effects may be less common when the

dose is gradually escalated, or when each dose

is preceded by a dose of aspirin. Vomiting,

diarrhea, and dyspepsia (indigestion) are also

common. Nicotinic acid can cause hepatitis

(rarely), elevate serum liver enzyme levels

without causing apparent disease, and raise

blood sugar levels in diabetics.

HMG CoA reductase inhibitors

The enzyme 3-hydroxy-3-methyl glutaryl

coenzyme-A (HMG CoA) reductase regulates

the rate of cholesterol synthesis in humans.

The drugs that inhibit this enzyme lower total

and LDL cholesterol by reducing the rate of

cholesterol synthesis. Formerly known as

mevinolin, lovastatin is the first HMG CoA

reductase inhibitor to be released in the

United States. Lovastatin raises or does not

affect plasma HDL.

There have been several multicenter trials of lovastatin (80,82,123). In one of these

studies, there was a dose-dependent reduction

of 32 percent in total cholesterol and 39 percent in plasma LDL cholesterol (80). HDL

cholesterol increased 13 percent. When

patients take cholestyramine in addition to

lovastatin, plasma LDL cholesterol falls by 50

percent .

Side effects of lovastatin are uncommon

and usually mild. None of the 101 patients

in one study had a side effect that required

stopping the drug. Liver enzymes (the transaminases) often rise in patients treated with

lovastatin, but the enzyme levels seldom exceed twice the upper limit of the normal

range. While clinical liver disease is rare

(80), monitoring serum liver enzymes is

recommended every 4 to 6 weeks for 15

months after starting lovastatin. Periodic eye

examinations are recommended because of a

possible association with cataracts (80). Because the drug is new, the side effects of

long-term therapy, if any, have yet to be

identified.

Fibric Acid Derivatives

Two fibric acid derivatives are currently

used in the United States to treat hyperlipidemia. The first, clofibrate, was initially

hailed as an important drug, but the indications for its use have narrowed as the results

of randomized trials have become known. In

the Coronary Drug Project, clofibrate reduced

serum cholesterol by only 6 percent (26). In

at least one large clinical trial, clofibrate significantly increased overall mortality and did

not reduce coronary heart disease (CHD)

mortality (24,25).

Clofibrate is generally well-tolerated, although it produces a variety of side effects in

a small proportion of patients. Increased appetite (5 percent), decreased libido (14 percent), and breast tenderness (9 percent) are

significantly more frequent among clofibratetreated patients than in subjects given a

placebo (26). Some patients get a flu-like

syndrome with severe muscle cramps whenever they take the drug. Clofibrate is also

associated with an increased incidence of

gallstones (3.5 percent over 5 years) (26).

Because clofibrate causes significant side effects, does not appear to reduce cardiovascular mortality, and may increase overall

mortality, most experts no longer recommend

it as a first-line drug for treating hypercholesterolemia.

Gemfibrozil, a newer fibric acid derivative, primarily lowers triglyceride levels. It

also lowers LDL and raises HDL levels. In
Costs and Effectiveness of Cholesterol Screening in the Elderly 27

one multicenter, placebo-controlled, randomized trial, total cholesterol decreased by

10 percent, non-HDL cholesterol fell 11 percent, and HDL cholesterol rose 11 percent

(84). In this study, patients on gemfibrozil

had a lower incidence of coronary heart disease than patients on placebo.

Gemfibrozil is generally well-tolerated.

Gastrointestinal distress is the principal side

effect. In the Helsinki Heart Study, moderate

to severe upper gastrointestinal symptoms occurred in 11 percent of patients on gemfibrozil and 7 percent of patients on placebo,

a highly significant difference (36). These

symptoms were much less frequent after the

first year of the study. Although gemfibrozil

may promote gallstone formation, this complication appears to be less frequent than

with clofibrate ( 17).

Other fibric acid derivatives, such as

fenofibrate, bezafibrate, and ciprofibrate, are

available in Europe but not in the United

States. Experience overseas suggests that

these drugs may have somewhat more favorable effects on the lipid profile than gemfibrozil or clofibrate and may be better

tolerated. In a short-term randomized trial in

the United States, fenofibrate decreased total

cholesterol levels by 17.5 percent, lowered

LDL-cholesterol levels by 20.3 percent, and

raised HDL-cholesterol levels by 11.1 percent

among individuals with hypercholesterolemia

and normal triglyceride levels. In individuals

who had elevations of triglycerides as well as

cholesterol, fenofibrate cut total and LDL

cholesterol by 16 and 6 percent, respectively,

and raised HDL cholesterol by 15.3 percent

(68).

Probucol

Probucol reduces serum LDL cholesterol

by 10 to 15 percent. However, it also lowers

serum HDL cholesterol, often to a greater degree than LDL cholesterol. There are no

studies of its effect on survival or primary

coronary heart disease events. The mechanism of action of probucol is unknown.

Probucol is well-tolerated, with gastrointestinal symptoms occurring in about 10 percent

of patients (17). Because of its adverse effect

on HDL levels, probucol is not widely used.

Costs of Treatment

Table 4 details the annual cost of using

the currently approved medications. Total

costs per year of treatment include both retail

drug prices, the costs of diagnostic procedures and physician services associated with

monitoring the potential side-effects of treatment, and the costs of semiannual lipoprotein

analysis to monitor the effectiveness of the

treatment. These cost figures assume that:

doctors prescribe the recommended dose

to achieve maximal cholesterol-lowering

effect,

patients are compliant,

laboratory monitoring as described in the

manufacturers’ package insert is performed regularly, and

physicians’ fees average $200 per patient

per year for monitoring and adjusting

therapy.

In order to estimate the retail cost of each

prescription drug, OTA obtained average allowed charges from a New Jersey State

pharmaceutical reimbursement program available to all non institutionalized persons over

age 65 (60,81). For niacin and slow-released

niacin, which are available without a

physician’s prescription, OTA obtained retail

prices for generic versions of the compound

from a Washington, DC retail drugstore chain

(38).

Under these assumptions, the least expensive regimen, nicotinic acid, costs over

$500 per year. Cholestyramine, often described as the agent of first choice, costs

$1,200 per year when purchased in bulk and

over $2, 100 annually when the more convenient pre-measured packets are employed.

Gemfibrozil costs $850 per year including

monitoring costs. The newest, and possibly

most effective, agent is lovastatin. It costs
28 Costs and Effectiveness of Cholesterol Screening in the Elderly

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Costs and Effectiveness of Cholesterol Screening in the Elderly 29

over $1,600 per year, including monitoring

Costs . Even purchasing at wholesale and

using the lowest cost laboratory available, as

might be the case for a public clinic or health

maintenance organization, these regimens are

expensive. Only nicotinic acid, available as a

generic product, costs less than several hundred dollars per year.

As more products become available (new

HMG CoA reductase inhibitors are in the

preliminary phases of approval by the Food

and Drug Administration) and as alternative

agents (psyllium or oat bran, for instance) are

evaluated, price competition may lower the

costs of treatment.

Health Outcomes of Treatment

There is little information about the effects of treating hypercholesterolemia in the

elderly. None of the randomized controlled

clinical trials of the treatment of hypercholesterolemia included significant numbers

of the elderly. Virtually all that is known

about the effects of treatment is based on

studies of middle- aged men. Several large

randomized trials have addressed the effects

of pharmacologic treatment in this population. Several other trials have assessed

dietary therapy.

Several lines of evidence suggest that

treatment might be effective. For example,

animal (83) and human studies ( 16,76) have

found that cholesterol reduction can slow or

even reverse the progression of atherosclerosis. Clinical trials have shown that

treatment can impede the development of

heart disease in hypercholesterolemic individuals. At least two studies found that reducing cholesterol levels that start above 260

mg/dl can diminish cardiovascular mortality,

and one study has shown that a cholesterollowering medication reduces 15-year allcause mortality among survivors of myocardial infarction.

Table 5 displays key findings from

several major studies of interventions to

reduce mortality by lowering cholesterol.

Asymptomatic, hypercholesterolemic individuals, such as those who would be identified

in a screening program, were the subjects of

several primary prevention trials. These trials

have shown that moderate cholesterol reduction lowers both the incidence of and

mortality from CHD among individuals who

have no clinical evidence of CHD. However,

the interventions did not significantly affect

all-cause mortality. The Lipid Research

Clinics-Coronary Primary Prevention Trial

(LRC-CPPT) is widely cited as the first randomized trial to show that drug therapy of

hypercholesterolemia in asymptomatic subjects reduces coronary disease morbidity and

mortal it y. The LRC-CPPT enrolled 3,806

men aged 35 to 59 whose serum cholesterol,

after an attempt at dietary management, was

at least 265. Both the intervention and control groups continued to receive a dietary intervention after the start of the trial. At an

average of 7 years of followup, the choles -

tyramine-treated group suffered less morbidity and mortality from ischemic heart disease than the control group. There was a

statistically significant (p<0.01) reduction in

the incidence of angina, which was experienced by 15 percent of the control group and

12 percent of the treatment group. CHD

mortality was also reduced by the intervention; 2.3 percent of the control group died

from definite or suspected CHD death, compared with 1.7 percent of the cholestyramine

group. However, all-cause mortality was 3.7

percent and 3.6 percent in the control and

cholestyramine-treated groups, respectively, a

difference that was not statistically significant

(78). Analysis of the cholestyramine-treated

patients showed that an 8-percent reduction

in serum total cholesterol was associated with

a 19-percent reduction in CHD incidence.

The magnitude of the reduction in the incidence of CHD corresponded to the degree

of reduction in total cholesterol levels. Thus,

the individuals who adhered closely to the intervention tended to have larger declines in

cholesterol and a lower incidence of CHD

(79). However, CHD incidence in the control

group did not show a statistically significant
(footnotes found on next page)
acho(esterol are levels reported in units of mg/dL.

@ercent of change is the difference between interventicm grow and ccmro( 9rouP cholesterol levets, expressed as percentage of original cholesterol level.

CHortality figur& are the c~[ative ~rs of &aths pe~ 100 s~jects during the fo[(ouup period, with exception of the Morld Health Organization trial, here

deaths per 100 subjects per annun are reported.

dLipid Research Clinics Program, llThe Lipid Research c~inics Corwry priMSry pRW?fItiOn Trial Results: I. R&3uction in Incidence of Coronary Heart Disease, M

J.A.M.A. 251:351-364, 1984; and Lipid Research Clinics Program, ItThe Lipid Research clinics cor~ry pri~ry Prevention Trial Results: Il. The Relation Of RedlJction in Incidence of Coronary Heart Disease to Cholesterol Lowering,~ J.A.M.A. 251:365-374, 1984.

‘difference between intervention and control groups is significant at p<O.05, two-tailed test.

fM.H. Frick, O. Elo, K. Haapa et al., llHe[sinki Heart st@: Primry-PrevmtiM Trial uith Gemfibrozil in Ri~te-Aged men With Dyslipidemia,ll N. EIW1. J. Med.

317:1237-1245, 1987.

9Coronary Drug Project Research Group, Ilclofibrate ad Niacin in Coronary Heart Disease,ll J.A.M.A. 231:360-381, 1975.

hp.L. canner, K.G. Berge, N.K. Henger et al., llFifteen year Mortality in Coronary Drug project Patients: Long-Term Benef

.8:1245-1255, 1986.

IComfnittee of Principat Investigators, 11A Cqrative Trial in the Pri~ry Prevention of Ischaemic Heart Disease Using C

Principal Investigators,n Brit. Heart. J. 40:1069-1118, 1978.

jDifference between intervention and control groups is significant at p<O.05, two-tai(d test, but in urong direction.

kcmittw of principal Investigators, to~HO Cqrative Trial on pri~ry prevention of lschaelllic Heart Disease Uith CtOf

t Uith Niacin,” J. Am. Coil. Cardiol.

ofibrate: Report From the Cotmnittee of

brate To Louer Serun Cholesterol: Fina[

Mortality FoLlow-up, u Lancet 2:600-604, 1984.

Lmultiple Risk Factor Intervention Trial Research Group, l$Mu(tiple Risk Factor Intervention Trial: Risk Factor Changes and Mortality Results,U J.A.M.A. 248:1465-

1477, 1982.

W. Dayton, M. Pearce, S. Hashimoto et al., MA cmtrol[~ C[inica[ Trial of a Diet High in unsaturated Fat in preventing Canptications of Atherosclerosis, tt Circulation 40(suppl. 2):11-1--11-63, 1969.

—

nEntire followup period; mean not reported.

ostatistica~ significance not reported in study,

PI. Hjermann, K.V. Byre, 1. Holme et al., I!Effect of Diet and SmkiM Intervention on the Incidence of Coronary Heart Disease: Report From the Oslo Study Group of

a Randanized Trial in Healthy Men,” Lancet 2:1303-1310, 1981.

ABBREVIATION: HDL = high-density lipoprotein.

SUJRCE: A. Garber, B. Littenberg, and H. Sex, IIScreening for Cardiac Risk Factors: Serun Cholesterol and Triglycerides,w forthcoming in Ann. Intern. Med.
32 ■ Costs and Effectiveness of Cholesterol Screening in the Elderly

relation to the degree of cholesterol lowering

due to diet (71). In summary, the LRCCPPT trial showed that cholestyramine given

to hypercholesterolemic, asymptomatic men

without a prior myocardial infarction

diminishes morbidity and mortality from

CHD but does not reduce overall 7-year

mortality.

The Helsinki Heart Study, anothe r

medication trial, obtained similar results in

4,081 asymptomatic, hypercholesterolemic

men aged 40 to 55 who were randomly assigned to receive either placebo or gemfibrozil (36). Beyond 2 years of followup,

gem fibrozil decreased total and LDL

cholesterol by about 9 percent each and

raised HDL cholesterol levels by 9 percent.

At 5 years of followup, compared to the controls, the gemfibrozil group experienced significantly fewer cardiac events but the same

overall mortality rate. Most of the excess

noncardiac deaths in the treatment groups of

both the LRC-CPPT trial and the Helsinki

Heart Study were due to accidents and

violence.

The Oslo Study (56), which enrolled

more than 1,200 men whose cholesterol levels

ranged from 290 to 380 mg/dl (average value,

328.9 mg/dl), found that a combined diet and

smoking intervention produced a large but

statistically insignificant fall in all-cause

mortality. By the end of the trial (averaging

5 years of observation), 2.6 percent of the intervention group died, compared with 3.8

percent of the control group (P=0.246).

Nearly 80 percent of the men smoked

cigarettes at the time of enrollment, and the

combined intervention decreased tobacco consumption by 45 percent. In a followup study

conducted after the termination of the trial

(between 8.5 and 10 years after enrollment),

the difference in overall mortality approached

statistical significance. By that time, 3.15

percent of the intervention group and 4.94

percent of the control group had died, corresponding to a one-sided p-value of approximately 0.05, not adjusted for multiple comparisons (57). Because the intervention substantially reduced cigarette smoking during

the trial, the trend toward a significant

decline in overall mortality could not be attributed to cholesterol reduction alone. This

trial enrolled men whose cholesterol levels

were higher than in the populations included

in the LRC-CPPT and Helsinki studies, and

its small sample size limited its power to

detect clinically significant differences in

outcomes.

Other trials that were designed to lower

coronary disease and death rates by reducing

cholesterol did not show a benefit from the

intervention. In at least one case, there may

have been no benefit because the intervention

did not lower the cholesterol level substantial y. In MRFIT, which tested a multifaceted intervention (designed to alter diet,

promote smoking cessation, and control blood

pressure), the cholesterol level in the intervention group fell by only 2 percent more

than in the control group, and neither CHD

nor all-cause mortality was lower in the intervention group.

Evidence from trials of individuals with

established CHD complements the findings

from primary prevention studies of cholesterol reduction. Established CHD might

not seem to be amenable to preventive efforts, so trials targeted toward middle-aged

men who have CHD might not seem directly

relevant to a screening population of asymptomatic elderly men and women. Despite

such concerns, these studies provide important clues to the likely effects of cholesterol

reduction in asymptomatic individuals. Men

with CHD are at such a high risk of death

from CHD and of recurrent cardiac morbidity

that secondary prevention might show a

benefit from cholesterol reduction in this

population, despite a relatively short period

of observation. The Coronary Drug Project,

a secondary prevention trial that tested

several cholesterol-lowering interventions in

this population, has provided evidence that

cholesterol reduction leads to lower all-cause

mortality. This study showed that nicotinic

acid, when given to 30 to 64 year-old male
Costs and Effectiveness of Cholesterol Screening in the Elderly 33

survivors of myocardial infarction, reduced

cholesterol levels by about 10 percent (21). It

had no effect on mortality at a followup period averaging 6 years. However, at an average of 15 years after the inception of the trial, the men treated with nicotinic acid had an

all-cause mortality rate that was 11 percent

lower than the placebo group (p=0.0004),

even though the Coronary Drug Project regimen only lasted for about 6 years. The

mortality reduction was primarily due to a

fall in the CHD mortality rate. Larger benefits were reported in another secondary prevention trial, the Stockholm Ischemic Heart

Disease Study (1 00), which found a 29 percent reduction in 5-year all-cause mortality

among survivors of myocardial infarction

treated with a combination of clofibrate and

nicotinic acid. However, only limited conclusions can be drawn from this trial, It was

small and not double-blinded; the authors did

not report whether the all-cause mortality

difference was statistically significant; and 24

percent of the intervention group withdrew

from the trial (as against only 10 percent of

the control group).

In the absence of direct evidence pertinent to the elderly, these studies must serve

as the most important basis for inferring the

effects of cholesterol reduction in older

Americans. Although cholesterol reduction

can reduce the incidence of CHD and the

rate of CHD death among middle-aged

asymptomatic men without clinical evidence

of heart disease, it has not been shown to

lower overall mortality in this population.

These studies may not have had sufficient

years of followup or numbers of subjects to

detect an overall mortality benefit, but benefits delayed for many years might not be

pertinent to the elderly, who have a high rate

of death from other causes. If the elderly

suffer more side effects from medication or

dietary interventions than the subjects of

these trials did, the case for treating hypercholesterolemia will be weakened.
—— .——

6. IMPLICATIONS FOR MEDICARE

Implications of Cholesterol

Screening in the Elderly for Total

Health Care Expenditures

The literature reviewed in the preceding

chapters suggests that the health benefits,

particularly as measured by total mortality, of

cholesterol screening in the elderly are unproven and may be smaller than in middleaged

■

■

■

people:

Cholesterol assays in routine clinical use

are not as reliable as those employed in

epidemiologic studies and may not predict risk as accurately.

The evidence that cholesterol level is a

risk factor for coronary heart disease

(CHD) in the elderly is not as consistent

and conclusive as the evidence for

middle-aged men. Furthermore, it appears not to be a risk factor for overall

mortality in the upper ages.

There are no randomized trials of the

impact of cholesterol reduction on CHD

or overall morbidity or mortality in the

elderly, and no randomized trial has

proven that cholesterol reduction lowers

overall mortality in the populations that

have been studied, with the exception of

a study of male survivors of myocardial

infarct ion.

Apart from diet, treatment in the elderly

may have more adverse side effects than

treatment in younger populations. The

elderly take more drugs on a regular

basis than do other patients. Multiple

drug therapies increase the risk of interactions among the different chemical

compounds. In addition, as individuals

age, they may be less able to tolerate the

unpleasant side effects of cholesterollowering drugs themselves.

Cholesterol reduction has been found to

reduce CHD morbidity and mortality in

middle-aged men, but it did not improve

overall survival during the study periods of

the randomized trials (usually less than 10

years). Consequently, data about existing

treatments do not provide convincing evidence that cholesterol reduction would increase life expectancy among the elderly.

Cholesterol reduction might improve quality

of life by reducing the symptoms of CHD,

but it would also require changes in diet or

suffering the side effects of medication.

Because no study has documented the

survival or morbidity benefits of cholesterol

reduction in the asymptomatic elderly, a precise estimate of the costs and effectiveness of

cholesterol screening is impossible. However,

the National Institutes of Health has sponsored the development of recommended cholesterol screening and treatment protocols for

the elderly (as well as for other age groups)

and has widely disseminated these recoin -

mendations to physicians and the public

(1 16). Therefore, OTA estimated the annual

national health care expenditures associated

with full implementation of the National

Cholesterol Education Program (NCEP)

screening and treatment protocols in the

elderly population,

The model, described in detail in appendix C, estimates both screening expenditures

and expenditures associated with treating all

diagnosed hypercholesterolemia in 1995. The

number of people who would be treated for

hypercholesterolemia, either with dietary

guidelines or ultimately, with medication, was

estimated with data on the distribution of

serum cholesterol and low-density lipoprotein

(LDL) levels in the elderly (1 18,1 19). When

data on important elements of the model were

unavailable, a range of costs was generated to

reflect the probable boundaries for specific

estimates. For example, the NCEP guidelines

call for dietary treatment in certain cholesterol and LDL ranges only when two or

more other risk factors (such as being male,

35
36 Costs and Effectiveness of Cholesterol Screening in the Elderly

Table 6--- Estimated Total Health Care Costs of Full Compliance With National Cholesterol

Education Program Protocola in the Elderly Population in 1995 (in millions of 1988 dollars)

Percent o f

populatio n Screening and

treate d diagnostic cost s Total cost s

aAdult Treatment Panel , National Cholesterol Education Program, National Heart, Lung, and Blood Institute ,

National Institutes of Health, U.S. Department of Health and Human Services, ‘Report of the Nationa l

Cholesterol Education Program Expert Panel on Detection, Evaluation , and Treatment of High Bloo d

Cholesterol in Adults,” Arch. Intern. Med. 148:36-69, 1988 .

b

Assunes

cAssunes

SOURCE:

that patients receiving medication pa y

that patients receiving medication pa y

Office of Technology Assessment, 1989 .

S525 per year for niacin and related monitoring.

$1,687 per year for lovastatin and re[ated monitoring .

hypertensive, a smoker, or having diabetes)

are present. Because data on the frequency

with which such risk factors occur in the

elderly population are unavailable, the number of elderly treated under the NCEP

protocols was estimated for frequencies ranging from 30 to 70 percent of the population.

In other cases, where uncertainty exists

about specific factors, the model is constructed to underestimate costs. For example,

the health care costs associated with monitoring people who are successful in controlling

cholesterol with diet are assumed to be zero.

Moreover, dietary intervention was assumed

to lower LDL levels by 10 percent, an effectiveness rate that is reasonably optimistic relative to the existing empirical evidence (32).

Medication costs were based on prices paid

by a State pharmaceutical assistance agency

on behalf of its beneficiaries. These prices

may be lower than the average retail prices

that would be paid by Medicare beneficiaries.

The results of the analysis are presented

in table 6. The costs of performing the

laboratory tests associated with screening and

followup are a very small part of the total

costs of screening and treatment. Treatment

costs, particularly the costs of medications,

constitute the vast majority of annual total

costs of the NCEP. Even if relatively inexpensive medications are chosen, the cost of

treating hypercholesterolemia is much greater

than the cost of detecting it. In 1995, the

costs of screening and followup testing would

be about $57 million, while total national

health care expenditures associated with

screening and treatment would range from at

least $2.9 billion to $14.2 billion.

The cost estimates in table 6 show what

would be spent nationally if all elderly people

were to comply with screening recommendations and adhere to the cholesterol lowering

therapy called for by the NCEP. Full cornpliance with the NCEP treatment guidelines
Costs and Effectiveness of Cholesterol Screening in the Elderly 37

would result in 47 to 57 percent of all elderly

Americans on some form of treatment, either

diet or medication. Many elderly people are

currently receiving cholesterol-lowering

therapy, so some of these costs are already

being incurred. But many others probably

would not comply with the recommended

screening or treatment protocols, even if

Medicare were to pay for cholesterol screening. For example, in a large well-established

and prevention-oriented health maintenance

organization in the Northeastern United

States, only 75 percent of elderly enrollees

had had a serum cholesterol test within the

previous 5 years (40). If compliance with the

NCEP screening and therapy guidelines were

as low as 25 percent, then only 12 to 14 percent of the elderly would actually enter

cholesterol-lowering treatment, and the annual health care costs of screening and treatment in the elderly would range from $782

million to $3.6 billion in 1995.

Although these cost estimates are based

on optimistic assumptions about the effectiveness of diet in controlling cholesterol and

LDL, total estimated costs are extremely

sensitive to this assumption. If, for example,

a dietary intervention were shown to be able

to produce a permanent reduction in LDL

levels by 15 percent in the elderly, then national health care costs associated with full

compliance in the elderly would fall somewhere between $1.9 billion to $10 billion in

1995. At present, however, there is no reason

to expect such a level of effectiveness to be

obtained through dietary intervention in the

elderly.

Costs to Medicare

Medicare currently does not pay for

serum cholesterol or other lipoprotein

measurement on a screening basis. However,

these procedures are all covered as diagnostic

services or as part of the management of previously diagnosed CHD or hypercholesterolemia. Medicare currently pays 80 percent of allowed charges after the beneficiary

has met an annual deductible. Assuming that

Medicare similarly were to pay 80 percent of

screening expenditures, Medicare costs for

screening only (including initial testing andfollowup, but not treatment) would be between $50 million and $62.6 million in 1995

under a regimen of full compliance with the

NCEP guidelines. In addition, Medicare

would pay 80 percent of allowed charges for

physician services and diagnostic procedures

necessary for monitoring drug therapy, which

would range from about $250 to $550 annually for each treated individual. If the entire

elderly population were to comply fully with

the NCEP guidelines, these Medicare expenditures would range from $1 billion to

$5.4 billion in 1995, depending on the frequency of risk factors and the mix of

medications prescribed for the population.

With a 25 percent compliance rate in the

elderly, Medicare’s expenditures would be

reduced proportionately to between $261 million and $1.3 billion.

Expenditures associated with actual drug

purchases would be covered by the prescription drug benefit of the Medicare Catastrophic Coverage Act of 1988 (Public Law

100-360). Cholesterol-lowering medications

will first be eligible for reimbursement in

1991, with each beneficiary facing a $600 annual deductible on all prescription drug purchases and a 50 percent copayment. Starting

in 1993, the deductible will be indexed so

that 16.8 percent of all Medicare beneficiaries

will have drug expenses that exceed the deductible. The coinsurance rate will be 20

percent. Precise estimates of the Medicare

burden for the costs of treating hypercholesterolemia diagnosed through a screening

program are not possible. Although only

three of the cholesterol-lowering drugs currently available are so expensive that they are

highly likely to exceed the annual deductible

(lovastatin, colestipol, and cholestyramine; see

table 4), Medicare beneficiaries using the

other cholesterol-lowering drugs may still become eligible for reimbursement if their total

annual prescription drug expenses exceed the

deductible. For those elderly who use multiple prescription drugs, a cholesterol screening
38 ■ Costs and Effectiveness of Cholesterol Screening in the Elderly

benefit would substantially increase Medicare’s financial burden for the treatment of

hypercholesterolemia. Only one choles-terollowering drug--niacin--whose annual retail

costs are estimated to be between $100 and

$300, would not be eligible for reimbursement under the Catastrophic Coverage Act

because it does not require a physician’s prescription.

Use of Cholesterol Screening

Services

Current Utilization

Little information exists on the current

use of cholesterol screening by the elderly.

None of the national household surveys conducted to date by the National Center for

Health Statistics have collected data on the

frequency of cholesterol measurements. The

Health Care Financing Administration’s

(HCFA) Medicare Procedures Databas e

(BMAD) allows estimation of the number of

procedures and allowed charges reimbursed

under the Medicare program. The database

records the use of all medical and surgical

procedures as defined in the Current Procedural Terminology (CPT) manual performed

in hospitals, ambulatory clinics, and physicians offices.

HCFA provided OTA with data from its

BMAD files for all lipoprotein measurement

procedures paid by Medicare during calendar

year 1986 (see table 7). However, these

numbers provide little information about the

proportion of elderly with no history of hyperlipidemia or CHD who receive periodic

cholesterol screening. First, since Medicare

currently reimburses cholesterol measurement

only when a patient has symptoms or has

been given a diagnosis, the BMAD numbers

theoretically should not include any tests done

purely for screening purposes. In addition,

since the BMAD database records use by procedures rather than by persons, the numbers

in table 7 represent more than one test for

some Medicare beneficiaries.

Table 7. --Total Number of Lipoprotein

Measurement Services Allowed Unde r

Medicare in 1986 by Type of Procedure

C P T

a

Number of ~

cod e Name of procedur e a 1 lowed services

82465 Total serum cholestero l 678,66 6

8247 0 Total serum cholestero l

and ester s 7,60 5

8370 0 Total blood lipid s 57,48 4

8370 5 Fractionated cholestero l

(cholesterol, triglycerides ,

and phospholipids )

8371 9 High-density lipoprotein s

by ultracentral fugatio n 32,83 3

8372 0 Lipoprotein fractionation b y

calculation formul a 91,57 8

aPhysicianls Current Procedural Terminology J.A.

Coy, C.M. Fanta, A.J. Finkel et al. (’eds. )

(Chicago, IL : American Medical Association, 1988) .

b

Data supplied by M . Newton, Health Care Financin g

Administration, Baltimore, MD, personal communi -

cation, October 1988 .

SOURCE : Office of Technology Assessment, 1989 .

Implementing a Cholesterol

Screening Benefit

A decision to include cholesterol screening under Medicare would present at least

two issues concerning payment for such services:

1. Paying for cholesterol screening as part

of a physician’s office visit .-- OTA’s

analysis of expenditures associated with

the diagnosis of hypercholesterolemia in

the elderly only includes the charges

for specific screening procedures; it

does not include the cost of visiting the

physician’s office. Because many (if

not most) cholesterol screenings would

take place in the physician’s office, this

model implicitly assumes that all elderly

have their cholesterol checked while

visiting their doctor for some other reason. For reimbursement purposes, this

assumption is not unreasonable, because

each procedure performed as part of a

screening program already can be billed

separately from the office visit charge
Costs and Effectiveness of Cholesterol Screening in the Elderly 39

2.

and has an assigned CPT code used by

Medicare in paying for services (28).

However, if beneficiaries make a special visit to the physician just to have

their cholesterol checked, the cost of

the office visit becomes part of the true

cost of the screening benefit. It is also

possible that the introduction of a

cholesterol screening benefit would lead

to an increase in the number of

physician office visits and other medical services used by Medicare beneficiaries by simply encouraging individuals to pay greater attention to their own

health.

Paying for cholesterol screening in

community settings. --As the analysis in

this paper indicates, the technology exists to perform cholesterol measurement

in community settings with “desk-top”

analyzers. Current data suggest that the

cost of screening in community settings

with such technology is lower than

charges for such procedures in physicians’ offices and laboratories. However, there currently is no mechanism

by which Medicare pays for medical

services offered in community facilities,

such as churches or senior citizens’ centers. If Medicare covered cholesterol

screening in these settings, HCFA

would have to develop reimbursement

policies for them. As suggested in

OTA’s earlier analysis of glaucoma

screening for the elderly, HCFA might

pay the sponsors of community screening programs--hospitals, nonprofit organizations, etc--- a set rate per patient

for all Medicare beneficiaries screened

(96). Because the accuracy and precision of desk-top analyzers are, in part,

a direct function of the proficiency and

care of individuals using the technology, policy makers would also need to

consider how to monitor the quality of

testing in community settings.

Costs and Effectiveness of

Cholesterol Screening

Is routine cholesterol screening a costeffective approach to the prevention of

coronary heart disease in the elderly? Costeffectiveness analysis usually assesses the cost

associated with a defined increase in a

measure of benefits. In health care, the most

commonly employed measure of effectiveness

is the change in life expectancy (or “qualityadjusted” life expectancy) brought about by a

health intervention. However, the costeffectiveness ratio (the ratio of the incremental costs of the interventions to the incremental health effects) is undefined when there

are no health effects or when the intervention

has deleterious effects on health.

Because there have been no randomized

controlled trials of the health effects of

cholesterol reduction in the elderly, particular

weight must be placed on observational and

epidemiologic data about cholesterol as a risk

factor in the elderly. As reviewed above,

cholesterol is not as powerful a risk factor for

CHD in the elderly as it is in the middleaged. Furthermore, epidemiologic studies

have found that the cholesterol level is either

not associated with overall mortality rates or

is inversely associated with all-cause

mortality. In addition, randomized controlled

trials of the health effects of cholesterol

reduction have not included elderly

participants. It would be difficult to infer

from available evidence that elderly individuals with an elevated blood cholesterol level

would benefit from cholesterol reduction,

even if the cholesterol could be lowered

without side effects from medication or

dietary change.

However, several developments may increase the effectiveness of cholesterol screening in coming years. First, cholesterol measurements in clinical laboratories and in other
40 Costs and Effectiveness of Cholesterol Screening in the Elderly

settings are likely to become more accurate,

in large part because of the efforts of the

Laboratory Standardization Panel of NCEP.

Standardization of high-density lipoprotein

and low-density lipoprotein measurements is

likely to improve as well, and one or both of

these lipoproteins may become the primary

screening tests for CHD risk in the elderly.

The powerful new medications to lower cholesterol that have recently become available

seem to have few short-term side effects and

may prove to be more effective at lowering

cardiovascular risk than previously available

treatments. If studies demonstrate that

cholesterol-lowering interventions reduce

CHD and all-cause mortality among the

elderly, the rationale for screening could become more persuasive.
APPENDIX A: ADVISORY PANEL

Gordon De Friese, Panel Chair

Health Services Research Center

University of North Carolina, Chapel Hill, NC

Marianne C. Fahs

Department of Health Economics

Mt. Sinai Medical Center

New York, NY

John Frank

Department of Preventive Medicine &

Biostatistics

University of Toronto

Ontario, Canada

Gary D. Friedman

Epidemiology and Biostatistics Division

Permanence Medical Group, Inc.

Oakland, CA

Lawrence Gottlieb

Clinical Guidelines Program

Harvard Community Health Plan

Brookline Village, MA

Mary Knapp

John Whitman and Associates

Philadelphia, PA

Risa Lavizzo-Mourey

Geriatrics Program

University of Pennsylvania

Philadelphia, PA

M. Cristina Leske

Department of Preventive Medicine

SUNY at Stony Brook

Stony Brook, NY

Donald Logsdon

INSURE Project

New York, NY

Mildred B. McCauley

American Association of

Retired Persons

Washington, DC

Peter McMenamin

Chevy Chase, MD

Meredith Minkler

Center on Aging

University of California, Berkeley

Berkeley, CA

Marilyn Moon

Public Policy Institute

American Association

of Retired Persons

Washington, DC

George Morley

Department of Obstetrics/Gynecology

University of Michigan Medical Center

Ann Arbor, MI

Gilbert Omenn

Dean, School of Public Health &

Community Medicine

University of Washington

Seattle, WA

George Pickett

Department of Public Health Policy

School of Public Health

University of Michigan

Ann Arbor, MI

Donald Shepard

Department of Health Policy

and Management

Harvard School of Public Health

Boston, MA

Barry Stults

Division of General Internal Medicine

University of Utah Medical Center

Salt Lake City, UT

Advisory Panel members provide valuable guidance during the preparation of OTA reports.

However, the presence of an individual on the Advisory Panel does not mean that individual

agrees with or endorses the conclusions of this particular paper.

41
APPENDIX B: ACKNOWLEDGMENTS

The OTA staff would like to express our appreciation of the following people for their

valuable guidance. This acknowledgement should not be construed in any way to imply that the

individuals agree with or endorse

David F. Adcock

Office of Disease Prevention and

Washington, DC

Lennie Caputi

Pharmacy Assistance to the Aged

Disabled Program

Trenton, NJ

Morris F. Cohen

Kaiser-Permanante

Oakland, CA

John M. Eisenberg

Medical Care

the conclusions of

Health Promotion

and

Program

Hospital of the University of Pennsylvania

Philadelphia, PA

Donald Fukuzawa

Foer’s Pharmacy

Washington, DC

Philip Greenland

University of Rochester Medical Center

Rochester, NY

David Iozzia

Blue Cross/Blue Shield of New Jersey

Newark, NJ

Robert L. Kane

University of Minnesota

Minneapolis, MN

Bruce Kinosian

University of Maryland

Baltimore, MD

this paper.

Thomas E. Kottke

Mayo Clinic

Rochester, MN

Martin Kroll

National Institutes of Health

Bethesda, MD

Lewis H. Kuller

University of Pittsburgh

Pittsburgh, PA

Claude Lenfant

National Institutes of Health

Bethesda, MD

Sanford Luger

Pharmacy Assistance to the Aged and

Disabled Program

Trenton, NJ

Odonna Matthews

Giant Pharmacy

Gaithersburg, MD

Charlotte Muller

Mt. Sinai Medical Center

New York, NY

Chuck Phelps, Ph.D.

University of Rochester

Rochester, NY

42
. .

APPENDIX C: EXPENDITURE MODEL FOR DIAGNOSIS AND

TREATMENT OF hypercholesterolemia IN THE ELDERLY

In order to analyze the cost implications

of a cholesterol screening benefit under

Medicare, OTA developed a model to estimate annual total direct health care expenditures associated with screening and treatment

of hypercholesterolemia in the elderly, This

appendix describes the model. The text of

the paper discusses the results of the analysis.

The Model

Several expert groups have recommended

periodic screening for hypercholesterolemia.

The most recent of these guide lines--

formulated by the Adult Treatment Panel of

the National Cholesterol Education Program

(NCEP)--provides a suggested model for the

detection and subsequent management of hypercholesterolemia. OTA has neither evaluated nor endorsed the protocol outlined by

the Adult Treatment Panel. However, because of the protocol’s wide dissemination

throughout the medical community, it is the

basis for estimating direct expenditures associated with cholesterol screening and treatment in the elderly.

The recommended protocol of NCEP is

as follows (1 16):

All adults should have their total serum

cholesterol measured at least once every

5 years.

If the cholesterol level is found to be

less than 200 mg/dl, it is classified as

“desirable, ” and no specific management

is required (educational materials about

diet and cardiac risk factors should be

provided).

If the cholesterol level is at least 200

mg/dl, the cholesterol test is repeated.

If the average of the two readings is between 200 and 239 mg/dl, it is classified

as “borderline-high” cholesterol. If the

average of the two readings is less than

200 mg/dl, further management is the

same as for individuals with a desirable

cholesterol level.

Table 8.--- NCEP Risk Factors for Coronary

Heart Disease

■

■

aNCEP does not specify the criteria for categor -

izing patients as diabetic or hypertensive .

ABBREVI AT IONS :

SOURCE: Offic e

■ If the average of two readings is greater

CHD ❑ coronary heart disease;

HDL = high density 1 ipoprotein;

NCEP = National Cholesterol

Education Program.

of Technology Assessment, 1989.

than 239 mg/dl, or if it is at least 200

mg/dl and the individual has either a

history of coronary heart disease (CHD)

(defined as prior myocardial infarction,

or myocardial ischemia such as angina

pectoris), or two other CHD risk factors,

as shown in table 8, lipoprotein analysis

is recommended. Lipoprotein analysis

includes measurement of fasting total

cholesterol, triglycerides, and highdensity lipoproteins (HDL), and calculation of the low-density lipoprotein

(LDL) level (from the Friedewald formula).

For persons who receive lipoprotein

analysis, further management is based

on the calculated LDL level. If it is less

than 130 mg/dl, the individual is considered to have “desirable LD L

cholesterol,” and no specific further

management is required. Management

of an LDL level above 130 mg/dl

depends on the presence of other risk

43
44 ■ Costs and Effectiveness of Cholesterol Screening in the Elderly

factors. All patients are started on a

dietary intervention for 6 months. If at

the end of that time they have failed to

achieve a desirable cholesterol level,

medications may be added, depending

on the LDL level, and the physician’s

discretion. These recommendations for

testing and therapy are summarized in

Figure 3.

Using an adaptation of this protocol,

OTA performed an analysis of the likely

health care expenditures associated with an

ongoing cholesterol screening and treatment

program for Medicare recipients. Because the

costs of medications vary widely, expenditures for a range of medical regimens were

estimated in 1988 prices.

Assumptions

The assumptions used in this analysis appear in table 9 . The basis for the assumptions is as follows:

Size of the population to be screened---

The analysis uses the projected number of

American men and women aged 65 and over

in 1995 (113). The year 1995 was chosen because it would represent the first year in

which full screening of the population could

be anticipated under an every-5-year screening program.

Participation. --OTA estimated the cost.

of full compliance with the NCEP protocols

by all elderly people. Of course, not all

Medicare recipients will avail themselves of

the screening program or will comply with

drug therapy. For example, one health

maintenance organization that provided OTA

with information on the use of preventive

services reported that of members over 6 5

years old, 75 percent had their cholesterol

measured at least once during a 5-year period

(40). Consequently, the model was constructed to estimate costs under various assumptions about levels of compliance.

Results are presented in the main body of

this report indicating how costs would change

Table 9--- Assumptions for Cholesterol Expenditure Model

LDL measurement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16.8 9

Annual costs of drug and monitor:

low-cost medication (niacin). . . . . . . . . . . . . . 525.00

high-cost medication (lovastatin). . . .....1,678.0 0

Lipid distribution s

Total cholesterol (mg/dl )

Mean

Standard deviatio n

LDL cholesterol (mg/dl )

Mean

Standard deviatio n

Correlation, tota l

and LDL cholesterol

Proportion wit h

cholesterol under 200 (mg/dl )

cholesterol under 240 (mg/dl)

Men Women

221.0 0 246.0 0

62.3 3 60.2 1

149.0 0 162.0 0

40.0 0 44.0 0

0.84 0.88

0.3 7 0.2 2

0.6 2 0.4 6

ABBREVIATION: LDL = low-density lipoprotein .

SOURCE: Office of Technology Assessment, 1989 .

if compliance with the NCEP screening and

therapy guidelines were only 25 percent in

the elderly.

Prevalence of risk factors.--The NCEP

protocol for determining lipoprotein fractions

and treatment depends not only on the serum

cholesterol but also on the presence of other

risk factors. A high-risk individual is identified as one with 2 or more of the risk factors. Information is unavailable about the

prevalence of other risk factors in relation to

the cholesterol level in the elderly. It seems

likely that a substantial number of Medicare

recipients will either have a history of CHD

or have two of the risk factors: about 20

percent of men and 15 percent of women
-.

Costs and Effectiveness of Cholesterol Screening in the Elderly ■ 45

Figure 3--- Protocol for Cholesterol Screening in the Elderly

t

Screened population

+

Con t I nue f13r)

4

0

130-1 !59

DL —

d(et

I v

>159

M e d I c ate

No

>

I

I

physician’s d(s cre t ton

I NO

ABBREVIAT 10NS : LDL = low-density [ ipoprotein; RF ❑ risk factors; TC = total cholesterol.

SOURCE : Off ice of Technology Assessment, 1989. Adapted from Adu[ t Treatment Panel, Nat i ona 1 Cholestero l

Educat ion Program, National Institutes of Health, U.S. Department of Hea 1 th and Hunan Services ,

llNat i ona [ Cho 1 estero [ Educat i on Program Expert Pane [ on Detect i on, Eva ( Uat i on, and Treatment of

H i gh B 1 ood Cho lestero( i n Adu[ ts, 1’ Arch. Intern. Med. 148:36-69, 1988 .
46 ■ Costs and Effectiveness of Cholesterol Screening in the Elderly

aged 65 and over are current smokers (122),

nearly 14 percent report that they have CHD,

and one half of Americans aged 65 to 74

have definite hypertension (121).

Because the precise number of elderly

individuals who have CHD or two other risk

factors is unknown, the analysis includes calculations for three different assumptions:

the low-prevalence estimates assume that

30 percent of the Medicare recipients

are high-risk based on a history of CHD

or two risk factors for CHD (other than

hypercholesterolemia),

the middle-prevalence estimates assume

that 50 percent have the risk factors,

and

the high-prevalence estimates assume

that 70 percent have risk factors.

OTA assumed that the prevalence of the risk

factors is not correlated with the cholesterol

level; this assumption probably leads to an

underestimate of the number of persons who

will need treatment, since it is likely that the

risk factors are more common among individuals whose cholesterol levels are elevated than

among those whose cholesterol levels fall below 200 mg/dl. Given that male sex is a risk

factor according to the NCEP framework, the

high-prevalence assumption (70 percent) may

be the most likely value for men over 65

years old.

Number of participants requiring further

testing or treatment .--The analysis assumes

that the repeat cholesterol assay will give the

same result as the initial assay. This assumption will underestimate screening expenditures

because it does not count the costs of repeat

total cholesterol screening for those people

whose initial readings are greater than 199

mg/dl, but who receive no further management on the basis of the second screening.

The magnitude of this effect should be slight

but depends on the accuracy and precision of

the screening tests.1

The number of people in alternative

treatment groups (e.g., those who do not have

a history of CHD or two other CHD risk factors, but do have a cholesterol level in excess

of 200 mg/dl and an LDL cholesterol level

above 190 mg/dl) is calculated by assuming

that the total cholesterol and the LDL -

cholesterol level have a joint bivariate normal

distribution.

Followup testing. - -In order to calculate

how many individuals will have repeat

cholesterol determinations, lipoprotein fractionation, and recommendations for testing,

OTA used data from the National Health and

Nutrition Examination Survey, reproduced in

the NCEP report. The analysis assumes that

the total cholesterol level and the LDL -

cholesterol level have a bivariate normal distribution in the Medicare population, and use

the published figures for the mean and standard deviation of cholesterol and LDL for the

65 to 74 year-old age group. The correlation between LDL cholesterol and total

cholesterol is assumed to be 0.84 for men,

and 0.88 for women, based on the Framingham Heart Study, as shown in table 2. The

predicted number of people whose cholesterol

is less than 200 mg/dl or less than 240 mg/dl

is consistent with the percentiles noted in

table 1.

Response to diet. - -The model assumes

that individuals treated with diet will uni -

1 Uhi le the accuracy and precision of cholestero l

measurement is important i n eva 1 uat i ng the effectiveness of a screening benefit, it is of less im -

portance in estimating the health care expenditure s

associated with such a benefit. Hence, OTA did no t

bui [d into its model more sophisticated mechanism s

for model ling how well the various screening tech -

nologies work .
Costs and Effectiveness of Cholesterol Screening in the Elderly 47

formly achieve a 10-percent reduction in

LDL. This is an optimistic assumption

regarding the effectiveness of dietary interventions in lowering LDL levels. The Multiple Risk Factor Intervention Trial of middleaged men led to a 7-percent reduction in

LDL with diet. Even in the subset of

participants with “best adherence,” LDL fell

by 8.6 percent (32).

Although the effectiveness of diet control

interventions appears to be limited, if a way

were found to reduce LDL levels more

dramatically through diet alone, the estimated

cost of the NCEP program would be greatly

reduced. Therefore, OTA also calculated how

costs might change if a 15 percent reduction

in LDL could be expected from diet.

Costs of testing. --The marginal cost of

performing lipoprotein analyses is uncertain.

Laboratory and physician charges for

cholesterol determinations are highly variable.

For this analysis, total cholesterol measurements were assumed to cost $6.79 per

determination (which includes drawing the

blood and performing the analysis), the

Medicare average allowed charge in 1986 inflated to 1988 prices by the Medicare Economic Index (87,94). This is more expensive

than the retail price of fingerstick cholesterol

determinations (47). The analysis assumes

that fractionation (measurement of HDL,

triglycerides, and total cholesterol, with a calculated value of LDL) costs $16.89, the average allowed Medicare charge in 1988 dollars.

As is discussed in greater detail in the

text, the model does not include the cost of a

physician visit in estimating expenditures for

screening. It assumes that cholesterol screening either would take place in a community

setting or would occur as part of a patient’s

visit to the physician for some other purpose.

It is possible, however, that the introduction

of a cholesterol screening benefit would increase the number of physician office visits

for Medicare beneficiaries and the health care

costs of the program would rise accordingly.

Costs of treatment protocols. --The analysis assumes that diet imposes no direct

health care costs. This assumption underestimates treatment expenditures, since

most patients participating in dietary therapy

require counseling with physicians or

dietitians in the establishment and monitoring

of their diets. The NCEP protocol recommends that people on dietary therapy have a

“complete clinical evaluation. ” The costs of

such an evaluation are not included in the

model.

Under certain conditions, if improvement

in LDL levels with diet is totally inadequate,

the NCEP protocol leaves it at the physician’s

discretion whether to continue with diet or to

initiate therapy with medication. The model

assumes that physicians will always be conservative in decisions and will not initiate

medication. Thus, the model is extremely

conservative in estimating the number of

elderly people who would end up on medication and the costs of their treatment.

For medications, OTA calculated the

estimated annual expenditures in 1988 dollars

for a low cost regimen of $525 per patient

per year for niacin, and a high cost regimen

of $1,687 for lovastatin, including the costs

of followup testing. The figures are obtained

from table 4, and the text of the paper describes how they were derived.
ACRONYMS

A HA

BMAD

CDC

CHD

CPT

CTF

CVD

EDTA

HCFA

HDL

HMG CoA

LDL

LRC-CPPT

MRFIT

NCEP

NHLBI

PVD

VLDL

--American Heart Association

--Medicare Procedure Database

--Centers for Disease Control

--Coronary heart disease

--Current procedural terminology

--Canadian Task Force

--Cardiovascular disease

--Ethylenediaminetetraacetate

--Health Care Financing Administration

--High-density lipoprotein

--3-hydroxy-3-methyl glutaryl coenzyme-A reductase

--Low-density lipoprotein

--Lipid Research Clinics-Coronary Primary Prevention Trial

--Multiple Risk Factor Intervention Trial

--National Cholesterol Education Program

--National Heart, Lung, and Blood Institute

--Peripheral vascular disease

--Very low-density lipoprotein

48
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0