United States General Accounting Office

GAO Report to the Ranking Minority Member,

Committee on Science, House of

Representatives

May 1996 CHOLESTEROL

TREATMENT

A Review of the

Clinical Trials Evidence

G O A

years

1921 - 1996

GAO/PEMD-96-7

GAO United States

General Accounting Office

Washington, D.C. 20548

Program Evaluation and

Methodology Division

B-266080 

May 14, 1996

The Honorable George E. Brown, Jr.

Ranking Minority Member

Committee on Science

House of Representatives

Dear Mr. Brown:

The death rate from coronary heart disease (CHD) declined dramatically

during the past decade, but CHD is still the most prevalent cause of death in

the United States. Public health efforts to prevent heart disease have

emphasized reducing risk factors such as smoking, hypertension, and

elevated blood cholesterol levels. The National Institutes of Health (NIH)

established the National Cholesterol Education Program (NCEP) in 1985 to

encourage Americans to modify their diet and lifestyle and to provide

clinical guidelines to help health care professionals identify and treat

persons whose risk of heart disease is high because their cholesterol levels

are high. The NCEP guidelines suggest that 52 million American adults are

candidates for dietary treatment and that 9 million to 18 million of these

have cholesterol levels that are sufficiently high to warrant drug treatment.

High cholesterol is now widely recognized by the scientific community

and the general public as an important risk factor for heart disease.

Physicians and the public are generally aware of the need to lower

cholesterol, and treating patients by lowering their cholesterol has met

with some success. National survey data indicate that the proportion of

adults whose cholesterol is high (greater than or equal to 240 mg/dl)

declined from 26 percent to 20 percent between 1976 and 1991.1

 The NCEP

guidelines have contributed to this decline, but key aspects of them have

been debated since the mid-1980s. A number of critics have questioned

whether the available scientific evidence clearly demonstrates that the

benefits of treatment outweigh any possible health risks and whether the

benefits are broad enough to support widespread screening and treatment

of the population as the NCEP guidelines advocate.

Concerned about the translation of medical knowledge into national policy

and about the high costs of cholesterol treatment, the former

Subcommittee on Investigations and Oversight of the House Committee on

Science, Space, and Technology asked us to review the clinical trials

1

C. T. Sempos et al., “Prevalence of High Blood Cholesterol Among U.S. Adults,” Journal of the

American Medical Association, 269 (1993), 3009-14.

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evidence that was used to support the development of the NCEP guidelines.

The guidelines were developed from a broad set of research that included

not only clinical trials but also epidemiological, animal, pathologic, and

genetic studies. We were asked to review the clinical trials because they

are uniquely designed to assess the effectiveness of interventions to

reduce the incidence of a disease.

The equivocal results of the many individual clinical trials that have been

conducted over the past 30 years, however, have made it difficult to

determine the efficacy of cholesterol-lowering treatments in preventing

CHD. Several trials have shown clear reductions in heart disease rates for

persons who were treated, but many trials showed no improvement either

because the types of treatment were not particularly effective in lowering

cholesterol or because the studies were not large enough to adequately

measure the expected benefits.

Recently completed studies called meta-analyses, which quantitatively

combine the results of many individual trials, provide new insights into the

interpretation of the overall benefits and risks of cholesterol-lowering

treatments. Therefore, we examined the benefits and risks of lowering

cholesterol reported from meta-analyses of available clinical trials. We

report these and the results of two recently completed clinical trials that

used newer, more effective drug treatments that were not included in the

published meta-analyses. These trials provide important new evidence

regarding cholesterol treatment and the reduction of CHD. In addition, we

assessed the extent to which the trials provide information on different

population subgroups, and we determined whether the clinical trials that

are currently planned are likely to fill any data gaps that exist.

Results in Brief Meta-analyses that combine previous clinical trial findings consistently

show that persons who receive cholesterol-lowering treatment, regardless

of whether or not they have a history of heart disease, have significantly

fewer nonfatal heart attacks than persons who do not receive treatment.

The evidence on CHD fatalities (deaths attributable to CHD) also shows a

modest treatment benefit, but the meta-analyses show that it is found

mainly in the group of trials that assessed persons who already had CHD. A

reduction in CHD fatality rates is also found for persons who had high

cholesterol and no history of CHD; however, the differences between

treatment and nontreatment groups are not statistically significant.

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With respect to total fatalities—that is, deaths from CHD and all other

causes—most meta-analyses show no significant difference and thus no

improvement in overall survival rates in the trials that included either

persons with known CHD or persons without it. This is partly because of an

increase in non-CHD deaths across the trials. This finding, that cholesterol

treatment has not lowered the number of deaths overall, has been

worrisome to many researchers and is at the core of much of the

controversy on cholesterol policy.

Various researchers have attributed the increase in non-CHD deaths to

chance, to the biological means by which cholesterol is lowered, to the

short duration of the trials, or to the side effects of some treatments.

However, several recent meta-analyses have identified important factors

that appear to help explain it. They show, for example, that the overall

death rate fell in the trials that included persons whose risk for CHD was

highest and in the trials in which cholesterol reductions were large. The

overall death rate rose significantly among persons whose risk of CHD was

lower, whose cholesterol was reduced less, or whose treatment used

certain drugs.

The finding that reductions in coronary events are greater with greater

amounts of cholesterol reduction is confirmed by two trials completed too

recently to be in the meta-analyses we reviewed. Using a new class of

cholesterol-lowering drugs—the statins, or HMG CoA reductase

inhibitors—they lowered cholesterol 20 to 25 percent. Previous trials using

other drugs lowered it 10 percent, on the average. One of the trials,

conducted in Scandinavia on persons who already had had a heart attack,

found that both CHD outcomes and total deaths fell significantly for those

who received treatment. The second trial, conducted in Scotland on

persons who had no previous history of heart disease, also found

reductions in coronary events, although the reductions in coronary deaths

and total deaths did not quite achieve statistical significance.

While the existing cholesterol trials provide important results about CHD

outcomes, they are not representative of the population at large. The trials

focused predominantly on middle-aged white men considered to be at high

risk of CHD. They provide very little information on women, minority men

and women, and elderly men and women. The few trials that opened

enrollment to these subgroups generally did not have large enough

numbers of them to conduct separate analyses. What is known about these

groups has been obtained from other types of research that cannot be

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used to make causal inferences about how lowering cholesterol affects

coronary outcomes.

Several new clinical trials under way are intended to provide additional

information about treatment outcomes regarding total fatalities, persons

whose short-term risk of a coronary event is moderate, and the

longer-term effects of the newer drugs being used. These trials will be

large and open to participants from a broader portion of the population

than previously studied. However, the numbers actually enrolled in many

of these trials have not yet been determined, so that the extent to which

the trials will provide information on groups other than middle-aged white

men is not yet known.

Background Nearly half a million persons die from heart disease each year. As many

women as men die from CHD, although women die about 7 to 10 years later

than men on the average. The American Heart Association estimates that

heart disease costs $55 billion or more each year. Taken together, these

figures provide a strong rationale for prevention and treatment.

Many factors can contribute to the development of CHD. A heart attack—a

temporary interruption of blood flow to the heart—stems partly from the

chronic buildup of fatty plaque in the arteries. For example, as figure 1

shows, there is a continuous and upward-sloping association between

higher cholesterol levels and the incidence of CHD. Some of the best-known

risk factors, such as high blood cholesterol, cigarette smoking, diabetes,

obesity, hypertension, and physical inactivity, can be treated or modified;

others, such as age and family history of heart disease, cannot.

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Figure 1: CHD Deaths by Cholesterol

Level Among Men Screened for the

MRFIT Triala

153 175 187 198 208 216 226 238 253 290

0

2

4

6

8

10

12

14

Total cholesterol (mg/dl)

No. of CHD deaths per 1,000

aDeaths over 6 years among more than 355,000 men screened in the early 1970s.

The National Cholesterol

Education Program

National Heart, Lung, and Blood Institute (NHLBI) education campaigns

address several of the modifiable risk factors, including high blood

cholesterol levels, smoking, obesity, and hypertension. As a result of an

NIH consensus development conference in 1984, NHLBI established NCEP to

inform the public of the risks associated with cholesterol and to provide

guidelines for physicians on how to manage and reduce those risks.

Accordingly, NCEP both promotes the reduction of cholesterol levels in the

general population through lifestyle changes and encourages the

identification of persons whose cholesterol is high as candidates for

intensive treatment to lower it.

In the latter, high-risk approach, the NCEP guidelines recommend that all

adults be tested for cholesterol at least once every 5 years. Test results are

used to classify each person free of CHD into one of three groups: desirable,

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borderline-high, or high total cholesterol levels.2 Taking other risk factors

into consideration, physicians then identify candidates for further testing

(to determine low-density lipoprotein (LDL) cholesterol levels) and

cholesterol-lowering treatment. The first line of intervention against high

cholesterol levels is diets that emphasize lowering the consumption of fat

(particularly saturated fat) and dietary cholesterol. Prescription drugs are

advised if cholesterol goals are not met through diet. For most patients,

treatment is maintained over the course of a lifetime in order to keep

cholesterol levels down.

NCEP revised several elements of the guidelines for adults in 1993,

principally by (1) including age with regard to gender in determining risk

status and in making treatment decisions; (2) increasing the emphasis on

screening and treating persons whose risk of CHD is high, such as elderly

persons and those who already have evidence of CHD; and (3) recognizing

the importance of high-density lipoprotein (HDL) cholesterol as an

independent risk factor for CHD.

3

The Controversy on

Cholesterol Policy

Debate after the NCEP guidelines were issued focused on the efficacy of

lowering cholesterol, on its possible risks, and on the advisability of

screening for cholesterol and lowering it among the many population

subgroups that had not been included in the trials the guidelines had been

based on. Additional, more recent data have brought greater agreement

that cholesterol treatment helps prevent deaths among persons who have

a history of CHD. Controversy remains, however, on how useful

cholesterol-screening is to the broader population of healthy people. The

American College of Physicians, professionally representing 85,000 U.S.

internists, recently published guidelines under which groups for whom

cholesterol-screening has no proven benefit would not be screened.

While there is considerable agreement about the risks associated with high

cholesterol, concerns have been raised about the extent to which

cholesterol-lowering treatments reduce the rates of death from CHD and

from all causes. Some researchers argue that the clinical trials have shown

no difference in total fatalities between groups of people who received

2

Desirable is below 200 mg/dl, borderline high is 200-239 mg/dl, and high is equal to or above 240 mg/dl.

Approximately 50 percent of the U.S. adult population has total cholesterol levels of 200 mg/dl or

higher.

3

For example, the guidelines no longer recommend drug treatment for men younger than 35 and

premenopausal women, both of whom tend to experience lower rates of CHD. HDL cholesterol, a

component of total cholesterol, is believed to help remove excess cholesterol from the blood and

prevent the buildup of plaque. A higher level of HDL cholesterol is associated with a lower risk of heart

disease, while a lower level of HDL cholesterol can increase the risk of heart disease.

Page 6 GAO/PEMD-96-7 Cholesterol Treatment
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treatment and those who did not and that cholesterol-lowering treatments

may increase the number of deaths from non-CHD causes. Advocates of the

NCEP guidelines argue that the trials were not designed to be large enough

or long enough to assess overall mortality; they say that the increases in

rates of non-CHD deaths within the treatment groups are likely to have

resulted from chance or specific treatments rather than from any adverse

effects of lowering cholesterol.

Because the clinical trials focused almost exclusively on men who had

either existing CHD or high cholesterol or both, they provide little

information about anyone whose risk of heart disease is lower. Some

researchers and health policy analysts therefore suggest that the U.S.

guidelines should be more limited in scope, as they are in some other

nations. Advocates of the current guidelines, however, believe that some

trial data and other, nonclinical trial research, such as epidemiological and

laboratory studies, allow the generalization that if cholesterol-lowering

benefits the tested groups, it will benefit others.

Objectives, Scope,

and Methodology

As we stated previously, the main objective of our study was to examine

the NCEP guidelines’ clinical-trials base of evidence regarding

cholesterol-lowering treatment.4

 We limited our scope to mainly

randomized clinical trials that, by virtue of their design features, provide

the best evidence for assessing the effectiveness of interventions to reduce

the incidence of a disease. Other important research was also used in

developing the NCEP guidelines. For example, many epidemiological

studies have compared population groups across nations, monitored the

health status of entire community populations, and assessed changes in

the health outcomes of recent immigrants. These studies have increased

knowledge about the link between diet, elevated cholesterol levels, and

increased risk of CHD. Because we did not review other types of

cholesterol-related research, we did not evaluate or report the overall

adequacy or utility of the scientific support for the guidelines.

We reviewed the clinical outcomes of cholesterol-lowering trials through

the published results of 15 meta-analyses.5

 The meta-analyses, which

4

In a clinical trial, participants are screened and randomly assigned to a group that receives treatment

or to a group that does not, which allows an unbiased comparison of outcomes between the two

groups.

5

We selected meta-analyses that aggregated data from cholesterol-lowering trials across one or more

of the following health outcomes: nonfatal heart attacks, CHD fatalities, CHD incidence (nonfatal and

fatal events combined), non-CHD fatalities, and total fatalities. Not all the meta-analyses, however,

reported on each of these outcomes.

Page 7 GAO/PEMD-96-7 Cholesterol Treatment
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statistically summarize the results of a number of individual trials, give an

overall assessment of treatment outcomes. By combining the results of

several trials, meta-analyses can increase statistical power and the

precision of results. Within certain methodological limits, they also

provide a means of comparing different subgroups of trials and of

exploring issues in ways that individual trials, which may be constrained

by their design or intent, cannot.

The many clinical trials that have evaluated cholesterol-lowering

treatments represent diverse types of treatment, health characteristics,

overall sample sizes, duration of trial and follow-up, and outcomes. The

main treatments consisted of different diets and drugs (alone or in

combination). Some studies focused on persons who had existing

symptoms of CHD (secondary prevention trials); others concentrated on

those who had no evidence of CHD (primary prevention trials); a few

combined both. Although virtually all the trials were designed to assess

CHD outcomes, not all measured and reported the same outcome variables.

The meta-analyses that combined the numerical results of these trials are

also diverse. They used different rules for deciding what trials to include

and exclude; in fact, all excluded one type of trial or another. Most of the

meta-analysts, for example, excluded trials that used more than one

intervention to treat persons who had multiple risk factors, and most also

excluded the hormone trials because the type of hormone treatment they

used is no longer recommended for men. As a result, the meta-analyses

included as few as 6 to as many as 35 trials.

To determine the benefits and risks of cholesterol-lowering treatments, we

present the results of the meta-analyses.6

 We examined the similarities and

differences among them, in terms of the individual trials they included and

their analyses. We then compared reported odds ratios (a measure of the

relative difference in outcomes between persons who were treated and

those who were not treated in the trials) and determined the extent to

which there was agreement or disagreement in the direction and statistical

significance of the results.

To address the issue of the coverage and comprehensiveness of the

clinical trials data, we identified the demographic and risk-related

6

We did not conduct our own meta-analysis because each of the meta-analyses that we selected to

review responded to the objectives of our study. The results of the different meta-analyses are not

statistically independent because many of the larger clinical trials tend to be included in most of the

meta-analyses. As a result, even though there is diversity among the meta-analyses, some convergence

of findings is to be expected.

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characteristics of participants in trials included by meta-analysts, the types

of treatment they received, and the outcomes. In the same vein, to identify

the important data gaps that others have found, we reviewed NHLBI

documents, medical literature, and other sets of guidelines developed

elsewhere. We also identified and reviewed the designs of ongoing and

planned trials in order to determine which data gaps may be filled in the

near future.7

Principal Findings

The Benefits and Risks of

Lowering Cholesterol

Nonfatal and Fatal CHD

Outcomes

The meta-analyses we reviewed consistently reported a statistically

significant reduction in the rates of nonfatal heart attacks for the trial

participants who were treated for high cholesterol compared to those who

did not receive treatment. As shown in figure 2, this finding holds true for

both individuals without existing evidence of CHD—that is, in the primary

prevention trials—and those with it—that is, in the secondary prevention

trials.8

7

Appendix I describes in detail our scope and methodology and their strengths and limitations. In

appendixes II and III, we summarize our findings from the meta-analyses and discuss the data gaps in

the clinical trials. Appendix IV describes U.S. cholesterol policy in the United States and abroad.

8

Our findings on the benefits and risks of lowering cholesterol from the meta-analyses are tabulated

and discussed further in appendix II.

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Figure 2: Nonfatal Heart Attacks

Reported in Meta-Analyses of

Cholesterol-Lowering Trialsa

aThe horizontal bars represent estimates (at the 95-percent confidence interval) of the difference

in the odds of nonfatal heart attacks occurring in the treatment and nontreatment groups studied

in meta-analyses. At 1, the center of the figure, treatment and nontreatment groups show no

difference in the likelihood that participants in either group will have a nonfatal heart attack. Bars

to the left of 1 indicate that treatment leads to a decrease in the rate of nonfatal heart attack; bars

to the right, that it leads to an increase. Bars that overlap 1 indicate that differences between

treatment and nontreatment groups are not statistically significant. The line at the center of each

bar represents the common odds ratio, or the point estimate of that difference (that is, it is the

ratio of the odds of nonfatal heart attacks occurring in the treatment groups to the odds of

nonfatal heart attacks occurring in the nontreatment groups). (Appendix II, table II.1, details the

numerical estimates for each meta-analysis.)

The results that the meta-analyses reported for deaths from CHD present a

somewhat different picture, shown in figure 3. All the meta-analyses

reported a reduction in the rate of coronary death among the participants

who were treated compared to those who were not but not as great a

relative reduction as that in nonfatal outcomes. Also, a different pattern is

apparent for the death rate of participants who were treated and had a

history of CHD compared to participants who were treated and did not. For

those who had a history, most of the meta-analyses found a significant

Page 10 GAO/PEMD-96-7 Cholesterol Treatment
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reduction favoring the treatment groups. For those who did not, the

meta-analyses that examined CHD deaths point in the direction of a small

reduction but none found it statistically significant.9

9

Another useful measure comparing the effects of treatment is the number of persons who would have

to be treated in order to prevent one adverse event. One meta-analysis calculated this number for

death from CHD and found a large difference between those who had existing CHD and those who did

not: to prevent one death from CHD, 38 persons with existing CHD would have to be treated while 675

persons with no evidence of CHD would have to be treated. This calculation does not reflect the larger

number of nonfatal heart attacks relative to fatal attacks and the proportionately larger number of

nonfatal attacks prevented by lowering cholesterol, nor does it reflect treatment with the statin drugs.

See J. S. Silberberg and D. A. Henry, “The Benefits of Reducing Cholesterol Levels: The Need to

Distinguish Primary from Secondary Prevention. 1. A Meta-Analysis of Cholesterol Lowering Trials,”

Medical Journal of Australia, 155 (1991), 665-70.

Page 11 GAO/PEMD-96-7 Cholesterol Treatment
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Figure 3: CHD Fatalities Reported in

Meta-Analyses of

Cholesterol-Lowering Trialsa

aThe horizontal bars represent estimates (at the 95-percent confidence interval) of the difference

in the odds of CHD fatalities occurring in the treatment and nontreatment groups studied in

meta-analyses. At 1, the center of the figure, treatment and nontreatment groups show no

difference in the likelihood that participants in either group will have a fatal heart attack from CHD.

Bars to the left of 1 indicate that treatment leads to a decrease in the rate of fatal heart attack;

bars to the right, that it leads to an increase. Bars that overlap 1 indicate that differences between

treatment and nontreatment groups are not statistically significant. The line at the center of each

bar represents the common odds ratio, or the point estimate of that difference (that is, it is the

ratio of the odds of CHD fatalities in the treatment groups to the odds of CHD fatalities in the

nontreatment groups). (Appendix II, table II.2, details the numerical estimates for each

meta-analysis.)

The lack of a statistically significant reduction in the rate of death among

participants in the primary prevention trials may be because the trials

generally lowered cholesterol levels by only a modest amount and the

number of events attributable to CHD during the trials was so small that

detecting statistical differences between the treatment and nontreatment

groups was difficult.10 Several of the recent meta-analyses found that the

10Cholesterol reduction across the individual trials ranged from around 1 percent to more than

20 percent, with an average of about 10 percent.

Page 12 GAO/PEMD-96-7 Cholesterol Treatment
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degree to which cholesterol is lowered is related to reductions in CHD

events among the trials. For example, one study reported that when

cholesterol was lowered by 10 percent or more, deaths from CHD fell

significantly, by 13 percent, and another reported that nonfatal heart

attacks and CHD deaths fell by 18 percent.11 Another meta-analysis found

that lowering cholesterol by 12 percent or more corresponded to a

27-percent fall in the death rate from CHD.

12

The extent to which the rate of death from CHD falls is also associated with

the level of risk for CHD that participants have at the start of a trial. In one

meta-analysis, participants in primary and secondary trials were

categorized according to higher, medium, and lower levels of risk. The

results showed a significant 26-percent fall in the rate of death from CHD

for those in the higher-risk category but no significant benefit for those in

the medium- and lower-risk categories. The higher-risk category was

dominated by participants who had a history of CHD (secondary prevention

trials), whereas the lower-risk category was dominated by participants

who did not (primary prevention trials).13

Non-CHD and Total Fatalities The extent to which overall survival rates improve from lowering

cholesterol has been addressed mainly in the meta-analyses. The

individual trials were mostly too short and had too few participants to

assess whether death from all causes fell. As shown in figure 4, the

meta-analyses that reported on deaths from non-CHD causes mainly show a

statistically significant increase within the primary prevention trials for

those who received treatment. The meta-analyses similarly point toward

an increase within the secondary prevention trials, but only one found it to

be statistically significant.

11A. L. Gould et al., “Cholesterol Reduction Yields Clinical Benefit,” Circulation, Circulation, 91 (1995),

2274-82, and M. R. Law et al., “By How Much and How Quickly Does Reduction in Serum Cholesterol

Concentration Lower Risk of Ischaemic Heart Disease?” British Medical Journal, 308 (1994), 367-73.

12D. J. Gordon, “Cholesterol Lowering and Total Mortality,” in B. M. Rifkind (ed.), Lowering

Cholesterol in High-Risk Individuals and Populations (New York: Marcel Dekker, 1995), pp. 33-48.

13G. D. Smith, F. Song, and T. A. Sheldon, “Cholesterol Lowering and Mortality: The Importance of

Considering Initial Level of Risk,” British Medical Journal, 306 (1993), 1367-73.

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Figure 4: Non-CHD Fatalities Reported

in Meta-Analyses of

Cholesterol-Lowering Trialsa

aThe horizontal bars represent estimates (at the 95-percent confidence interval) of the difference

in the odds of non-CHD fatalities occurring in the treatment and nontreatment groups studied in

meta-analyses. At 1, the center of the figure, treatment and nontreatment groups show no

difference in the likelihood of non-CHD fatalities among participants in either group. Bars to the

left of 1 indicate that treatment leads to a decrease in the rate of non-CHD fatalities; bars to the

right, that it leads to an increase. Bars that overlap 1 indicate that differences between treatment

and nontreatment groups are not statistically significant. The line at the center of each bar

represents common odds ratio, or the the point estimate of that difference (that is, it is the ratio of

the odds of non-CHD fatalities in the treatment groups to the odds of non-CHD fatalities in the

nontreatment groups). (Appendix II, table II.2, details the numerical estimates for each

meta-analysis.)

When the trial data are aggregated through the meta-analyses, total fatality

rates increase among treated participants who had no evidence of CHD (see

figure 5). However, none of the meta-analyses found these rates to be

statistically greater among participants who were treated than among

those who were not. The meta-analyses found a small relative decrease in

total fatalities for participants who were treated and had a history of CHD;

Page 14 GAO/PEMD-96-7 Cholesterol Treatment
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only one found it to be statistically significant (see figure 5).14 That total

fatalities did not fall significantly after cholesterol-lowering treatment may

be because fatality rates from non-CHD causes were high among these

participants. These high rates were large enough to cancel out the modest

reduction in CHD deaths after cholesterol-lowering treatment.

Figure 5: Total Fatalities Reported in

Meta-Analyses of

Cholesterol-Lowering Trialsa

aThe horizontal bars represent estimates (at the 95-percent confidence interval) of the difference

in the odds of total fatalities occurring in the treatment and nontreatment groups studied in

meta-analyses. At 1, the center of the figure, treatment and nontreatment groups show no

difference in the likelihood of total fatalities among participants in either group. Bars to the left of 1

indicate that treatment leads to a decrease in the rate of total fatalities; bars to the right, that it

leads to an increase. Bars that overlap 1 indicate that differences between treatment and

nontreatment groups are not statistically significant. The line at the center of each bar represents

the common odd ratio, or the point estimate of that difference (that is, it is the ratio of the odds of

total fatalities in the treatment groups to the odds of total fatalities in the nontreatment groups).

(Appendix II, table II.2, details the numerical estimates for each meta-analysis.)

14The one meta-analysis that found a statistically significant reduction weighted the result for the

degree of cholesterol-lowering.

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Some analysts explain the increase in non-CHD fatalities as a matter of

chance. Others speculate that lowering cholesterol itself produces these

results. Still others point to the side effects of one or more of the drugs

used for treatment. Although the meta-analyses have not resolved this

issue—because non-CHD deaths were not as carefully reported in some of

the individual trials as were deaths from CHD—they have shed some light

and have identified areas that warrant further investigation.

When one meta-analyst differentiated between the trials whose

participants had higher, medium, and lower risk for CHD, deaths from all

causes fell significantly among those who were at higher risk for CHD and

received cholesterol-lowering treatment, whereas deaths increased

significantly for those who were at lower risk. Furthermore, a few other

meta-analyses have shown that the more that cholesterol is lowered, the

greater is overall survival.15 Finally, recent meta-analyses have found that

the greater numbers of non-CHD deaths associated with

cholesterol-lowering treatment are more likely to be seen in trials that

used certain drug treatments, particularly hormones and fibrates.

Two Recent

Cholesterol-Lowering

Trials

The Scandinavian Simvastatin Survival Study (4S), a secondary prevention

trial, and the West of Scotland Coronary Prevention Study (WOSCOPS), a

primary prevention trial, treated men whose total cholesterol averaged

more than 260 mg/dl with either a statin drug or a placebo.16 The results of

both trials are consistent with the several meta-analyses that found that

greater reductions in cholesterol yielded greater reductions in CHD events.

The 4S trial is the first to find that lowering cholesterol can significantly

reduce the total fatality rate of cardiac patients who are at very high risk

for heart attack. The WOSCOPS trial found that lowering cholesterol lowered

CHD fatalities, although this fell short of statistical significance. There were

no increases in non-CHD fatality, and total fatalities fell. The reduction in

CHD deaths in 4S means that 29 patients diagnosed with CHD would have to

be treated with simvastatin at the trial dosages for 5.4 years (the median

length of the trial) to prevent one CHD death. Given the WOSCOPS trial data,

143 middle-aged men with no evidence of a previous heart attack would

15One meta-analysis found that when cholesterol was lowered by at least 10 percent, total mortality fell

about 10 percent. Another reported that a 12-percent or greater reduction in cholesterol led to a

20-percent reduction in total mortality.

16Scandinavian Simvastatin Survival Study Group, “Randomized Trial of Cholesterol Lowering in 4,444

Patients with Coronary Heart Disease: The Scandinavian Simvastatin Study (4S),” Lancet, 344 (1994),

1383-89, and J. Shepard et al., “Prevention of Coronary Heart Disease with Pravastatin in Men with

Hypercholesterolemia,” New England Journal of Medicine, 333 (1995), 1301-7.

Page 16 GAO/PEMD-96-7 Cholesterol Treatment
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have to be treated for 5 years to prevent one death from cardiovascular

causes.

Another concern in the controversy is that lowering cholesterol may

simply substitute one cause of death for another. The meta-analyses

summarizing most past trials found that lowering cholesterol had the

clearest benefit among men who had been diagnosed with CHD, that the

magnitude of coronary benefits is related directly to the degree to which

cholesterol is lowered, and that higher rates of non-CHD fatality are likely

to be associated with specific treatments. The 4S and WOSCOPS trials, which

did not find a greater risk of death from non-CHD causes, support the

meta-analytic findings that it is particular treatments to lower cholesterol,

rather than the lowering itself, that increase non-CHD fatality rates. These

data may be encouraging, but it should be noted that these were 5-year

studies and that drug treatment would be expected to continue for longer

periods.

The Population and

Treatment Gaps in the

Clinical Trials

The Population Studied The clinical trials conducted over the past 30 years concentrated on white,

middle-aged men who were considered to have a high risk of CHD. Useful

trial data are lacking for women, minority men and women, elderly men

and women, and people who have moderate cholesterol readings and are

generally at lower risk. The trials that did enroll them did not do so in

numbers large enough to allow for separate analyses of the trial results. To

achieve sufficient statistical power at the least cost, researchers selected

the participants they felt were most likely to experience a large number of

CHD events within a trial’s duration.

Because the numbers for women and elderly men and women are so small

and the trials did not separate them out for analysis, the meta-analyses

generally did not report them separately either. Fewer than half the trials

considered in the meta-analyses were open to women, and women

constitute only about 7 percent of the participants across all the trials. The

average age of participants in the trials ranged from 45 to 66, with a

median of about 52 across all the trials.

Page 17 GAO/PEMD-96-7 Cholesterol Treatment
B-266080 

The trials examined in the meta-analyses provide very little information

about people whose risk of heart disease as defined by the NCEP guidelines

is moderate. Most trials included either persons who were known to have

evidence of CHD or persons who had no evidence of CHD but had high

cholesterol and other risk factors. Even primary prevention trials included

high-risk groups. The median total cholesterol for all trials was close to

260 mg/dl.

Types of Treatment Several of the trials tested various dietary treatments, but most of these

used diets that differ from the ones that are now recommended and used

to treat persons with high cholesterol. The diet trials were also conducted

mainly in institutions, where the participants’ diet could be strictly

controlled. Therefore, several reviewers of the trials have questioned the

extent to which their findings apply to people who do not live in

institutions.

The older drug treatments, those predominantly used in the trials we

examined, have some side effects, and a few have seriously negative

effects. The long-term effects of the statins, now the most widely used

cholesterol-lowering drugs, have not been extensively investigated. These

drugs were developed and marketed in the 1980s, after most of the

existing trials were designed or conducted.

Planned Clinical Trials The gaps in what is known about the relationship between lowering

cholesterol and CHD outcomes are generally recognized by most experts,

including the authors of NCEP’s reports. Many are being addressed by new

trials that should help answer some of the questions about non-CHD deaths

and total fatalities, CHD outcomes for persons whose short-term risk of

heart disease is moderate, CHD outcomes for population groups other than

middle-aged white men, and the long-term effects of the statin drugs.

We identified 13 large trials in different stages of design and

implementation in the United States and Europe. They tend to be large and

long and should have greater statistical power than previous trials to

assess total fatalities.17 Most will use one of the statin drugs. Therefore,

trial investigators expect larger improvements in CHD outcomes.

Many of the trials plan to provide information about different levels of CHD

risk. At least 3 trials will study participants who have no history of CHD,

17All but one of these trials will have 2,500 participants or more. One trial will have a follow-up period

of 3 years; the others will run for 5 years or more.

Page 18 GAO/PEMD-96-7 Cholesterol Treatment
B-266080 

and 5 have broadened the range of cholesterol levels generally studied to

include borderline-high cholesterol levels of 200 to 240 mg/dl. Three will

evaluate whether drug treatment can raise HDL cholesterol levels and thus

improve CHD outcomes. Previous trials have not generally focused on

treating persons whose HDL cholesterol was low.

Several of the new trials will enroll older participants. One is designed

only for elderly participants. Two of the new trials will include a high

percentage of women, but it may be difficult to attribute any observed

outcome to cholesterol-lowering treatment because both will use several

interventions to target different risk factors. Women will number fewer

than 20 percent of the participants in the other new trials. Depending on

how many women in all are actually enrolled, there may or may not be

sufficient information to assess coronary outcomes with respect to

cholesterol-lowering treatment. Only one trial will recruit a large

percentage of African Americans.

Conclusions We have four main conclusions from our evaluation of the meta-analyses

and the clinical trials they studied:

1. The meta-analyses have consistently shown that cholesterol-lowering

treatment benefits middle-aged white men who have high cholesterol

levels and a history of heart disease. This appears to be so particularly

when the treatment is effective in lowering cholesterol.

2. The meta-analyses also show that men with moderate-to-high

cholesterol levels and no history of heart disease have lower rates of

nonfatal heart attacks but no statistically significant reductions in rates of

CHD death or total fatalities as a result of cholesterol-lowering treatment.

3. The trials generally have not evaluated the efficacy of

cholesterol-lowering treatment for several important population groups,

such as women, elderly men and women, and minority men and women.

Thus, they provide little or no evidence of benefits or possible risks for

these groups.

4. Two recent trials using a new drug class, the statins, show greater

reductions in coronary events with their greater reductions in cholesterol

and no increase in non-CHD fatalities. One trial studied men and women

who had CHD and found a significant reduction in total fatalities; the other,

Page 19 GAO/PEMD-96-7 Cholesterol Treatment
B-266080 

which studied only men who did not have CHD, showed encouraging but

not statistically significant reductions in CHD fatalities.

Recommendation While the clinical trials have answered many important questions about

the benefits and risks of various cholesterol-lowering treatments, they also

leave unanswered several questions about likely coronary outcomes for

persons at different levels of CHD risk and for persons in population

subgroups that they have not thoroughly studied. These questions will be

answered to some extent by several trials that are under way, but it is

likely to be several years before they are completed. We recommend that

the director of NHLBI take steps to closely monitor these trials, evaluate

their outcomes, and determine whether additional trials should be planned

in order to fill in data presently lacking on women, elderly men and

women, minority men and women, and persons whose cholesterol levels

are relatively low or who otherwise are members of low-risk groups.

Agency Comments Officials from NHLBI reviewed a draft of this report and provided the

written comments that are reprinted in appendix VI. In general, the

officials found our report to be technically accurate and agreed with our

main findings. They believed, however, that we placed too much emphasis

on the aggregated results of the previous trials and not enough on the two

recently completed trials that NHLBI believes conclusively demonstrate the

benefits of lowering cholesterol for patients who do and do not have CHD.

We agree that these recent trials did produce relatively large CHD

reductions compared to previous trial results, and we have tried to reflect

this in our report. While the results of the new trials are compelling, it is

important to recognize that they were designed to demonstrate the

efficacy and safety of particular statin treatments in only selected high-risk

populations for a period of 5 years.

NHLBI was also concerned that in our report we did not sufficiently take

into account the other sources of nontrial evidence that it believes

provides a basis for treating various population subgroups. We agree that

our report is limited by our not having reviewed other nontrial sources of

information about cholesterol treatment. While it is important to consider

the full range of evidence, we were asked to review clinical trials because

they provide the strongest evidence for establishing treatment benefits. In

light of this request, our study findings can help the Congress and other

readers understand the limits of the trial information that was available in

Page 20 GAO/PEMD-96-7 Cholesterol Treatment
B-266080 

the past while cholesterol policy and treatment efforts were being

developed in this country.

As we arranged with your office, unless you publicly announce the report’s

contents earlier, we plan no further distribution until 30 days after the date

of this letter. At that time, we will send copies of this report to the

National Institutes of Health and other health-related agencies. We will

also make copies available to others on request. If you have any questions

or would like additional information, please call me at (202) 512-3092.

Major contributors to this report are listed in appendix VII.

Sincerely yours,

Kwai-Cheung Chan

Director of Program Evaluation

 in Physical Systems Areas

Page 21 GAO/PEMD-96-7 Cholesterol Treatment
Contents

Letter 1

Appendix I 

Objectives, Scope,

and Methodology

26

The Objectives and Scope of Our Study 26

Our Methodology 26

The Strengths and Limitations of Our Study 43

Appendix II 

The Meta-Analyses of

Cholesterol-Lowering

Trials and the Health

Outcomes They

Report

46

A Summary of Our Major Findings 46

Three Recent Research Trends 47

Primary and Secondary Prevention Trial Results Compared 49

A Final Note 58

Appendix III 

Data Gaps in

Randomized Clinical

Trials

59

Completed Clinical Trials 59

Trials Proposed and Under Way 66

Appendix IV 

Cholesterol Policy in

the United States and

Abroad

70

The National Cholesterol Education Program 72

Other Cholesterol Policies Compared to NCEP 80

Appendix V 

Experts We Consulted

84

Appendix VI 

Comments From the

U.S. Department of

Health and Human

Services

87

Page 22 GAO/PEMD-96-7 Cholesterol Treatment
Contents

Appendix VII 

Major Contributors to

This Report

94

Bibliography 95

Meta-Analyses We Cited 95

Clinical Trials Cited in the Meta-Analyses 97

Meta-Analyses We Omitted 104

Tables Table I.1: Basic Features of 15 Meta-Analyses of

Cholesterol-Lowering Trials

30

Table I.2: Fifteen Meta-Analyses and the Cholesterol-Lowering

Trials They Studied

36

Table II.1: Meta-Analysis Results for CHD Incidence and Nonfatal

CHD

50

Table II.2: Meta-Analysis Results for CHD, Non-CHD, and Total

Fatality

52

Table III.1: Basic Features of 42 Cholesterol-Lowering Trials 60

Table III.2: Data Gaps in Cholesterol-Lowering Trials and 13 New

Studies Attempting to Fill Them

67

Table IV.1: National Cholesterol Education Program Milestones

Since 1984

73

Table IV.2: U.S. Cholesterol-Lowering Drugs and Their Effect 79

Table IV.3: Cholesterol-Lowering Policies in the United States,

Australia, Canada, and Europe

81

Figures Figure 1: CHD Deaths by Cholesterol Level Among Men Screened

for the MRFIT Trial

5

Figure 2: Nonfatal Heart Attacks Reported in Meta-Analyses of

Cholesterol-Lowering Trials

10

Figure 3: CHD Fatalities Reported in Meta-Analyses of

Cholesterol-Lowering Trials

12

Figure 4: Non-CHD Fatalities Reported in Meta-Analyses of

Cholesterol-Lowering Trials

14

Figure 5: Total Fatalities Reported in Meta-Analyses of

Cholesterol-Lowering Trials

15

Figure III.1: Cholesterol Levels in the Clinical Trials Compared to

U.S. Adult Total Cholesterol Distribution

66

Page 23 GAO/PEMD-96-7 Cholesterol Treatment
Contents

Figure IV.1: Cholesterol and CHD Death Distributions in the

MRFIT Trial

71

Figure IV.2: Recommended Advice and Treatment for U.S. Adults

by Cholesterol Level

76

Abbreviations

4S Scandinavian Simvastatin Survival Study

ACP American College of Physicians

ALLHAT Anti-hypertensive and Lipid-Lowering Treatment to

Prevent Heart Attack

CHD Coronary heart disease

HDL High-density lipoprotein

LDL Low-density lipoprotein

NCEP National Cholesterol Education Program

NHLBI National Heart, Lung, and Blood Institute

NIH National Institutes of Health

WOSCOPS West of Scotland Coronary Prevention Study

Page 24 GAO/PEMD-96-7 Cholesterol Treatment
Page 25 GAO/PEMD-96-7 Cholesterol Treatment
Appendix I 

Objectives, Scope, and Methodology

The Objectives and

Scope of Our Study

Our work is set within the context of NIH’s NCEP guidelines. We describe

the guidelines and compare them with cholesterol-screening treatment

guidelines developed elsewhere, particularly in Australia, Canada, and

Europe. (See appendix IV.) We did not evaluate the process by which the

guidelines were developed or the adequacy or utility of either the NCEP

guidelines or others. We focused on clinical trials evidence, one portion of

the broad base of evidence that undergirds the NCEP guidelines.

Accordingly, our three objectives were to

• review the benefits and risks associated with the cholesterol-lowering

treatments in published randomized clinical trials,

• review the extent to which the information from these trials provides

information on different population groups, and

• identify and review the ongoing and planned cholesterol-lowering clinical

trials to determine whether identified data gaps are likely to be filled.

Our first objective encompasses 42 individual randomized

cholesterol-lowering clinical trials and 15 meta-analyses of them.1

 The

trials were conducted over the past 30 years and were mainly designed to

test whether lowering cholesterol reduces the incidence of coronary heart

disease. The meta-analyses were published from 1987 through April 1995.

The scope of our second objective includes the 42 completed

cholesterol-lowering trials within the 15 meta-analyses whose designs we

had examined for key demographic and risk-related characteristics among

the participants. Our third objective considers the NCEP documents and

medical literature we reviewed as well as the design characteristics of 13

planned or ongoing trials.

Our Methodology

Rationale Our purpose was to assess the evidence regarding the efficacy of

cholesterol-lowering interventions on measured health outcomes. We

examined the benefits and risks associated with cholesterol-lowering

through available clinical trials evidence. We selected randomized clinical

1

In the words of Glass, “meta-analysis” refers to “the statistical analysis of a large collection of analysis

results from individual studies for the purpose of integrating the findings” (G. V. Glass, “Primary,

Secondary, and Meta-analysis,” Educational Researcher, 5 (1976), 3, cited in H. Cooper and L. V.

Hedges (eds.), The Handbook of Research Synthesis (New York: Russell Sage Foundation, 1994), p. 5).

Meta-analysis is a relatively new analytic procedure, although its practice has been growing steadily

over the past two decades.

Page 26 GAO/PEMD-96-7 Cholesterol Treatment
Appendix I 

Objectives, Scope, and Methodology

trials because they are considered the “gold standard” in medical research.

People who participate are assigned randomly to either a treatment group

that receives the intervention or a nontreatment group that does not. This

ensures that a comparison of the two groups’ outcomes will be unbiased

because the two groups are more or less equivalent, differing only in the

factor being tested—in our case, cholesterol-lowering interventions.

The NCEP guidelines were developed not only from the evidence from

randomized clinical trials but also from a broad range of observational

studies in epidemiology, animal physiology, pathology, and genetics. Many

observational studies, for example, compared population groups across

nations, monitored the health status of entire community populations, and

assessed changes in the health outcomes of recent immigrants. These

studies are important because they enlarged our knowledge of how diet,

cholesterol, and the risk of CHD are linked. However, only randomized

clinical trials are uniquely designed to attribute potential reductions in CHD

specifically to cholesterol-lowering interventions.

However, the individual trials differed in the collection and reporting of

outcome variables. Few of them were designed to respond to the debate

about the ability of cholesterol-lowering to extend the life span; they often

had too few participants or were too short in duration. Therefore, we

summarized the results of cholesterol-lowering trials through the

meta-analyses to examine the evidence for the effect that lowering

cholesterol has on five health outcomes: CHD incidence (nonfatal and fatal

heart attacks combined), nonfatal heart attacks, CHD fatalities, non-CHD

fatalities, and total fatalities.2

Meta-analyses statistically combine the results of individual randomized

cholesterol-lowering clinical trials to estimate the extent to which

cholesterol-lowering treatments reduce the incidence of CHD events.

Therefore, we elected to provide a descriptive synthesis of the

meta-analyses whose purpose had been to assess the benefits and risks of

cholesterol-lowering interventions.

Meta-analysis pools data from trials that have addressed essentially the

same research question in a statistically rigorous manner, thereby

(1) improving statistical power, (2) improving estimates of effect size,

(3) resolving uncertainty where reports disagree, (4) answering

theoretically relevant questions that were not initially posed or not

2

We present these five outcomes separately since CHD incidence cannot be derived from summing

nonfatal heart attacks and CHD fatalities. This is because any one trial participant may have more than

one nonfatal heart attack.

Page 27 GAO/PEMD-96-7 Cholesterol Treatment
Appendix I 

Objectives, Scope, and Methodology

possible to address within a single study, and (5) evaluating the conditions

under which effects occur as well as exploring the mediating processes

that may account for them. Meta-analysis can point toward fruitful

directions for future primary research.

However, meta-analysis can be limited by the availability and quality of the

studies whose results it aggregates. Some criticisms of meta-analysis are

that it (1) does not detect publication bias and thus can lead to spurious

conclusions, (2) obscures potentially relevant differences between

combined trials, and (3) biases findings through its inclusion and

exclusion criteria. Nevertheless, we examined the meta-analyses we did

because we believed they offered the best available guide to what is

generally known and not known about the effects of lowering cholesterol

among U.S. adults. Since our intent was to shed light on the consistencies

and inconsistencies in all the available and relevant trial data, we did not

conduct our own meta-analysis.

We examined the clinical trials evidence and other policy groups’

interpretation of that evidence. We also looked at the characteristics of the

cholesterol-lowering clinical trials and their applicability to the NCEP

guidelines. Specifically, we looked at the extent to which the available

data applied to different population groups. Further, we examined ongoing

and proposed new trials to determine if they would fill any of the data

gaps that have been identified.

Our Database

Development and Its

Characteristics

Our Selection of Meta-Analyses We searched MEDLINE, a comprehensive bibliographic database, and

reviewed agency and other documents. We also surveyed 11 experts for

their opinion on the relevance of the meta-analyses we had located and

asked them for additional references that we had failed to uncover. In this

way, we identified 42 meta-analyses and other studies that synthesized

information from the available cholesterol-lowering trials. We judged 30 of

these as inappropriate to our objectives for the following reasons:

(1) individual trials were not quantitatively aggregated, (2) aggregated

trials were not primarily cholesterol-lowering interventions, (3) analytic

detail was insufficient (for example, we excluded a meta-analysis when we

were unable to determine the number or identity of the studies it

Page 28 GAO/PEMD-96-7 Cholesterol Treatment
Appendix I 

Objectives, Scope, and Methodology

included), (4) the number of individual trials was insufficient (for

example, we excluded meta-analyses that included no more than two

randomized trials of a year or more in duration), (5) the study was not

published or not published in English, and (6) the clinical CHD outcomes

we focused on had not been examined. To the 12 meta-analyses that

passed this screen, we added 9 that were published or located after the

NCEP guidelines were issued and otherwise passed our screen. This

resulted in a core set of 21 meta-analyses.

Our Selection of Individual

Clinical Trials

When we reviewed the results of this search, we located 85 references to

54 individual cholesterol-lowering studies. Most of the

cholesterol-lowering clinical trials of the past 30 years were conducted in

the United States and Europe with participants who were mainly

middle-aged white men who were considered to be at high risk for CHD

(see table III.1). We asked the 11 experts about our including these trials.

They differed on whether we should include multifactor trials, hormone

trials, and nonrandomized trials. One or more of them also voted to

exclude some studies that had been included in a meta-analysis. We

decided to consider all trials that had been referenced by a meta-analyst,

thus restricting our review to the mainly randomized trials in the

meta-analyses. (The meta-analyses and trials are listed in the

bibliography.)

Our Analysis Decisions Since more than one of the 21 meta-analyses were completed by the same

lead author, we set the following criteria to reduce redundancy. (1) When

more than one meta-analysis had been completed by the lead author, we

selected the more recent one if it represented all previous trials and if it

used similar configurations of trials to examine the same outcomes. (2) If

the earlier meta-analysis reported on a specific outcome that was not

addressed in the more recent meta-analysis, we retained the information

from the earlier one. (3) If the more recent meta-analysis resulted in a

substantial improvement in quality over a previous one, we replaced the

earlier meta-analysis with the later one. (4) When an estimate was based

on a very select set of studies that made comparisons with other

meta-analyses improper, we dropped the estimate. When we had followed

these criteria, the meta-analyses totaled 15, as listed in table I.l.3

3

In table I.1, we retained only the Muldoon 1990 analyses that were not updated in Muldoon 1993. We

did the same for Rossouw 1991 and 1995. The Law I 1994 meta-analysis (Law, Thompson, and Wald)

relies on the same set of trials as the Law II 1994 meta-analysis (Law, Wald, and Thompson). The

former includes data on women, and the two address different questions.

Page 29 GAO/PEMD-96-7 Cholesterol Treatment
Appendix I 

Objectives, Scope, and Methodology

Table I.1: Basic Features of 15

Meta-Analyses of

Cholesterol-Lowering Trialsa

Outcome

Meta-analysis Clinical focus Other T

Yusuf 1987 CHD incidence and CHD and

non-CHD fatality for diet and

drug trials

Identified dose response

relationship between lowering

cholesterol and CHD incidence

Muldoon 1990a CHD, non-CHD, and total

fatality (all trials); CHD and

total fatality for diet versus

drug trials

Summarized results for cancer

and nonillness fatality

(accident, violence, trauma,

and suicide)

6

Rossouw 1991 Nonfatal, fatal, and all heart

attacks; cardiovascular,

noncardiovascular, and total

fatality for drug trials

Summarized % reduction in

heart attacks for primary and

secondary prevention trials

and by treatment type (diet

and various drugs)

4

Silberberg 1991 CHD incidence, nonfatal heart

attacks, and CHD and total

fatality for drug trials

Compared CHD benefits of

primary and secondary trials

and estimated the number

needed to prevent an event

9

Ravnskov 1992 Nonfatal heart attacks and

CHD and total fatality

Compared CHD benefits by

trial type and duration, gender,

and diet and drug treatment

type

2

CTF 1993a Nonfatal heart attacks and

CHD, non-CHD, and total

fatality

Summarized results for

gallbladder events and death

from cancer and violence

6

Cucherat 1993 CHD incidence, nonfatal heart

attacks, and CHD and total

fatality

Summarized results for death

from cancer and death not

related to illness; compared

CHD benefits of primary and

secondary prevention trials

Holme 1993 CHD incidence and total

fatality in different trial types

with different diet and drug

treatments

Summarized dose-response

relationship between lowering

cholesterol and CHD

incidence and total fatality

2

Muldoon 1993 CHD fatality in different trial

types with different diet and

drug treatments

Summarized results for

nonillness-related suicide and

death from trauma in different

trial types with different diet

and drug treatments

8

Smith 1993h CHD, non-CHD, and total

fatality stratified by risk of CHD

death

Summarized results for CHD,

non-CHD, and total fatality

stratified by risk of CHD death

in drug and other interventions

3

Law I 1994j CHD fatality (all trials);

non-CHD and total fatality in

different trial types with

different diet and drug

treatments weighted by

degree of cholesterol-lowering

Summarized results for death

from accident, suicide, and

cancer and other diseases

2

Page 30 GAO/PEMD-96-7 Cholesterol Treatment
Appendix I 

Objectives, Scope, and Methodology

Total number Treatment

Trial unitsb Participantsc Gender Included Expressly excludedd

e

19 36,050 Men, women Diet, drug Hormones, multifactor trials

6 24,847 Men Diet, drug Multifactor trials

4 diet, 8 drug 1,915 diet, 25,295 drug Men, women Diet, drug Hormones, multifactor trials

9 26,609 Men, women Drug Hormones, multifactor trials

26 115,960 Men, women Diet, drug, hormones,

multifactor trials

e

6 24,847 Men Diet, drug Multifactor trials

19 48,273 Men, women Diet, drug, surgeryf Hormones, multifactor trials

22 125,673 Men, women Diet, drug, multifactor

trials, surgeryf

e

8 30,696 Men Diet, drug, surgeryf g

35 57,124 Men, women Diet, drug, hormones,

surgeryf

i

28 52,350 Men, women Diet, drug, surgeryf Hormones, multifactor trials

(continued)

Page 31 GAO/PEMD-96-7 Cholesterol Treatment
Appendix I 

Objectives, Scope, and Methodology

Outcome

Meta-analysis Clinical focus Other T

Law II 1994j CHD incidence weighted by

degree of cholesterol-lowering

by trial duration

Compared trial and treatment

types for CHD incidence by

trial duration differences

2

Gordon 1995 CHD incidence and CHD,

non-CHD, and total fatality

Compared results by trial type,

treatment type, and degree to

which cholesterol was lowered

2

Gould 1995 CHD, non-CHD, and total

fatality by trial type weighted

by degree of

cholesterol-lowering

Separated effects of lowering

cholesterol from effects of

treatment type

3

Rossouw 1995 CHD incidence, nonfatal heart

attacks, and CHD, non-CHD,

and total fatality

Summarized results for CHD

incidence, lesion progression,

and regression in

angiographic trials

5

9

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Appendix I 

Objectives, Scope, and Methodology

Total number Treatment

Trial unitsb Participantsc Gender Included Expressly excludedd

28 46,254 Menk Diet, drug, surgeryf Hormones

22 31,098 Men, women Diet, drug, hormones,

surgeryf

Multifactor trials

35 71,313 Men, women Diet, drug, hormones,

multifactor trials, surgeryf

i

5 primary, 14 secondary,

9 angiography

21,639 primary, 11,636

secondary, 1,435

angiography

Men, women Diet, drug, surgeryf Hormones, multifactor trials

aAll 15 meta-analyses summarized the published reports of varying numbers of the 42 clinical

trials we reviewed. Muldoon (1990) and CTF included only primary prevention trials; all the other

meta-analysts analyzed primary and secondary prevention trials. Complete facts of publication

are given in the bibliography. Trial types are indicated in table I.2.

bSome meta-analysts count the individual treatment arms of a single trial rather than analyzing the

whole trial as a unit. Therefore, the number of trial units does not always match the totals in table

I.2.

cIncludes both treatment and nontreatment groups. Totals differ for different analyses.

dExcludes other trial types also.

eRavnskow (1992) and Holme (1993) specifically exclude angiographic trials—that is, trials in

which measuring coronary arteries allows an assessment of the progression or regression rate of

atherosclerosis. Angiographic trials used various cholesterol-lowering treatments and recorded

clinical outcomes that could be included in a meta-analysis.

f

Partial ileal bypass surgery.

gMuldoon (1993) excluded 7 randomized secondary prevention trials that failed to report

nonillness-related fatalities (trauma and suicide) in addition to CHD fatalities.

hIncluded unpublished data.

i

Not reported.

j

Law I and Law II included the same set of 28 randomized trials, supplemented by unpublished

data.

k

A small minority of women were included when gender-specific data were unavailable.

Page 33 GAO/PEMD-96-7 Cholesterol Treatment
Appendix I 

Objectives, Scope, and Methodology

We did not develop formal criteria for evaluating the quality of the

meta-analyses we selected.4

 The investigators used accepted approaches

for quantitatively combining results, and most of the meta-analyses

appeared in peer-reviewed journals. Only one meta-analysis reported

having assessed the variability in the methodological soundness of the

clinical trials that it aggregated. However, each meta-analysis included

mainly randomized trials. We gave all the meta-analyses equal weight.

Our Comparisons of the

Meta-Analyses

The meta-analyses we examined included as few as 6 clinical trials up to

as many as 35 trials, for quantitatively aggregated information on a range

of about 1,500 to more than 125,000 participants. Their strategies differed

by whether they analyzed data only on men; by whether they considered

treatment duration, the effects of specific drug interventions, and the

degree of cholesterol-lowering; and on how they analyzed trials that

included more than one treatment.5

 The studies also differed by how they

classified mixed-risk interventions—trials that included participants both

with and without manifest CHD. The more recent meta-analyses differed

from the earlier ones in being able to include more-recent trials and

additional follow-up data.

We compared the 15 meta-analyses for the descriptive characteristics

displayed in table I.1. The meta-analysts’ decision rules differed. For

example, 9 included a trial that used a surgical intervention. Six included

trials in which elevated cholesterol, treated with diet, was only one of

several risk factors treated; these are multifactor trials. All but 4

meta-analyses excluded trials with only hormone interventions (because

they represented cholesterol-lowering interventions that are no longer

recommended as a treatment option for men). Nine of the 15 meta-analysts

included trials that had an angiographic component.6

 Some meta-analysts

used trial data that had been reported in published articles; others

4

One difficulty in doing this relates to publication practice. For example, the description of a

meta-analyst’s search strategy is one important criterion on which to base a quality assessment.

However, only 5 meta-analysts discussed their literature search strategy. This failure could mean that

no systematic search had been undertaken, or it could mean that the search strategy was not reported

because of the journal’s space limitations.

5

This is a particular problem for the large Coronary Drug Project study, which receives considerable

weight in a meta-analysis. The trial as designed had five treatments (clofibrate, niacin, estrogen 5.0 mg,

estrogen 2.5 mg, and dextrothyroxine). The last three were discontinued early in the trial when

adverse effects were observed. Therefore, an investigator who includes all five treatments may bias

results in a negative direction. Some analysts pool the data from the clofibrate and niacin treatments,

which can bias results in a positive direction.

6

In angiography, measurement of the coronary arteries allows investigators to assess the effect of

cholesterol-lowering on the rate of progression or regression of atherosclerosis.

Page 34 GAO/PEMD-96-7 Cholesterol Treatment
Appendix I 

Objectives, Scope, and Methodology

obtained additional data directly from the authors of the individual trials.

In all, the 15 meta-analyses included varying numbers of the 42 individual

trials we reviewed.

Table I.2 shows that none of the meta-analyses examined all 42 of the

individual trials. Seven contained less than half. Still, 9 meta-analysts

included 18 of the same trials; this overlap means that the results of the

meta-analyses are not statistically independent of one another.

Page 35 GAO/PEMD-96-7 Cholesterol Treatment
Appendix I 

Objectives, Scope, and Methodology

Table I.2: Fifteen Meta-Analyses and

the Cholesterol-Lowering Trials They

Studieda

Trial by

prevention type Treatment

Yusuf

1987

Muldoon

1990

Rossouw

1991

Silberberg

1991

Primary

LA VA 

(1969, 1971)

Diet • • •b

Oslo DA (1981)c Diet, other

MRFIT (1982)c Diet, other

WHO F (1983,

1986)d

Diet, other

Gothenburg 

(1986)c

Diet, other

Minnesota (1975,

1989)e

Diet • •

Retinopathy (1969)f Clofibrate

Begg (1971) Clofibrate

Upjohn (1978) Colestipol • • •g

Finnish (1985)c Diet, clofibrate,

probucol, other

Helsinki (1987,

1988)

Gemfibrozil • • •

WHO 

(1978, 1980, 1984,

1992)

Clofibrate • • • •

LRC CPPT (1984a,

1984b, 1992)

Cholestyramine • • • •

Excel (1990, 1991,

1992)

Lovastatin

Secondary

Corn Oil (1965) Diet •j

MRC Low Fat

(1965)

Diet • •

Oslo DH

(1966, 1970)

Diet • •

MRC Soya (1968,

1974)

Diet •k •

Sydney (1978) Diet •

DART (1989) Diet

India (1992) Diet

Estrogen (1961) Estrogen

Long-Term

Estrogen (1962)

Estrogen

Chicago (1963) Estrogen

Page 36 GAO/PEMD-96-7 Cholesterol Treatment
Appendix I 

Objectives, Scope, and Methodology

Ravnskov

1992

CTF

1993

Cucherat

1993

Holme

1993

Muldoon

1993

Smith

1993

Law I

1994

Law II

1994

Gordon

1995

Gould

1995

Rossouw

1995

• • • •b • •b • • • •

• • •

• • •

• •

• •

• • • • • • • •

•

• •

• • • •g • •g •g •g • •

• • •

• • • • • • • • • • •

• • • • •h •h •h •h •h •h •h

• • • • • • • • • • •

•i •i •i •i

• • • • • • • •j

• • • • • • • • •

• • • • • • • • •

• • • • • • • •

• • • • • • • •

• • • • •

•

• • • •

•l •

• •

(continued)

Page 37 GAO/PEMD-96-7 Cholesterol Treatment
Appendix I 

Objectives, Scope, and Methodology

Trial by

prevention type Treatment

Yusuf

1987

Muldoon

1990

Rossouw

1991

Silberberg

1991

Newcastle

(1971)

Clofibrate • • •

Scottish (1971,

1972)

Clofibrate • • •

Acheson (1972) Clofibrate •

St. Vincents (1973) Colestipol

Veterans

Cardiology (1968,

1974)

D-thyroxine;

D-thyroxine +

estrogen;

estrogen; estrogen

+ nicotinic acid;

nicotinic acid

•m •m

Veterans W.

Roxbury (1981)

Probucol

NHLBI (1984) Cholestyramine,

dieto

• p

CDP (1970, 1972,

1973, 1975, 1986)

Clofibrate,

D-thyroxine,

estrogen 2.5 mg,

estrogen 5.0 mg,

niacin

•q •q •q

CLAS (1987) Colestipol, niacino p

Stockholm (1977,

1980, 1988)

Clofibrate,

nicotinic acid

• • •

FATS (1990) Lovastatin +

colestipol; niacin +

colestipolo

p

Lifestyle (1990)c Diet, othero

POSCH (1990) Partial ileal bypass

surgery

SCOR (1990)t Colestipol,

lovastatin, niacino

Restenosis (1991,

1992)

Lovastatino

STARS (1992) Diet, diet +

cholestyramineo

Ancillary Helsinki

(1993)

Gemfibrozil

MARS (1993) Lovastatino

Trials (total = 42)v 17 6 11 9

% of total trials 40 14 26 21

Page 38 GAO/PEMD-96-7 Cholesterol Treatment
Appendix I 

Objectives, Scope, and Methodology

Ravnskov

1992

CTF

1993

Cucherat

1993

Holme

1993

Muldoon

1993

Smith

1993

Law I

1994

Law II

1994

Gordon

1995

Gould

1995

Rossouw

1995

• • • • • • • • •

• • • • • • • • •

• • •

• • •

•m •m •m •m •m •m

•n •n •n

• • • • • • •

•q •q •q •q •q •q •q •q •q •q

• • • • •

• • • • • • • • •

• • • •r •

•s

• • • • • • • • •

• •

• • • •

• • • •u •u •

• • • • • •

•

22 6 18 22 8 35 28 28 18 29 23

52 14 43 52 19 83 67 67 43 69 55

aComplete facts of publication for the 15 meta-analyses and the reports of the 42 individual trials

in this table are given in the bibliography.

Page 39 GAO/PEMD-96-7 Cholesterol Treatment
Appendix I 

Objectives, Scope, and Methodology

bThis trial had primary and secondary prevention components. All meta-analysts treated it as a

primary prevention trial except Holme, who classified it as secondary. Roussouw (1991) did not

classify diet trials by prevention type; Smith did not conduct analysis by trial type.

cA multifactor trial, targeting multiple risk factors simultaneously with more than one intervention.

dA multifactor trial that randomized 66 factories (comprising 49,781 men) rather than individuals.

eThis trial had primary and secondary prevention components; primary predominated.

f

Participants were being treated for diabetic retinopathy. About 40 percent were diagnosed as

having peripheral or coronary vascular disease.

gAll meta-analysts treated this as a primary prevention trial except Silberberg, who separated its

primary and secondary components; Holme, who treated the trial as secondary; and Law I and

Law II, who classified it as a “mixed” trial. Smith did not analyze it by trial type.

hIncluded the results of the WHO 1992 intention-to-treat analysis.

i

This trial had primary and secondary prevention components. Cucherat treated it as primary,

Smith did not analyze it by trial type, and Law I and Law II classified it as a “mixed” trial.

j

Yusuf and Rossouw (1995) included both corn oil and olive oil components.

k

Treated as a drug trial.

l

Combined three estrogen treatments: anvene, lynoral, and premarin.

mSilberberg and Rossouw (1995) included the nicotinic acid trial arm only; Yusuf, Law I, and Law

II included the nicotinic acid arm and the arm containing estrogen and nicotinic acid; Gordon and

Gould included all trial arms except estrogen only; Smith included all five treatment arms.

nThis trial had primary and secondary prevention components. Smith did not conduct the analysis

by treatment type. Law I and Law II classified it as a “mixed” trial.

oA trial in which measuring coronary arteries allows an assessment of the progression or

regression rate of atherosclerosis. Angiographic trials used various cholesterol-lowering

treatments and recorded clinical outcomes that could be included in a meta-analysis.

pDiscussed the three angiographic trial results descriptively; they are not in the trials total.

qEstrogen 2.5 mg and 5.0 mg and dextrothyroxine were discontinued because of toxic side

effects. Yusuf, Roussouw (1991 and 1995), Silberberg, and Cucherat treated the clofibrate and

niacin arms as two separate trials; Holme, Muldoon (1993), and Law I and Law II combined them

as one. Gordon and Gould treated the clofibrate, D-thyroxine, and niacin arms separately.

Ravnskov treated the five arms as separate trials; Smith combined them.

r

Separated results for colestipol and lovastatin from results for colestipol and niacin.

s

Smith later corrected his original analysis to say that he should not have included this multifactor

trial with the other, single-intervention trials; the one death recorded for it did not affect his results.

t

Participants had heterozygous familial hypercholesterolemia. About half of the nontreatment

group received a low dose of colestipol.

uGordon treated diet and drug components separately. Gould analyzed cholestyramine and diet

together but also analyzed diet separately.

v

Totals are only for the number of trials included in each meta-analysis, not the number of

treatment arms totaled in table I.1.

Page 40 GAO/PEMD-96-7 Cholesterol Treatment
Appendix I 

Objectives, Scope, and Methodology

Eleven of the 15 meta-analysts combined data across all trial types and

interventions to investigate one or more of the health outcomes we

focused on. This allowed them to see whether the effect of lowering

cholesterol could be discerned for a common risk factor among trials

whose designs varied greatly. However, clinical and statistical

heterogeneity can make it difficult to interpret findings if aggregating some

trials with others disproportionately affects the results. NCEP

acknowledges that broad aggregation can yield such heterogeneity and

that it is potentially misleading.

Eight of these 11 meta-analysts conducted separate analyses by trial

type—primary and secondary prevention trials—which enabled them to

create less heterogeneous trial groupings.7

 The results of 4 meta-analyses

were reported only at lower levels of aggregation, such as those that

considered results mainly for primary prevention trials. Some

meta-analysts also analyzed the aggregated trials to isolate the effect of

dietary treatment from that of drugs. Technically, these subgroup analyses

are also meta-analyses. Almost all the 15 meta-analysts thus conducted

multiple meta-analyses, and we report some of the main results in the

tables in appendix II.

How We Report

Cholesterol-Lowering

Effects

The meta-analyses we studied statistically combined individual trial results

to improve the precision of the estimates of the extent to which their

cholesterol-lowering treatments reduced CHD risk with regard to CHD

incidence, nonfatal heart attacks, and CHD, non-CHD, and total fatalities.

Most of the meta-analyses expressed their results in terms of a common

odds ratio and confidence interval.

For an individual trial, the odds ratio is the ratio of two ratios. It is defined

as the odds of events—such as death from coronary heart disease—to

nonevents in the treatment group divided by the odds of events to

nonevents in the nontreatment group. An odds ratio lower than 1 (such as

0.90) indicates that the rate of CHD events within the treatment group fell

compared to the nontreatment group. An odds ratio higher than 1 (such as

1.12) indicates that the rate of CHD events within the treatment group rose

7

The distinction between primary and secondary trial participants is regarded as somewhat artificial

from clinical and methodological standpoints. From a clinical standpoint, participants in primary

prevention trials may have had underlying coronary atherosclerosis as evidenced by those who

developed clinical symptoms during the trial. From a methodological standpoint, investigators have

used different criteria for classifying primary and secondary prevention trials so that such

classifications do not directly reflect a stratification of the risk of death from CHD.

Page 41 GAO/PEMD-96-7 Cholesterol Treatment
Appendix I 

Objectives, Scope, and Methodology

compared to the nontreatment group. For aggregated trials in a

meta-analysis, a common odds ratio is similarly interpreted.

The imprecision that results from combining individual odds ratios is

expressed by a confidence interval. In the meta-analyses that reported a

common odds ratio, the confidence interval was set at 95 percent, meaning

that if a meta-analysis were replicated 100 times and the confidence

interval were calculated for each odds ratio, 95 of these 100 confidence

intervals would contain the true odds ratio, even if it were not precisely

known.

With one exception, we did not attempt to re-analyze the common odds

ratios of meta-analyses that reported them.8

 However, to present our

findings consistently, we converted the results of meta-analyses that used

a different measure to common odds ratios or obtained confidence

intervals.9

 We forwarded all our changes to the studies’ authors for their

review, and we point them out in our tables in appendix II.

Not all meta-analysts reported on all five health outcomes or on pertinent

groupings of them, such as primary or secondary prevention trials or

specific treatments. Therefore, the tables do not show 15 meta-analysis

entries for each outcome. Our tables show the direction of effects and

indicate the findings’ statistical significance (that is, whether the findings

showed that differences between the treatment and nontreatment groups

were not likely to have occurred by chance alone).

In summarizing the meta-analyses’ reports of treatment effects, we used

the following general rule. If the 95-percent confidence interval for a

common odds ratio included 1 (the point of equivalent odds), then there

was no statistically significant difference (at the 0.05 level) between the

treatment and nontreatment groups on the outcome of interest. In

summarizing the statistical significance of their findings, we recognize that

a statistically significant effect is not necessarily a clinically meaningful

8

We recalculated the odds ratios in Muldoon’s 1993 meta-analysis in order to include his published,

updated data.

9

We used the Mantel-Haenszel method and the STAT XACT program produced by Cytel Software of

Cambridge, Massachusetts. This program uses the Breslow-Day method of testing for homogeneity of

odds ratios. We also calculated the confidence intervals surrounding the odds ratios with the STAT

XACT program, basing our calculations on the variance estimation method of Robins, Breslow, and

Greenland. See N. Mantel and W. Haenszel, “Statistical Aspects of the Analysis of Data from

Retrospective Studies of Disease,” Journal of the National Cancer Institute, 22 (1959), 719-48; N. E.

Breslow and N. E. Day, The Analysis of Case-control Studies (Lyon, France: IARC Scientific

Publications, 1980); and J. Robins, N. Breslow, and S. Greenland, “Estimators of the Mantel-Haenszel

Variance Consistent in Both Sparse Data and Large-strata Limiting Models,” Biometrics, 42 (1986),

311-23.

Page 42 GAO/PEMD-96-7 Cholesterol Treatment
Appendix I 

Objectives, Scope, and Methodology

one. Where the meta-analysts’ results were discrepant, we provide

potential explanations for the discrepancies.

Not all the detail that the meta-analysts reported is summarized in the

tables in appendix II. Several meta-analysts provided information on how

their results were influenced by degree of cholesterol reduction, duration

of trials, individual risk status, and interventions in which adverse effects

outweighed the benefits of treatment. Since analyses that considered these

factors are important in the interpretation of the effects of lowering

cholesterol, we discuss them in the body of appendix II.

The Strengths and

Limitations of Our

Study

Summarizing and integrating studies through meta-analysis is, like primary

research, a research process in its own right. Meta-analysis imposes

methodological standards and statistical principles that require the analyst

to adhere to explicit research and reporting rules. These in turn allow

other researchers to replicate the study. Further, meta-analysis helps

develop comprehensive knowledge beyond the limits of individual studies.

It is for these reasons that we chose to review and summarize

meta-analyses rather than perform a more traditional literature review.

Meta-analysis techniques capitalize on accumulating evidence by making

estimates more precise and reliable; they also permit the testing of

hypotheses that may not have been addressed in the individual trials.

Moreover, these techniques enable meta-analysts to evaluate the

circumstances of the effects, such as how different treatment modalities

or the characteristics of different population groups are related to an

effect. They also allow meta-analysts to explore what may underlie an

effect, such as the particular degree to which cholesterol has been

lowered.

Because meta-analysis can increase statistical power and the precision of

estimates of effects, it facilitates the examination of noncoronary

fatalities, even where recorded deaths from specific causes were few in

number. Moreover, meta-analysis allows investigators to examine whether

lowering cholesterol affects the life span. Most individual trials were not

designed to test the effect on total deaths of lowering cholesterol: either

they had too few participants, rendering them low in statistical power, or

they were too short in duration to examine this outcome.

The meta-analysis results we present were intended to yield a coherent,

general conclusion about the benefits and risks associated with

Page 43 GAO/PEMD-96-7 Cholesterol Treatment
Appendix I 

Objectives, Scope, and Methodology

cholesterol-lowering treatments. However, the trials’ considerable clinical

heterogeneity in terms of participants and treatments can result in

statistical heterogeneity such that the meaningfulness of any overall

estimate can be called into question. This problem is not always detected

in formal testing. Although only a few of the meta-analyses specifically

addressed this issue, their various subgroup analyses did derive from its

recognition as they attempted to provide more homogeneous groups of

participants and treatments.

Therefore, it is important to note that the overall significance tests we

present in our tables do not imply that a treatment effect existed in all

primary or secondary trial circumstances. The common odds ratios that

are a guide to overall treatment benefit do not accurately estimate the

treatment benefit or risk achieved in any particular trial. The confidence

interval that expresses the statistical precision achieved for a common

odds ratio does not allow for any potential variation in the magnitude of

true effect between trials (or between treatments or types of participants).

The results of the meta-analyses we report should not be extrapolated

beyond the circumstances from which they were derived.

Further, since the individual clinical trials did not report the effects of

lowering cholesterol on the incidence of nonfatal diseases other than CHD,

the meta-analysts could not evaluate these effects. Finally, the results of

the different meta-analyses are not statistically independent when they

include the same trials. Many of the larger single-intervention trials that

the analysts included weigh heavily in the results. This means that some

convergence of findings can be expected despite the diversity of the

meta-analyses.

The meta-analyses considered only total serum cholesterol levels, because

LDL and HDL were not always recorded in the individual trials. It is

noteworthy that the NCEP guidelines call for treatment decisions that base

distinctions on LDL and HDL levels. Therefore, the results may be less

applicable to population groups in which the configuration of total

cholesterol subfractions differs from those found in the trials. The

guidelines also call for basing cholesterol-lowering treatment on

distinctions of age and gender, but the major participants in the clinical

trials were mainly middle-aged white men with elevated cholesterol levels.

Only a few of the clinical trials combined in the meta-analyses that we

reviewed used recent, more efficacious treatments such as the statin

drugs. Some of the interventions for men in large trials that weigh heavily

Page 44 GAO/PEMD-96-7 Cholesterol Treatment
Appendix I 

Objectives, Scope, and Methodology

in the results have been discontinued or had cholesterol-lowering

treatment regimens that have declined in use. Nonetheless, it is important

to examine the results of the meta-analyses that aggregated these data

because the cholesterol-lowering trial results are integral to the evidence

on which the NCEP treatment guidelines were based.

Page 45 GAO/PEMD-96-7 Cholesterol Treatment
Appendix II 

The Meta-Analyses of Cholesterol-Lowering

Trials and the Health Outcomes They Report

In this appendix, we summarize our major findings from the 15

meta-analyses for the five health outcomes we focused on: CHD incidence

(fatal and nonfatal heart attacks combined), nonfatal heart attacks, CHD

fatalities, non-CHD fatalities, and total fatalities. The results apply mainly to

middle-aged white men who had elevated serum cholesterol levels,

because they have had the greatest representation in the

cholesterol-lowering clinical trials over the past 30 years. Meta-analysts

continue to actively analyze these data. We discuss in appendix III the

issue of extrapolating data to other population groups.

A Summary of Our

Major Findings

The trials included in the meta-analyses we reviewed lowered serum

cholesterol 10 percent on the average (the range in the individual trials

was from less than 1 percent to more than 20 percent). Several

meta-analysts identified the extent to which cholesterol was lowered as a

mediating factor in the efficacy of cholesterol-lowering interventions.

Deaths from causes other than CHD were not related to a reduction in

cholesterol level. In fact, these fatalities were fewer when cholesterol

reduction was greater. This suggests that excess non-CHD risk results not

from lowering cholesterol itself but from particular types of

cholesterol-lowering treatment.

With some differences in the magnitude of benefits, the meta-analysis

results concur that participants with and without manifest heart disease

benefit from cholesterol-lowering interventions. Statistically significant

reductions in the rates of CHD incidence and nonfatal heart attacks favor

treatment groups.

Statistically significant reductions in CHD fatality rates were found mainly

for high-risk participants in treatment groups and for treated participants

in secondary prevention trials. For lower-risk participants who had

elevated cholesterol levels and for participants in primary prevention

trials, evidence was absent that cholesterol-lowering interventions

reduced CHD fatality rates more in treatment than in nontreatment groups.

Lower-risk participants who had elevated cholesterol levels and treatment

groups in the primary prevention trials showed statistically significant

increases in non-CHD fatalities. In secondary prevention trials, lowered

rates of CHD death appear to offset the increased rates of non-CHD death. As

a result, the overall death rates for treatment groups were mainly

favorable but differences from nontreatment groups were not statistically

significant.

Page 46 GAO/PEMD-96-7 Cholesterol Treatment
Appendix II 

The Meta-Analyses of Cholesterol-Lowering

Trials and the Health Outcomes They Report

For drug trials, the meta-analyses show statistically significant reductions

in rates of CHD incidence and nonfatal heart attacks favoring treated

participants. However, increases in rates of death from non-CHD causes

among treatment groups compared to nontreatment groups were also

statistically significant. There were no statistical differences between drug

treatment and nontreatment groups in CHD fatalities or total fatalities. CHD

death rates favored treatment groups, whereas overall fatality rates were

close to 1 (the point of equivalent odds between treatment and

nontreatment groups). Two recent meta-analyses identified two broad

classes of cholesterol-lowering interventions—fibrates and hormone

treatment in men—as accounting for statistically significant increases in

non-CHD fatality rates. The beneficial effects of treatment outweighed the

adverse effects of resins and niacin.

Generally, overall survival rates did not improve for cholesterol-lowering

treatment groups compared to nontreatment groups. Survival rates were

shown to improve when analyses specifically considered the participants

who were at the highest risk or accounted for the extent of cholesterol

reduction. Greater reductions in serum cholesterol were associated with a

reduction in deaths from all causes.

The diet trials included in the meta-analyses used dietary interventions

that are not currently recommended. The meta-analyses mainly show no

distinctions between dietary treatment groups and nontreatment groups

with regard to the five health outcomes.

Three Recent

Research Trends

Three recent trends in cholesterol-lowering research are notable before

we present the details of our findings in the text and tables in this

appendix. The first trend is that angiographic trials have been included in

meta-analyses of cholesterol-lowering trials more frequently since 1993

than before. Angiographic trials are secondary prevention trials because

their participants are at very high risk or had existing symptoms of heart

disease. Although the trials’ principal end point is the arteriographic

measurement of coronary arteries, their clinical outcomes in

cholesterol-lowering trials are available for meta-analysis. Collectively,

they have shown that intensive cholesterol-lowering slows the progression

of atherosclerotic lesions; in some patients, it even causes the lesions to

regress. Interventions as diverse as dietary therapy, drugs, and partial ileal

bypass surgery yield similar results.

Page 47 GAO/PEMD-96-7 Cholesterol Treatment
Appendix II 

The Meta-Analyses of Cholesterol-Lowering

Trials and the Health Outcomes They Report

The second trend relates to ongoing trials of the statin drugs, a relatively

new drug class that appears to lower LDL cholesterol levels 20 to

40 percent, although their long-term safety is still being evaluated. Two

recently completed statin trials found clinical benefits favoring treatment

groups and no differences in adverse effects between treatment and

nontreatment groups. In 4S, the total cholesterol of cardiac patients fell

25 percent. Among other clinical benefits, the study demonstrated

statistically significant reductions in the frequency of nonfatal heart

attacks, fatal heart attacks, and total fatalities favoring participants treated

with simvastatin within its 5-year span.1

 The study’s authors cautioned

against extrapolating their results to other secondary prevention trials

using other statin agents, and they also advised caution in the

extrapolation of their results to primary prevention trials.

WOSCOPS, a study of men who had never had a heart attack, lowered total

cholesterol levels by 20 percent with the drug pravastatin. The results,

which favored the treatment group, showed statistically significant

reductions in fatal and nonfatal heart attacks combined, all cardiovascular

deaths, and death from definite and suspected CHD (but not definite CHD

deaths considered independently). The results almost reached statistical

significance for reductions in the rates of death from all causes.

The 4S and WOSCOPS trials were too recent to be included in the

meta-analyses we reviewed. However, their results—which showed no

statistical difference in deaths from noncardiovascular causes between the

treatment and nontreatment groups—tend to support meta-analysis

reports of earlier trials in which increases in non-CHD fatality rates were

associated not with lowering cholesterol but with particular

cholesterol-lowering treatments.

The third research trend is that investigators are more frequently trying to

analyze specific interventions, independently of how well they lower

cholesterol, in order to determine their specific effects on clinical

outcomes. Treatments with hormones and fibrates have shown

statistically significant increases in non-CHD fatalities and total fatalities.

Hormone treatments at doses used in several individual trials examined by

meta-analysts are not currently recommended for men. The fibric acid

derivatives clofibrate and gemfibrozil are effective primarily in lowering

triglycerides, but the use of clofibrate declined after the World Health

1

Other beneficial results included statistically significant reductions in major coronary events for

women and for patients younger and older than 60. Fewer coronary bypass surgery and angioplasty

procedures were conducted for patients taking simvastatin; the differences between treatment and

nontreatment groups were statistically significant.

Page 48 GAO/PEMD-96-7 Cholesterol Treatment
Appendix II 

The Meta-Analyses of Cholesterol-Lowering

Trials and the Health Outcomes They Report

Organization trial results were published.2 Gemfibrozil is currently

recommended only for the treatment of primary prevention patients who

have a combination of high triglycerides, elevated LDL, and low HDL.

Primary and

Secondary Prevention

Trial Results

Compared

As we discussed in appendix I, the individual trials represent considerable

clinical heterogeneity in treatments and patients. The meta-analyses show

the overall average effect of lowering cholesterol across these trials and

introduce both clinical and statistical heterogeneity that can make results

difficult to interpret and less reliable. For greater homogeneity,

investigators classify trials broadly by prevention type (primary or

secondary) or by treatment type (diet or drugs) or both. We summarized

the meta-analysts’ findings for diet and drug treatment trials earlier in this

appendix. As for prevention, the relative risk of death for participants who

already show evidence of CHD (secondary prevention trials) is about five to

seven times greater than that for participants who do not (primary

prevention trials). We summarize these results below.

CHD Incidence and

Nonfatal Heart Attacks

Table II.1 shows the results of the meta-analysts who examined CHD

incidence and nonfatal CHD. It separates the results of the meta-analysts

who combined the primary prevention trials from the results of those who

combined the secondary prevention trials. The predominant finding is

statistically significant reductions in the rates of CHD incidence and

nonfatal heart attacks for participants in cholesterol-lowering treatment

groups compared to nontreatment groups.3

 Across primary prevention

trials, the common odds ratios range from 0.85 to 0.77 for CHD incidence

and from 0.83 to 0.74 for nonfatal CHD.

4

 Similar benefits are reported

across secondary prevention trials. The odds ratios range from 0.86 to 0.76

for CHD incidence and from 0.96 to 0.76 for nonfatal CHD.

5

2

The Food and Drug Administration approves clofibrate for patients who have very high triglycerides

and who are at risk for pancreatitis and for patients with familial dysbetalipoproteinemia.

3

Nonfatal heart attacks predominate in the CHD incidence category, which represents the combination

of fatal and nonfatal heart attacks.

4

This range does not include the separate estimate for diet trials indicated for Holme (1993) in table

II.1. In this meta-analysis, dietary treatment lowered cholesterol 3.2 percent, but the dietary trials were

mainly multifactor trials, which taken as a group lowered total cholesterol only 0.7 percent.

5

The difference between treatment and nontreatment groups in Ravnskov (1992) lacked statistical

significance. Among meta-analysts examining nonfatal CHD, only Ravnskov included hormone trials,

but the analysis has been strongly criticized.

Page 49 GAO/PEMD-96-7 Cholesterol Treatment
Appendix II 

The Meta-Analyses of Cholesterol-Lowering

Trials and the Health Outcomes They Report

Table II.1: Meta-Analysis Results for CHD Incidence and Nonfatal CHDa

CHD incidence Nonfatal CHD CHD incidence Nonfatal CHD

Primary prevention Secondary prevention

Meta-analysis Odds ratio Interval Odds ratio Interval Odds ratio Interval Odds ratio Interval

Yusuf 1987b 0.85 0.76-0.96 0.81 0.74-0.88

Silberberg 1991 0.77 0.67-0.89 0.75 0.64-0.87 0.79 0.71-0.88 0.78 0.67-0.90

Ravnskov 1992 0.83 0.75-0.92 0.96 0.89-1.04

CTF 1993 0.74 0.64-0.85

Cucherat 1993 0.82 0.74-0.92 0.74 0.65-0.86 0.76 0.70-0.83 0.76 0.68-0.86

Holme 1993 0.78c 0.68-0.89c 0.80c 0.71-0.89c

Gordon 1995d 0.77 0.67-0.87 0.86 0.79-0.93

Rossouw 1995e 0.80 0.71-0.89 0.75 0.65-0.86 0.83 0.76-0.90 0.77 0.68-0.87

aComplete facts of publication are given in the bibliography. CHD incidence is fatal and nonfatal

heart attacks combined. Intervals are 95-percent confidence intervals for the common odds

ratios. The meta-analyses did not report data for the empty cells.

bFor consistency, we recalculated the results from risk ratios and combined diet and drug trials

for primary and secondary prevention trials. Using the Breslow-Day (B-D) method, we tested for

homogeneity of the odds ratios. The B-D statistic was 8.40 (p = .08) for primary prevention trials

and 36.55 (p = .05) for secondary prevention trials.

cThese data are for drug trials. Separately reported results for diet trials were primary prevention

CHD incidence 1.02, 0.94-1.10; secondary prevention CHD incidence 0.78, 0.63-0.96.

dFor consistency, we recalculated the results from percentage change in risk for primary and

secondary prevention trials. We recalculated results for primary and secondary trials combined in

order to obtain confidence intervals. Using the Breslow-Day (B-D) method, we tested for

homogeneity of the odds ratios. The B-D statistic was 1.30 (p = .73) for primary prevention trials

and 33.6 (p = .05) for secondary prevention trials.

eRoussouw’s separate analysis for secondary prevention angiography trials showed a statistically

significant reduction in CHD events for the treatment groups. The 0.55 odds ratio had a wide

95-percent confidence interval of 0.30-0.99.

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The Meta-Analyses of Cholesterol-Lowering

Trials and the Health Outcomes They Report

CHD Fatalities Table II.2 shows that in the primary prevention trials, CHD fatality rates fell

with treatment, but because all the confidence intervals exceed 1, the

possibility cannot be ruled out that the CHD death rate increases in

treatment groups compared to nontreatment groups. Gould

(1995) suggests that differences between treatment and nontreatment

groups may not be apparent because of the greater variability of the

estimate when primary prevention trials are aggregated, the small number

of univariate primary prevention trials, and the narrow range of

cholesterol reductions in these trials, all of which decrease the precision

necessary to find statistical significance.

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The Meta-Analyses of Cholesterol-Lowering

Trials and the Health Outcomes They Report

Table II.2: Meta-Analysis Results for CHD, Non-CHD, and Total Fatalitya

CHD Non-CHD Total

Primary prevention

Meta-analysis Odds ratio Interval Odds ratio Interval Odds ratio Interval

Yusuf 1987b 0.93 0.76-1.14 1.19 1.04-1.37

Muldoon 1990 1.07 0.94-1.21

Silberberg 1991 0.85 0.64-1.14 1.14 0.96-1.36

Ravnskov 1992 0.92 0.83-1.02 1.02 0.95-1.08

CTF 1993 0.90 0.71-1.14 1.19 1.03-1.39 1.07 0.94-1.22

Cucherat 1993 0.90 0.75-1.09 1.07 0.96-1.19

Holme 1993 1.20c 1-1.45c

Muldoon 1993d 0.93 0.77-1.12

Law I 1994e 1.11 0.99-1.24 1.06 0.97-1.17

Gordon 1995f 0.93 0.75-1.14 1.26 1.06-1.49 1.13 0.98-1.29

Gould 1995 0.88 0.72-1.07 1.21 1.02-1.43 1.09 0.95-1.24

Rossouw 1995 0.91 0.75-1.11 1.25 1.06-1.47 1.08 0.95-1.24

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Trials and the Health Outcomes They Report

CHD Non-CHD Total

Secondary prevention

l Odds ratio Interval Odds ratio Interval Odds ratio Interval

0.89 0.80-0.98 1.14 0.97-1.36

6 0.84 0.75-0.95 0.90 0.80-1

8 0.96 0.88-1.04 1.02 0.95-1.10

2

9 0.87 0.78-0.96 0.93 0.85-1.03

c 0.93c 0.83-1.04c

7 0.99 0.83-1.18 0.90 0.84-0.97

9 0.90g 0.82-0.99g 1.22 1.02-1.46 0.97 0.89-1.05

4 0.94 0.86-1.02 1.17 0.98-1.40 0.99 0.91-1.07

4 0.89 0.81-0.99 1.07 0.87-1.34 0.94 0.85-1.04

aComplete facts of publication are given in the bibliography. Intervals are 95-percent confidence

intervals for the common odds ratios. The meta-analyses did not report data for the empty cells.

bFor consistency, we recalculated the results from risk ratios and combined diet and drug

treatments for primary and secondary prevention trials. Using the Breslow-Day (B-D) method, we

tested for homogeneity of the odds ratios. The B-D statistic for primary prevention trials was 4.34

(p = .30) for CHD fatality and 6.35 (p = .17) for non-CHD fatality; for secondary prevention trials, it

was 19.42 (p = .11) for CHD fatality and 4.68 (p = .46) for non-CHD fatality.

cThese data are for drug trials. Separately reported results for diet trials were primary prevention

total fatality 1.07, 1-1.5; secondary prevention total fatality 0.98, 0.81-1.19.

dThese data are the result of our recalculating Muldoon’s data after we included the WHO 1992

intention-to-treat analysis furnished by Muldoon. Using the Breslow-Day (B-D) method, we tested

for homogeneity of the odds ratios. The B-D statistic was 9.30 (p = .10). Muldoon’s results

excluding this analysis were 0.85, 0.69-1.05.

eOdds ratios are relative odds per 0.6 mmol/l (10 percent) cholesterol reduction.

f

For consistency, we recalculated the results from percentage change in risk for primary and

secondary prevention trials and recalculated the odds ratios given for primary and secondary

trials combined in order to obtain confidence intervals. Using the Breslow-Day (B-D) method, we

tested for homogeneity of the odds ratios. The B-D statistic for primary prevention trials was 4.46

(p = .22) for CHD fatality, 2.04 (p = .56) for non-CHD fatality, and 4.50 (p = .21) for total fatality.

For secondary prevention trials, it was 29.68 (p = .05) for total fatality; we used Gordon’s

calculations for CHD and non-CHD fatalities.

gGordon reported these data as statistically significant with a 0.996 upper bound of the

confidence interval. Tests for homogeneity of odds ratios were not reported.

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Looking at the ranges of the odds ratios shows that cholesterol-lowering

treatment has nearly the same effect size in primary prevention trials (0.93

to 0.85) as in secondary prevention trials (0.96 to 0.84). Reductions in CHD

death rates in the secondary prevention trials favored the treatment

groups; moreover, differences between treatment and nontreatment

groups were statistically significant, except in Ravnskov (1992) and Gould

(1995).6

Putting these results in context requires looking at patients’ risk levels. For

example, Smith and his colleagues demonstrated in 1993 that the

magnitude of net benefit depends on the level of CHD risk. They found

statistically significant reductions in CHD death rates only for treatment

groups with the highest risk. The common odds ratios for participants

treated for elevated cholesterol who were at lower risk showed that their

rate of CHD death increased.7

Although odds ratios are similar for primary and secondary trials in terms

of absolute risk, lowering cholesterol has the clearest benefit for

participants in secondary prevention trials who are at greater risk and who

have higher fatality rates. For example, an analysis directly comparing

drug interventions in primary and secondary prevention trials estimates

that one death from CHD could be prevented by treating 675 participants in

primary prevention trials but only 38 participants in secondary prevention

trials (Silberberg, 1991).8

In reporting an additional analysis that considered how much cholesterol

was reduced, Gould (1995) found that for every 10 percentage points of

cholesterol-lowering, CHD death rates fell 13 percent (p < .002).

6

Ravnskov (1992), Gordon (1995), and Gould (1995) were the only meta-analysts examining CHD

fatalities in secondary prevention trials who included hormone trials. Gordon and Gould included the

dextrothyroxine arm of the large Coronary Drug Project. Ravnskov included all three hormone

arms—estrogen 2.5 mg, estrogen 5.0 mg, and dextrothyroxine—but all three were discontinued early in

this trial because of their toxic side effects.

7

This analysis was stratified by the degree of risk of CHD death that is represented by the CHD

fatalities in the nontreatment groups. The odds ratios (and confidence intervals) were 0.74

(0.60-0.91) for participants at high risk of CHD fatality (more than 50 deaths per 1,000 person years);

0.92 (0.77-1.09) for participants at medium risk (10-50 deaths per 1,000 person years); 1.15

(0.80-1.64) for participants at lower risk (fewer than 10 deaths per 1,000 person years). See G. D.

Smith, F. Song, and T. A. Sheldon, “Cholesterol Lowering and Mortality: The Importance of

Considering Initial Level of Risk,” British Medical Journal, 306 (1993), 1367-73.

8

Silberberg’s meta-analysis did not include treatments with the recent statin drugs. These drugs’

greater ability to lower cholesterol may affect CHD fatality and, in turn, change these numbers. For

example, in 4S, which used simvastatin, the estimated number of those who had to be treated to

prevent one CHD death was 29.

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Trials and the Health Outcomes They Report

Non-CHD Fatalities The investigators who examined deaths from noncoronary causes as an

outcome in primary and secondary prevention trials also focused on the

potentially adverse effects of specific treatments used in lowering

cholesterol and the concern that lowering it may simply exchange one

cause of death for another. Table II.2 shows that decreases in CHD fatality

rates in primary prevention trials were not sufficient to offset non-CHD

fatality rates. As a result, total fatality rates were unfavorable for

treatment groups, but differences from nontreatment groups were not

statistically significant. The rates of death from non-CHD causes were

higher for participants who received cholesterol-lowering treatment; the

higher rate was statistically significant in all but one meta-analysis. The

common odds ratios range from 1.11 to 1.26.

Similarly, the non-CHD death rate was mostly higher for treatment groups

than for nontreatment groups in secondary prevention trials. The common

odds ratios range from 0.99 to 1.22. Except in Gordon (1995), the

differences between treatment and nontreatment groups were not

statistically significant. In the secondary prevention trials, unlike the

primary, reductions in rates of CHD fatalities do appear to have offset the

higher non-CHD fatalities but not to the extent of achieving a statistically

significant reduction in overall deaths.

Smith and his colleagues in 1993 reported a favorable but not statistically

significant reduction in non-CHD fatality rates for higher-risk treatment

groups but unfavorable non-CHD fatality rates for medium-risk and

lower-risk treatment groups. The odds ratios show that compared to

nontreatment groups, non-CHD fatality rates increased. For the lower-risk

participants, the increase was statistically significant.9

 Drug treatment

trials, but not nondrug trials, showed higher death rates from causes other

than CHD.

One problem in interpreting these data is that in some trials, deaths from

causes other than heart attack were not reported. The earlier

meta-analyses either attributed the increases in non-CHD death in

cholesterol-lowering intervention trials to chance or considered the

increases reasonable given that CHD deaths decreased and that death from

other causes could be expected. Because non-CHD deaths recorded in

individual trials were few in number, the greater statistical power of

meta-analysis could potentially find any real differences between

treatment and nontreatment groups in noncoronary fatality outcomes.

9

The odds ratios (and confidence intervals) were 0.95 (0.65-1.40) for participants at high risk, 1.07

(0.94-1.21) for participants at medium risk, and 1.33 (1.09-1.63) for participants at lower risk.

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However, large individual trials with adverse effects that pertain to

specific treatments can dominate the findings of a meta-analysis that

combines such trials with smaller ones.

The results from several sizable individual trials have alerted the medical

community to the risks associated with fibrates, dextrothyroxine, and high

estrogen dosage in men. The biological means through which these drugs

lower cholesterol plausibly account for the higher non-CHD death rates.10

Less readily explained are the higher, statistically significant rates of

fatality not related to illness (as from accident, violence, and suicide)

among participants in treatment groups compared to nontreatment

participants in primary prevention trials. Muldoon (1993) addressed these

findings.11 The increases in non-CHD death rates have led recent

investigators to examine whether lowering cholesterol is itself harmful or

whether the treatment that lowers it is responsible for the adverse effects.

Total Fatalities Table II.2 reveals greater increases in rates of death from any cause in

treatment groups in primary prevention trials. The odds ratios range from

1.02 to 1.20. Differences between treatment and nontreatment groups were

not statistically significant in any meta-analysis. The confidence intervals

extend on either side of 1. Holme (1993), who aggregated diet and drug

primary prevention trials separately, is an exception.

The odds ratios range from 0.90 to 1.02 for total fatalities in secondary

prevention trials. They all fall in a favorable direction except in Ravnskov

(1992), although only Law I (1994) shows statistically significant

reductions in the rate of total deaths in cholesterol-lowering treatment

groups.12 In the remaining meta-analyses, the confidence intervals extend

on either side of 1. Therefore, the possibility cannot be ruled out that

overall death rates in secondary prevention trials increase in

10For example, non-CHD fatality was higher and statistically significant in the World Health

Organization primary prevention trial that used clofibrate. These deaths were caused by stroke,

cancers (mainly of the liver and gastrointestinal tract), gallbladder disease, and CHD that may have

been related to drug toxicity. The Coronary Drug Prevention secondary prevention trial also weighs

heavily in a meta-analysis; as noted above, the three hormone interventions were discontinued early

because of their adverse effects.

11He found statistically significant increases in fatality rates not related to illness in treatment groups

for primary but not for secondary prevention trials and in drug but not diet interventions. The results

of the analysis suggest an association between greater nonillness-related fatalities and

cholesterol-lowering but are not regarded as definitive.

12Law, Thompson, and Wald weighted the odds ratio from each trial by a 0.6 mmol/l (about 10 percent)

reduction is serum cholesterol concentration.

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The Meta-Analyses of Cholesterol-Lowering

Trials and the Health Outcomes They Report

cholesterol-lowering treatment groups; the same is true for primary

prevention trials.

Smith and his colleagues found a net benefit in terms of overall survival

but only among trial participants whose initial CHD risk was highest.13

Lower-risk participants in treatment groups had higher, statistically

significant death rates compared to those in nontreatment groups.14

The failure of cholesterol-lowering treatment to extend the life span has

become an active topic of investigation and is debated among

meta-analysts and others. Some investigators have shown that total fatality

results may be mediated by the degree to which cholesterol is lowered.

Holme, for example, found in 1992 that when cholesterol was not lowered

at all, the risk of death rose about 10 percent. He also noted that

cholesterol had to fall at least 8 to 9 percent to outweigh treatment’s

adverse side-effects on overall survival rates.15 In his 1993 meta-analysis,

Holme noted that greater reductions in cholesterol were related to greater

reductions in total fatalities. In contrast, Ravnskov (1992) found no

relationship between the net mean cholesterol reduction in each trial and

total mortality.16

However, Gould (1995) demonstrated that for every 10 percentage points

that cholesterol fell, total fatality rates also fell 10 percent (p < .03). When

Gordon (1995) regrouped the trials he had analyzed by whether

cholesterol reductions were greater or less than the overall median of

12 percent, he found 11 trials that exceeded this median and that reduced

total fatality by 20 percent (p < .002).17 These findings are consistent with

those of the 4S secondary prevention trial, in which total cholesterol fell by

25 percent and total fatalities fell by 30 percent.

13This net benefit can be expected in nontreatment groups in which the rate of CHD death is greater

than 3 percent a year. Conversely, total mortality can be expected to increase when CHD death in

untreated participants is less than 3 percent.

14The odds ratios (and confidence intervals) were 0.74 (0.60-0.92) for participants at high risk, 0.96

(0.90-1.02) for participants at medium risk, and 1.22 (1.06-1.42) for participants at lower risk.

15I. Holme, “Meta-Analysis of Cholesterol Reduction Trials: Coronary Disease and Mortality,” Primary

Cardiology, 18:7 (1992), 63-70.

16Law I (1994) criticized Ravnskov’s analysis because he did not specify his methods and, therefore, his

analysis cannot be replicated.

17Gordon’s regrouped analyses are not reflected in table II.3, which reports only common odds ratios

and confidence intervals for CHD, non-CHD, and total fatalities.

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The Meta-Analyses of Cholesterol-Lowering

Trials and the Health Outcomes They Report

A Final Note The results from the meta-analyses point to important issues warranting

further investigation into the potentially adverse effects of

cholesterol-lowering interventions. Collaborative meta-analyses that have

been planned will include results from recently completed and ongoing

statin trials that may help resolve questions about the effects of lowering

cholesterol. Because such analyses will be prospective, they will have the

advantage of specifying in advance the relationships to be tested.

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Appendix III 

Data Gaps in Randomized Clinical Trials

A formal accounting of the data gaps in the clinical trials shows that much

data are still needed from direct clinical trial evidence, or from

complementary nontrial data, if patients, doctors, and policymakers are to

be well-informed about the benefits and risks of lowering cholesterol.

NCEP’s evolution has been toward recommending less treatment for

less-researched groups; however, NCEP’s policy would continue intensive,

physician-directed cholesterol-lowering for several of these groups.

In this appendix, we report the kinds of data we did not find when we

examined the individual trials aggregated in the meta-analyses we studied.

We also report on whether the published commentary of NHLBI, other

cholesterol policy groups, and researchers proposing new

cholesterol-lowering trials confirms the gaps we found.1

 We also discuss

recent and proposed clinical trials that may fill the data gaps by 2000.

Useful randomized clinical trials data are generally lacking for women,

minority men and women, elderly men and women, young men, the

majority of Americans with the most common total cholesterol readings

(those between 200 and 231 mg/dl), and groups whose risk of heart disease

is moderate. Clinical trial data on the most common modern

interventions—low-fat diets and widely prescribed cholesterol-lowering

drugs—are minimal. The effect of lowering cholesterol on non-CHD and

total fatality rates has been poorly explored.

Completed Clinical

Trials

The clinical trials that have evaluated cholesterol-lowering treatments

represent diverse treatments, risk categories, overall sample sizes, and

trial durations.2

 Most looked at lowering cholesterol through a single

intervention, the main ones being diet and drugs, but several studied other

interventions. Most studies focused on people who had existing symptoms

of CHD (secondary prevention trials) while others concentrated on those

who had no evidence of CHD (primary prevention trials) and a few

combined both. Many trials were very small, half being constituted of

fewer than 500 subjects, while the largest included more than 10,000.

Although virtually all trials intended to assess CHD outcomes, not all trials

reported the same outcome variables. Table III.1 summarizes the

individual clinical trials we examined.

1

Virtually all the clinical trials we studied were examined for the NCEP guidelines.

2

The trials were conducted mainly in the United States and Europe and were funded by government

agencies or the private sector. NIH has funded a relatively small number of the trials but some of these

have been among the largest, such as MRFIT and LRC.

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Data Gaps in Randomized Clinical Trials

Table III.1: Basic Features of 42 Cholesterol-Lowering Trialsa

Trial by prevention typeb Treatment Duration (years) No. of participantsG

Primary

LA VA (1969, 1971)d Diet ≤8 846M

Oslo DA (1981)e Diet, other 6-7.5 1,232M

MRFIT (1982)e Diet, other 6-8 12,866M

WHO F (1983, 1986)e Diet, other 5-6 49,784fM

Gothenburg (1986)e Diet, other 10 20,015M

Minnesota (1975, 1989)d Diet 1 9,057M

Retinopathy (1969)g Clofibrate 1 63M

Begg (1971)h Clofibrate 5 155

Upjohn (1978)d Colestipol 2 2,278M

Finnish (1985)e Diet, clofibrate, probucol, other 5 1,222M

Helsinki (1987, 1988) Gemfibrozil 5 4,081M

WHO (1978, 1980, 1984, 1992) Clofibrate 5 10,627M

LRC CPPT (1984a, 1984b, 1992) Cholestyramine 7 3,806M

Excel (1990, 1991, 1992)d Lovastatin 0.9 8,245M

Secondary

Corn Oil (1965) Diet 2 80

MRC Low Fat (1965) Diet 3 264M

Oslo DH (1966, 1970) Diet 5 412M

MRC Soya (1968, 1974) Diet 2-7 393M

Sydney (1978) Diet 2-7 458M

DART (1989) Diet 2 2,033M

India (1992) Diet 1 406M

Estrogen (1961) Estrogen 5 100M

Long-Term Estrogen (1962) Estrogen 5 432M

Chicago (1963) Estrogen 5 275M

Newcastle (1971) Clofibrate 3.5 497M

Scottish (1971, 1972) Clofibrate 3 717M

Acheson (1972) Clofibrate 7 95M

St. Vincents (1973) Colestipol 1-3 52M

Veterans Cardiology (1968, 1974) D-thyroxine; D-thyroxine +

estrogen; estrogen; estrogen +

nicotinic acid; nicotinic acid

5 570M

Veterans W. Roxbury (1981)d Probucol 1 118M

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Data Gaps in Randomized Clinical Trials

Age

Participants’ characteristics

sGender Absolute Average Ethnic group Cholesterolc

6Men 66 White 90%; nonwhite 10% 233

2Men 40-49 45 3 25

6Men 35-57 46 2 53

f

Men 40-59 48 2 16

5Men 47-55 250

7Men 49%; women 51% 30-70 207

3Men and women 40-59 250+

5

8Men 48%; women 52% Men 51; women 57 Men: white 86%, nonwhite 14%;

women: 76%, nonwhite 24%

Men 308; women 321

2Men 40-55 48 275

Men 40-55 270

7Men 30-59 248

6Men 35-59 48 White 288

5Men 59%; women 41% 18-70 Men 54; women 58 White 92%; nonwhite 8% 266

0 55 259

4Men Up to 65 263

2Men 30-64 56 296

3Men Up to 60 270

8Men 30-59 282

3Men 30-69 57 250

6Men 90%; women 10% 51 227

0Men 35-64 236

2Men 50-70 White 74%; Jewish 11%; black

10%; Mexican 5%

5Men Up to 50 248

7Men 80%; women 20% Men 52; women 54 Men 246; women 265

7Men 83%; women 17% 40-69 Men 52; women 54 Men 269; women 290

5Men 68%; women 32% 288

2Men 29%; women 71% 36-80 Men 55; women 58 310

0Men 28-75 51 White 92%; nonwhite 8% 241

8Men 50 White 98%; black 2% 305

(continued)

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Data Gaps in Randomized Clinical Trials

Trial by prevention typeb Treatment Duration (years) No. of participantsG

NHLBI (1984) Cholestyraminei 5 143M

CDP (1970, 1972, 1973, 1975, 1986) Clofibrate, D-thyroxine, estrogen

2.5 mg, estrogen 5 mg, niacin

6 8,341M

CLAS (1987) Colestipol, niacini 2 188M

Stockholm (1977, 1980, 1988) Clofibrate, nicotinic acid 5 555M

FATS (1990) Lovastatin + colestipol; niacin +

colestipoli

2.5 146M

Lifestyle (1990)e Diet, otherj 1 48M

POSCH (1990) Partial ileal bypass surgery 9.7 838M

SCOR (1990)k Colestipol, lovastatin, niacini 2 97M

Restenosis (1991, 1992) Lovastatini 2 157M

STARS (1992) Diet, diet + cholestyraminei 3 90M

Ancillary Helsinki (1993) Gemfibrizol 5 628M

MARS (1993) Lovastatini 2 270M

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Data Gaps in Randomized Clinical Trials

Age

Participants’ characteristics

sGender Absolute Average Ethnic group Cholesterolc

3Men 81%; women 19% 21-55 325

Men 30-64 White 93%; nonwhite 7%j 251

8Men 40-59 244

5Men 80%; women 20% Men 59; women 63 248

6Men Up to 62 271

8Men and women 35-75 2 36

8Men 90%; women 10% 30-64 51 2 51

7Men 43%; women 57% 19-72 3 72

7Men and women 6 0 20 9

0Men Up to 66 2 79

8Men 4 9 27 1

0Men 91%; women 9% 35-67 58 2 30

aData were not available for empty cells.

bComplete facts of publication for the reports of the individual trials are given in the bibliography.

cMean baseline cholesterol in mg/dl.

dThis trial had primary and secondary prevention components; primary predominated.

eA multifactor trial—that is, a trial that targets multiple risk factors simultaneously with more than

one intervention.

f

This trial randomized 66 factories comprising 49,784 men.

gParticipants were being treated for diabetic retinopathy. About 40 percent were diagnosed as

having peripheral or coronary vascular disease.

hLittle information from this report is available in English.

i

A trial in which angiography measured changes in cardiovascular lesions effected by lowering

lipid levels. While angiography was the main measured result, clinical outcomes were also

recorded.

j

These percentages are from the clofibrate, nicotinic acid, and nontreatment arms.

k

Participants had heterozygous familial hypercholesterolemia.

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Data Gaps in Randomized Clinical Trials

Treatments Many of the trials that used diet to lower cholesterol were published

before 1985, but most of them were designed in the 1960s and 1970s and

do not reflect current judgments about the need to reduce saturated fat

and overall fat. They represent participants in institutions whose

experience may not typify that of individuals who are outside institutions

and concerned about their cholesterol. Similarly, the completed drug trials

we examined hardly included tests of today’s most commonly prescribed

preventive drugs—the statin drugs and estrogen replacement therapy for

women. Few trials have studied these interventions, although some trials

of statin drugs have recently been completed.

Population Groups

Women More than half of the trials we examined either did not include women as

participants or did not report that they did. The remainder included in

total more than 8,500 women. Women usually constituted less than

25 percent of the participants in a trial; in some, their numbers were too

small to be analyzed.3

 Where women numbered more than 25 percent of a

trial’s participants, the trial either had very few participants or was too

brief to yield clinical differences in coronary outcomes. In some cases, the

major publication reporting trial results did not fully include the women’s

data.

The three trials that included at least 500 women reveal why so little

concrete evidence on the efficacy of lowering women’s cholesterol

resulted from them. The Minnesota primary prevention dietary trial in

mental hospitals has limited value because the diets are no longer

recommended, the study design suffered from the shifting of the

institutional population, and it is questionable whether an institutional diet

is applicable to the general population. The data on women in the Upjohn

primary prevention trial were not included in the original analysis. The

EXCEL trial was too brief (0.9 year) to show a clinical benefit.4

3

Because women’s rates of coronary events are much lower than men’s until after the age of 70, a small

group of women in a trial is not likely to be analyzed separately.

4

When Walsh and Grady pooled the primary prevention data on women who had no history of heart

disease, they found no significant difference in CHD fatality in the group whose cholesterol was

lowered. When they pooled the secondary prevention data on women who had a history of heart

disease, they did find a significant benefit in terms of CHD fatality. See J. M. E. Walsh and D. Grady,

“Treatment of Hyperlipidemia in Women,” Journal of the American Medical Association, 274:14 (1995),

1152-58.

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Appendix III 

Data Gaps in Randomized Clinical Trials

The Old and the Young Most clinical trials have focused on middle-aged men, although

participants’ ages are not consistently reported. Many of the trials set

upper age limits; when average ages are given, they ranged from 45 to 66.

The young and the old are therefore underrepresented in the clinical trials

data.

Minority Men and Women Almost no clinical trials data exist on groups other than white men. No

clinical trials focus on the largest U.S. minority groups—blacks and

Hispanics. Therefore, we have little understanding of the efficacy of

lowering cholesterol for the genetic diversity represented in the United

States.

Risk Profiles Most clinical trials focused on middle-aged white men who had already

had a heart attack or were otherwise at very high risk in order to make the

trials practicable: these were the people who would experience the largest

number of CHD events in the trials’ 2-to-5-year periods. When the

researchers did recruit non-CHD patients, even these were middle-aged

white men who had multiple risk factors. Very few trials other than those

in institutions included participants whose risk was low or moderate.

Thus, even the primary prevention trials typically included very-high-risk

groups.

The participants of all but 14 of the 42 trials either had had a heart attack

or had been diagnosed with CHD. It is not known how the results from the

high-risk primary prevention trials or from the secondary prevention trials

apply to non-CHD participants whose cholesterol levels are only moderate

and who have few risk factors.

The trial participants commonly had high cholesterol levels, as shown in

table III.1. According to the NCEP guidelines, total cholesterol between 200

mg/dl and 239 mg/dl is borderline high and beyond the desirable, but there

are few clinical trials data on persons within this range. When we

compared average baseline cholesterol levels in the trials to the most

recent U.S. cholesterol distribution, we found that most of the trials chose

participants with total cholesterol levels of 240 mg/dl or higher, while most

U.S. adults had total cholesterol levels below that.5

 (See figure III.1.)

5

In the most recent U.S. national sample, 75 percent of adult cholesterol had fallen to below 231 mg/dl,

average adult cholesterol to 204 mg/dl.

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Data Gaps in Randomized Clinical Trials

Figure III.1: Cholesterol Levels in the

Clinical Trials Compared to U.S. Adult

Total Cholesterol Distribution

143 153 162 176 201 231 247 260 276 299 300+

0

5

10

15

20

25

30

Total cholesterol (mg/dl)

Percent

% trials % U.S. population

Thus, there is a gap in what we know about the most common cholesterol

levels. The NCEP guidelines’ recommendations for lowering common

cholesterol levels have largely been generalized from trials whose

participants had higher cholesterol levels and from observational and

other studies. In contrast to the clinical trials, the observational studies did

not lower cholesterol; instead, they compared disease rates at different

cholesterol levels and found better CHD outcomes at lower total

cholesterol levels.

Trials Proposed and

Under Way

Table III.2 summarizes the data gaps that NHLBI, other policy groups, and

the designs for proposed trials have identified. It demonstrates the

considerable agreement among these sources and supports our

conclusions. It also indicates that newer studies are attempting to fill some

of the gaps by the end of the century.6

6

New studies include trials too recent to be included in the meta-analyses of the 42 trials we describe.

Some new studies are planned; others are under way; several have been completed.

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Table III.2: Data Gaps in

Cholesterol-Lowering Trials and 13

New Studies Attempting to Fill Thema

Source identifying gapa

Data gap NHLBI Other policies New trials

No. of new

studiesb

Treatment

Diet • • • 1

Statin drugs • • • 11

Estrogenc • • • 1

Other • • • 4

Population

Women • • • 11

Younger than 40,

older than 60

• • • 9

Non-Caucasian • d d 3

Risk group

Low-risk non-CHD • • • 3

Borderline-high

cholesterol

• • • 5

Low HDL cholesterol • • • 3

Genetic variation • • d 1

Outcome

Non-CHD events • • • 5

Fatal CHD • • 6

Total fatality • • • 4

Quality of life • • • 5

Statistical powerd • • • 12

aSources include published and unpublished information available from the U.S. General

Accounting Office, Program Evaluation and Methodology Division. “Other policies” include

non-NHLBI national policies and other sources such as interviews and selected published

meta-analyses.

bIncludes only trials with 1,000 or more participants.

cWe did not review the several estrogen replacement studies as cholesterol-lowering trials. We

did, however, include the Women’s Health Initiative because it combines estrogen therapy with

low-fat diet.

dThe source did not identify a gap.

Treatments Most of the new trials will use the widely prescribed and highly effective

cholesterol-lowering statin drugs. Estrogen replacement therapy is under

study in preventing cardiac disease in postmenopausal women, but it is

not a cholesterol-lowering treatment.

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Population Groups Women will be included in 11 of 13 new trials, but because their numbers

will generally be restricted to 20 percent or less, these trials may or may

not allow analysis of the women’s data.7

 The Women’s Health Initiative

will incorporate 48,000 older women in a randomized trial of a

fat-restricted diet and 25,000 women in an estrogen-replacement trial, but

it reportedly has design flaws. Critics of this trial have reservations about

its similarities to MRFIT, another large multiple-intervention trial, in which

the results were difficult to attribute to specific interventions. Several

commentators have also expressed concern that ensuring that a low-fat

diet is actually maintained for 10 years seems infeasible.

As for ethnic minorities, only ALLHAT will include a large number of African

Americans. Indeed, it appears to be bearing the burden of past studies’

limitations regarding women, black men and women, and elderly persons.

Since it studies more than one intervention, trying to lower both

cholesterol and blood pressure, it may be difficult to attribute differences

in results, if any, to particular sources.

Risk Profiles Three new trials will focus on persons who have never had a heart attack;

5 others will include mainly persons with borderline-high cholesterol

levels (200 to 239 mg/dl). These trials will go a long way toward filling

critical gaps in what is known about these moderate-risk groups.

Outcomes Four of the new trials are planned to detect changes in total fatalities. Not

even the largest of the previous trials found significant reductions in total

fatalities. Although the planned trials will mostly study more than 3,000

participants, their designs may still not yield data that will fill the gaps.

Investigators are counting on substantial lowering of cholesterol from the

new drugs to reduce total fatalities, within the limits of the participant

populations and trial durations.

Statistical Power Most of the new studies will increase statistical power over that of the 42

existing studies that we reviewed by recruiting large numbers of

participants, primarily participants whose risk for coronary events is very

high, or by running their trials longer. There is a prospective plan to

combine the analyses of several of the trials in a meta-analysis that may

yield more information than individual trials. All this suggests that some of

7

Two exceptions are the Women’s Health Initiative, with only women participants, and the

Anti-hypertensive and Lipid-Lowering Treatment to Prevent Heart Attack (ALLHAT) study, with fewer

than 50 percent women.

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the constraints on the statistical power of past trials may be overcome,

providing answers to several outstanding questions about how to reduce

the rates of CHD and non-CHD fatality and how to lengthen the survival of

persons who have certain attributes. However, pressure to recruit

high-risk participants continues; thus, answers to several remaining

questions will be found at the expense of finding out whether lowering

cholesterol benefits lower-risk groups.

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Cholesterol Policy in the United States and

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Cholesterol policies to prevent coronary heart disease by lowering

cholesterol in the United States and other nations typically follow two

complementary and simultaneous strategies: (1) a population-based

strategy that educates the general public about dietary change and (2) a

high-risk strategy that identifies persons whose high cholesterol levels

warrant physician-directed measures to reduce CHD risk. The policies

differ considerably, though, in the breadth of cholesterol-screening they

recommend and in their definition of “high risk.” NCEP recommends testing

all adult blood cholesterol levels and suggests various intensities of

cholesterol-lowering treatment depending on individual risk. The

guidelines indicate that 29 percent of U.S. adults need a physician’s

assistance to lower their cholesterol. Several other U.S. and foreign

policies recommend screening and intensive cholesterol-lowering for

fewer adults.

Coronary heart disease, a major cause of death and disability in most

developed nations, is believed to be partly the result of high-fat diets, little

exercise, obesity, and smoking and, thus, appears to be preventable.

Formulating policy, however, is complicated by the interpretation of the

underlying data. A large number of clinical trials have tested

cholesterol-lowering treatments. Although clinical trials are the most

rigorous type of evidence for establishing the efficacy of a medical

treatment, they do not include the range of patients, treatments, and

outcomes in medical practice, limiting the ability to predict risks and

benefits for many groups.

Further, while small average reductions in a population’s cholesterol may

result in dramatic reductions in CHD fatality rates, this may provide only a

negligible chance of improvement for any particular person. This has been

termed the paradox of public health prevention.1

 While CHD rates rise with

rising cholesterol levels, the ability to predict outcomes for individuals is

poor. Many who have died from heart disease did not have elevated

cholesterol levels.

The large 1982 MRFIT trial demonstrates the paradox. Men whose total

cholesterol measured 291 mg/dl or higher constituted only 2 percent of the

total study group and 2 percent of total CHD deaths (figure IV.1), but they

represent the highest rate of CHD death (figure 1). Meanwhile, men whose

total cholesterol was between 213 and 271 mg/dl experienced 63 percent

of the CHD deaths, by far the majority. Thus, any who would make national

cholesterol policy must determine whether to focus on (1) physician1

Geoffrey Rose, The Strategy of Preventive Medicine (New York: Oxford University Press, 1992).

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Cholesterol Policy in the United States and

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directed cholesterol-lowering efforts at the highest end of the cholesterol

range, where men have the greatest individual likelihood of having a heart

attack, or (2) preventive activity in the middle range, where most heart

attacks occur but individual risk is much lower. The latter choice would

apply the high-risk procedures to many people with very low individual

risk because the ability to predict individual outcomes is poor.

Figure IV.1: Cholesterol and CHD

Death Distributions in the MRFIT Triala

136 155 174 194 213 232 252 271 290 310

0

5

10

15

20

25

Total cholesterol (mg/dl)

Percent

% total CHD deaths % of men screened

aMore than 355,000 men screened for the MRFIT trial were followed for 6 years. Cholesterol levels

were lower than 155 mg/dl in about 9 percent of the CHD deaths.

Source: Adapted from Geoffrey Rose, The Strategy of Preventive Medicine (New York: Oxford

University Press, 1992), p. 23.

The various cholesterol policymaking groups here and abroad have

handled differently the data limitations and the paradox of prevention. For

example, several North American policy groups concluded that applying

an aggressive cholesterol-lowering policy to women, young men, and

elderly persons does not seem warranted because of the absence of trial

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Cholesterol Policy in the United States and

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data and the lack of support from nontrial studies. Similarly, several

foreign policies have set drug cholesterol-lowering targets closer to those

included in the trials and, therefore, considerably higher than NCEP’s

targets. Overall, the policies cover a wide spectrum, from screening and

treating narrowly to NCEP’s more comprehensive policy.

The National

Cholesterol Education

Program

The 1984 NIH consensus development conference concluded from the

accumulated evidence of clinical, epidemiologic, metabolic, and animal

research that CHD risk is related to serum cholesterol levels. A recently

completed NHLBI-funded study of coronary heart disease among high-risk

men who had never had a heart attack had found a significant reduction in

combined CHD in the group whose cholesterol was lowered by means of

drugs. The conference therefore proposed that Americans whose total

blood cholesterol was above the 75th percentile of the population

distribution be given advice and treatment to lower it. The conference also

recommended the development of NCEP. Table IV.1 summarizes the past 12

years of NCEP policy.

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Table IV.1: National Cholesterol

Education Program Milestones Since

1984

Year Action Background

1984 NIH consensus conference

held

CHD associated with high total cholesterol

Population distributions of cholesterol

recommended for treatment: 75th

percentile for diet, 90th for drugs

Diet and exercise recommended as

cholesterol-lowering treatments

1987 First adult treatment

guidelines issued

Highest desirable cholesterol level set at

50th percentile

Adult cholesterol measurement set at

5-year intervals

Treatments established: diet first, followed

by drugs

1988 Laboratory standards issued

1990 Population strategy issued

1991 Children’s strategy issued

1993 Adult guidelines revised High risk redefined for treatment

• Drug treatment reserved for groups with

high CHD rates

• HDL declared beneficial

• Drug treatment delay recommended for

men younger than 45 and women younger

than 55

The guidelines of 1987 focused on identifying and treating high-risk adults

but also recommended regular universal screening, defined various

cholesterol levels as alerts and goals, and established a method of

classifying a person’s CHD risk. Recommendations were made in 1990-91

for cholesterol-screening for both the general population and children and

adolescents. The adult treatment guidelines were revised in 1993, although

they continue recommendations for universal adult screening and

cholesterol levels. The current adult guidelines refine the risk assessment

leading to treatment and differentiate cholesterol goals for different

groups.

NCEP’s Definition of CHD

Risk

The NCEP guidelines recommend physician-directed interventions for

high-risk adults and diet and exercise changes for the entire population.

NCEP’s definition of desirable, borderline, and high total blood cholesterol

levels is uniform for men and women of all adult ages:

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• desirable = 200 mg/dl or less

• borderline high = 200-239 mg/dl

• high = 240 mg/dl or higher.2

Risk factors that NCEP believes are associated with CHD and that can be

modified are high blood cholesterol, obesity, physical inactivity,

hypertension, diabetes, and cigarette smoking. Unmodifiable factors that

also influence the probability of CHD and are, thus, included in the

assessment of patient risk and decisions to treat include increasing age,

being male, and having a family history of CHD.

The total cholesterol of about half of all adult Americans is higher than 200

mg/dl; the policy requires medical consideration of their total coronary

risk profile, including risk factors. For this group, NCEP recommends

intensive treatment to lower cholesterol for persons who have coronary

heart disease or for those with no evidence of CHD but with two or more

risk factors such as smoking or having a family history of coronary heart

disease. Individuals from groups with moderate to low rates of CHD can

also be recommended for vigorous cholesterol-lowering by NCEP’s

high-risk policy if they have two risk factors. For example, a man whose

LDL cholesterol was 190 mg/dl or more would be a candidate for aggressive

cholesterol-lowering if he were older than 45.

Classifying a Patient’s CHD

Risk

Under current U.S. policy, all adults are to have their cholesterol tested

every 5 years in order to classify them by their need for

cholesterol-lowering. Initial screening that reveals their total blood

cholesterol and HDL levels informs the preliminary risk classification.3

Subsequent risk classification may include more cholesterol tests along

with consideration of other equally weighted risk factors.

Figure IV.2, adapted from the latest NCEP guidelines, shows the schematic

that they recommend that physicians follow in classifying a patient for

treatment and advice. Starting with the original cholesterol screening (at

the left of the figure), the physician can arrive at one of six

recommendations for advice and treatment intensity. For example, adults

2

According to the NCEP Adult Treatment Panel, these numbers were based partly on the arbitrary 50-

and 75-percent levels for the population distribution of cholesterol and partly on the observation of the

increasing rates of CHD incidence among persons with more than 200 mg/dl total cholesterol in the

MRFIT study. See NIH, Expert Panel on Detection, Evaluation, and Treatment of High Blood

Cholesterol in Adults (Bethesda, Md.: 1989), p. 67.

3

As we noted earlier, LDL, usually the largest component of total serum cholesterol, leads to greater

risk of CHD the higher it is. It is therefore the main target of cholesterol reduction. HDL is a much

smaller component of total cholesterol and is beneficial: low amounts are considered to increase the

risk of heart disease.

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whose total cholesterol measure is “desirable,” or below 200 mg/dl, but

whose HDL measures 35 mg/dl or more should be given general advice

about CHD risk. (Approximately 51 percent of U.S. adults fall into this

category.) Adults whose total cholesterol is between 200 mg/dl and 239

mg/dl and who have HDL lower than 35 mg/dl or two or more risk factors

(the remaining 49 percent) should be given a second test, from which LDL

cholesterol is calculated, and their risk should be reevaluated.4

4

In Cholesterol Measurement: Test Accuracy and Factors That Influence Cholesterol Levels,

GAO/PEMD-95-8 (Washington, D.C.: 1994), we explored the considerable imprecision in typical

cholesterol testing, concluding that decisions to classify patients should be based on the average of

multiple measurements, as recommended by NCEP’s guidelines.

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Figure IV.2: Recommended Advice and

Treatment for U.S. Adults by

Cholesterol Levela

HDL <35 mg/dl

Measure total


and HDL blood


cholesterol

Desirable:


<200 mg/dl

Borderline-high:


200-239 mg/dl

HDL <35 mg/dl


or 2 or more


risk factors

HDL >35 mg/dl _

HDL >35 mg/dl


and fewer than


2 risk factors

_

Offer risk advice

Measure fasting


cholesterol and


calculate LDL

B

A

High:


>240 mg/dl _

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Cholesterol Policy in the United States and

Abroad

LDL 160 mg/dl


and 2 or more


risk factors

LDL 190 mg/dl


and fewer than 2


risk factors

Begin diet


therapy

Retest

Desirable


LDL:


<130 mg/dl

Borderline-high


LDL:


130-159 mg/dl

High LDL:


>160 mg/dl _

Optimal


LDL:


<100 mg/dl _

Higher-than-optimal


LDL:


>100 mg/dl

No


evidence


of CHD

Evidence


of


CHD

Perform


clinical evaluation

Fewer than 2


risk factors

Two or more


risk factors

Instruct for


individual diet


and activity

Perform


clinical


evaluation

Offer risk


advice

Consider drug


therapy

A

B

Begin diet


therapy

Retest

LDL >100 mg/dl

aShaded areas are NCEP’s alternative recommendations for advice and treatment intensity.

Source: Adapted from National Cholesterol Education Program, Expert Panel on Detection,

Evaluation, and Treatment of High Blood Cholesterol in Adults, 2nd report (Bethesda, Md.: 1993).

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After determining whether or not the patient has evidence of CHD, the

physician places the patient in an LDL category that then leads to one of the

remaining recommendations, depending on the number of other risk

factors. For example, according to figure IV.2, after performing a clinical

evaluation, a physician should recommend a reduced-fat diet for a patient

who has no evidence of CHD, LDL of at least 130 mg/dl, and two or more

other risk factors. If dietary therapy does not successfully lower LDL to

target levels, the physician may then consider cholesterol-lowering drugs,

which are usually taken indefinitely.

Beyond this schematic, the guidelines advise physicians generally for

certain subgroups. They urge more-vigorous efforts to lower the

cholesterol of CHD patients and elderly persons, in both of whom CHD

fatality rates are high. For groups with fewer CHD fatalities, such as

premenopausal women (who are protected by higher HDL levels than men)

and men younger than 45, the guidelines urge that drugs be delayed in

favor of dietary intervention. They leave considerable discretion to the

physician regarding how to treat several groups who register

unsatisfactory cholesterol readings and have no other risk factor, such as

men older than 45 and postmenopausal women with borderline-high

cholesterol. These decisions hinge on the accuracy of the risk

classification laid out in figure IV.2.5

Dietary and Drug

Treatments

Reducing dietary fat is central to advice recommended for the general

population; physician-directed diet therapy and subsequent drug therapy

are reserved for high-risk persons. Dietary therapy follows one of two

diets that limit total fat to 30 percent of calories. The Step I diet limits

saturated fat to 8 to 10 percent of total calories, cholesterol consumption

to 300 mg a day. If the Step I diet fails to lower cholesterol to appropriate

levels, the Step II diet further restricts saturated fat to 7 percent of calories

and cholesterol to less than 200 mg a day.6

5

A recent assessment of NCEP’s guidelines by Grover and colleagues found that they predicted fatal

heart attacks at a rate 24-percent better than random chance. Their model, based on several large

databases, predicted CHD fatality better than NCEP. That the NCEP guidelines quantify cholesterol

only, weighting all other risk factors equally, may explain the lesser ability of the guidelines to predict

risk. See S. A. Grover et al., “Identifying Adults at Increased Risk of Coronary Disease,” Journal of the

American Medical Association, 274 (1995), 10.

6

The 30-percent fat limit demanded by these two diets is close to the diet consumed, on the average, in

the United States. Nutrition experts have suggested that a lower limit might yield more dramatic

results.

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Although NCEP’s guidelines estimate that the Step I diet can reduce serum

cholesterol from 3 to 14 percent, Ramsay, Yeo, and Jackson have

concluded that cholesterol-reduction in populations who live outside

institutions averages only up to about 4 percent.7

 These authors call for a

more realistic assessment of dietary response to guide treatment practice.

Thus, NCEP-recommended screening plus risk assessment can lead many

patients through diet therapy to drug therapy.

Table IV.2 lists cholesterol-lowering drugs available in the United States

and their major effects. Gastrointestinal distress and skin flushing are

generally side effects of the older drugs, although a few have more serious

negative effects. The newer statins generally produce few side effects, but

their long-term effects are not known. Occasionally, they cause mild liver

toxicity and muscle pathology.

Table IV.2: U.S. Cholesterol-Lowering

Drugs and Their Effect

Class Drug Raises HDL Lowers LDL

Lowers

triglycerides

Bile acid-binding

resin

Cholestyramine •

Colestipol •

Estrogen Multiple

preparations

• •

Fibrate Clofibrate • •

Gemfibrozil • •

HMG-CoA

reductase inhibitor

Fluvastatin •

Lovastatin •

Pravastatin •

Simavastatin •

Nicotinic acid Water-soluble

vitamin

• • •

Probucol Probucol a •

aLowers HDL. Lower amounts of HDL increase the risk of heart disease.

Source: A. Chait, “The High Risk Strategy for Adults,” in B. M. Rifkind (ed.), Lowering Cholesterol

in High Risk Individuals and Populations (New York: Marcel Dekker, 1995), pp. 1-32.

7

L. E. Ramsay, W. W. Yeo, and P. R. Jackson, “Dietary Reduction of Serum Cholesterol Concentration:

Time to Think Again,” British Medical Journal, 303 (1991), 953.

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Cholesterol Policy in the United States and

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Other Cholesterol

Policies Compared to

NCEP

After reviewing NCEP, we compared it to six recent cholesterol policy

statements from the United States and other nations with similarly high

CHD rates. The four other nations share not only CHD problems of similar

magnitude but also the published clinical trials, yet their policies differ in

the breadth of screening they recommend and in the definition of the

high-risk group they would treat intensively.8

 Several groups

recommending the less-active policies are in the United States. Differences

in their willingness to generalize to untested groups from the results of a

limited trial database are a possible source of policy variation.

In addition to reviewing the U.S. and foreign policies, we reviewed

statements from two medical societies in the United States. Although the

U.S. and foreign policies and statements differ considerably in their aims

and contents, they can be compared in terms of the comprehensiveness of

the groups to be screened for cholesterol and the use of cholesterol levels

and other risk factors to trigger intensive treatment. One policy is similar

to NCEP’s recommendation of universal screening and lower cholesterol

levels for intensive treatment. Others are directed toward a less ambitious

program of screening fewer adults or propose different risk classifications.

(See table IV.3.)

8

In a recent comparative study of CHD rates, the United States shared the higher rates found in

Australia, Britain, and Canada rather than the much lower rates in France and Japan. See Office of

Technology Assessment, International Health Statistics: What the Numbers Mean for the United States

(Washington, D.C.: 1993), p. 118.

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Table IV.3: Cholesterol-Lowering Policies in the United States, Australia, Canada, and Europea

Group screened Risk factor b

Protocolc

Policy Young Middle age Old Total cholesterold Plus others Treatment

Universal

European Specialty

Association 1992

Yes Yes Yes 250 No other Diet

250 Risk greater than 2% Diet, drugs

300 No other Diet, drugs

NCEP 1993 Yes Yes Yes Up to 200 CHD patient and LDL

100+

Diet, drugs

200-239 Non-CHD patient and

LDL 180+

Diet, drugs

240+ No other Drugs

Selective

Canadian Health

Examination 1993

No Yese No Up to 265 Male None

265+ Male Diet, drugs

American College of

Physicians 1995

No Yes No f f f

U.S. Preventive Services

Task Force 1995

No Yes No f f f

Unspecified

Australian 1992 250 Cardiovascular disease Drugsg

290 No cardiovascular

disease

Drugsg

British 1993 200 CHD patient Drugs

250 Drugs

aComplete facts of publication are in the bibliography. Data were not available for empty cells.

bYoung = men 20-34, women 20-44; middle age = men 35-65, women 45-65; old = men and

women 65 and older.

cThese are protocols that we selected for illustration from the many available in NCEP.

dMean baseline cholesterol in mg/dl.

eMen 30-59.

f

Not reported. Several policies reported only screening or only treatment advice.

gThe Australian policy declines to specify “a threshold above which drug therapy should be given

and below which it should not because the long-term net clinical benefit (total mortality and

morbidity) has not been established for these patients.” The policy considers HDL cholesterol of

58 mg/dl and higher to be protective.

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For instance, while the European Specialty Association and NCEP policies

recommend universal adult screening, two others in the United States and

one in Canada recommend screening selectively.9

 The Canadian Health

Examination, the American College of Physicians, and the U.S. Preventive

Services Task Force recommend screening only segments of the adult

population for whom clinical trials have clearly shown that lowering

cholesterol is beneficial—that is, mainly high-risk middle-aged white men.

The policies in table IV.3 also differ in their use of high cholesterol and

other risk factors to determine whether to apply diet and drug treatments.

As we noted in figure IV.2, NCEP’s separation of desirable cholesterol (or up

to 200 mg/dl) from borderline-high cholesterol (200-239 mg/dl) places

many persons who are at moderate risk on a route to physician-directed

treatment. However, NCEP also refines the cholesterol levels requiring

dietary treatment or drugs, as do several other policies: they assign

more-intensive action to groups whose CHD rate is high and less-intensive

action to groups whose CHD rate is low.10 This focuses the most intensive

preventive interventions on the patients who are most likely to benefit.

Another point of comparison between the policies is their willingness to

generalize from the data on the populations studied in the randomized

clinical trials. Most of the policies, including NCEP’s, are based not only on

the clinical trials but also on observational research that did not test an

intervention or use controlled designs. This research included autopsy

reports, cross-country comparisons, community studies, migration studies,

and the like. Although the clinical trials evidence is mainly restricted to

high-risk middle-aged white men, NCEP has generalized the data to try to

9

On the European Specialty Association, see the task force of the European Society of Cardiology,

European Atherosclerosis Society, and European Society of Hypertension, in Atherosclerosis, 110

(1994), 121-61. The Australian and British policies do not specify breadth of screening. Several policies

refer only to general-population screening and do not comment on treatment or prevention. NCEP’s

alert levels for total cholesterol are the best known, but NCEP encourages physicians to incorporate

LDL and HDL levels into their treatment decisions. LDL is the largest part of total cholesterol,

calculated from total cholesterol, and, within a range, predictable from it.

10NCEP recommends different intensities of action for different risk groups, although these have not

been widely publicized. For example, “if after an adequate trial of diet therapy, LDL cholesterol

remains 190 mg/dl in the absence of risk factors, 160 in their presence, or 130 in subjects with

established atherosclerotic disease, drug therapy is recommended.” (See A. Chait, “The High-Risk

Strategy for Adults,” in Basil M. Rifkind (ed.), Lowering Cholesterol in High-Risk Individuals and

Populations (New York: Marcel Dekker, 1995), p. 4.) The level for initiating cholesterol-lowering

interventions in women otherwise free of coronary heart disease and with fewer than two other risk

factors is 270 mg/dl (Rifkind, pp. 4-31).

Page 82 GAO/PEMD-96-7 Cholesterol Treatment
Appendix IV 

Cholesterol Policy in the United States and

Abroad

cover some of the gaps.11 Two of the four policies that recommend

selective rather than universal screening are based primarily on the

clinical trials evidence.

Several policies are less willing to generalize. For example, the European

Specialty Association guidelines express the concern that “no randomized

controlled trials have specifically addressed hyperlipidemia in women. It is

not known whether the results of existing drug trials can be extrapolated

to women.”12 The Canadian Health Examination and the U.S. Preventive

Services Task Force require at least one well-conducted clinical trial per

population group before recommending screening or intensive

cholesterol-lowering for that group.

To sum up, policies differ widely within North America. At one end, NCEP

applies its physician-directed high-risk options most broadly: several

untested groups, including elderly men and women, middle-aged men and

women whose cholesterol levels are moderate, and others whose CHD risk

is moderate, may be advised to pursue intensive physician-directed

cholesterol-lowering therapy. At the other end, the Canadian Health

Examination screens only middle-aged white men and treats no one, other

than CHD patients, whose total cholesterol is lower than 265 mg/dl. The

U.S. Preventive Services Task Force screens only middle-aged persons.

Beyond North America, some policies are similar to NCEP’s in scope while

others, such as the Australian, treat CHD patients whose total cholesterol is

250 mg/dl or higher but not others unless their cholesterol exceeds 290

mg/dl.

11“[E]vidence from RCT [randomized control trials] is strongest in middle-aged men with high initial

cholesterol levels. However, the complete set of evidence, including the epidemiologic observations

and animal experiments, strongly supports the generalization that reducing total and LDL cholesterol

levels is also likely to reduce CHD in younger and older men, in women and in individuals with more

moderate elevations of cholesterol.” (NIH, Report of the Expert Panel on Detection, Evaluation, and

Treatment of High Blood Cholesterol in Adults (Bethesda, Md.: 1989), p. 16.) Similarly, the updated

NCEP policy document states that “Lack of clinical trial data proving that cholesterol-lowering therapy

reduces age-adjusted mortality in individuals with moderately high blood cholesterol and without

other CHD factors, however, does not preclude efforts to reduce cholesterol levels in this group.”

(National Cholesterol Education Program, Expert Panel on Detection, Evaluation, and Treatment of

High Blood Cholesterol in Adults, 2nd report (Bethesda, Md.: 1993), p. I-7.)

12K. Pyorala et al., “Prevention of Coronary Heart Disease in Clinical Practice: Recommendations of the

Task Force of the European Society of Cardiology,” Atherosclerosis, 110 (1993), 151.

Page 83 GAO/PEMD-96-7 Cholesterol Treatment
Appendix V 

Experts We Consulted

Alexia Antczak-Boukoms, D.Sc.

Decision Sciences and Outcomes Research

Bristol-Myers Squibb Pharmaceutical Research Institute

Wallingford, Connecticut

Trudy Bush, M.D.

School of Medicine

University of Maryland

Baltimore, Maryland

Thomas Chalmers, M.D. (deceased)

Meta Works

Boston, Massachusetts

Charles S. Davis, Ph.D.

Department of Preventive Medicine and Environmental Health

University of Iowa

Iowa City, Iowa

Alan M. Garber, M.D., Ph.D.

School of Medicine

Stanford University

Stanford, California

Michael Glade, M.D.

Chicago, Illinois

David J. Gordon, M.D., Ph.D.

Lipid Metabolism Atherogenesis Branch

National Heart, Lung, and Blood Institute

Bethesda, Maryland

Michael Gurr, Ph.D.

Maypole Scientific Services

Isles of Scilly, United Kingdom

Stephen Hulley, M.P.H., M.D.

Department of Epidemiology and Biostatistics

Prevention Sciences Group

University of California

San Francisco, California

Page 84 GAO/PEMD-96-7 Cholesterol Treatment
Appendix V 

Experts We Consulted

Telba Irony, Ph.D.

Department of Operations Research

George Washington University

Washington, D.C.

Kathleen Jablonski, Ph.D.

Medlantic Research Institute

Washington, D.C.

Mark Lipsey, Ph.D.

Institute for Public Policy Studies

Vanderbilt University

Nashville, Tennessee

Donald Mattison, M.D.

School of Public Health

University of Pittsburgh

Pittsburgh, Pennsylvania

Robert Murray, M.D.

College of Medicine

Howard University

Washington, D.C.

Henry S. Sacks, M.D.

Clinical Trials Unit

Mt. Sinai School of Medicine

New York, New York

Ernst J. Schaefer, M.D.

Jean Mayer USDA Human Nutrition Research Center on Aging

Tufts University

Boston, Massachusetts

George Davey Smith, M.D.

Department of Clinical Epidemiology

University of Bristol

Bristol, England

Meier Stampfer, M.D.

Harvard Medical School

Boston, Massachusetts

Page 85 GAO/PEMD-96-7 Cholesterol Treatment
Appendix V 

Experts We Consulted

Simon G. Thompson, M.Sc.

Medical Statistics Unit

London School of Hygiene and Tropical Medicine

London, England

Janet Wittes, Ph.D.

Statistics Collaborative

Washington, D.C.

Paul Wortman, Ph.D.

Department of Psychology

State University of New York at Stony Brook

Stony Brook, New York

Page 86 GAO/PEMD-96-7 Cholesterol Treatment
Appendix VI 

Comments From the U.S. Department of

Health and Human Services

Note: GAO comments

supplementing those in the

report text appear at the

end of this appendix.

Page 87 GAO/PEMD-96-7 Cholesterol Treatment
Appendix VI 

Comments From the U.S. Department of

Health and Human Services

See comment 1.

See comment 2.

See comment 3.

See comment 4.

Page 88 GAO/PEMD-96-7 Cholesterol Treatment
Appendix VI 

Comments From the U.S. Department of

Health and Human Services

See comment 5.

See comment 6.

Page 89 GAO/PEMD-96-7 Cholesterol Treatment
Appendix VI 

Comments From the U.S. Department of

Health and Human Services

Page 90 GAO/PEMD-96-7 Cholesterol Treatment
Appendix VI 

Comments From the U.S. Department of

Health and Human Services

The following are GAO’s comments on the HHS December 13, 1995, letter.

GAO Comments 1. Since the 1980s, applying meta-analysis to health and medical research

has been viewed as a research process in its own right. Meta-analysis

offers a statistically rigorous way of pooling the results of clinical trials,

and it has the advantage of increasing the statistical power of individual

trials by combining them. In the absence of a constant bias pervading a

whole set of trials, the bias of any one analyst within the set is minimized.

NIH has paid considerable attention to the use of meta-analysis in health

and medical research, as evidenced by its 1986 Workshop on

Methodological Issues in Overviews of Randomized Clinical Trials.1

 In

June 1994, NHLBI sponsored a workshop specifically on meta-analyses of

cholesterol-lowering trials. NCEP included meta -analyses in the evidentiary

sources it cited in support of the Adult Treatment Panel II guidelines. The

federal legislation that established the Agency for Health Care Policy

Research required that guidelines on clinical practice be based on

systematic reviews of research evidence.

Our task for this report was to provide an overview of the clinical trials

evidence that had been used, among other evidence, to support the NCEP

guidelines. Given that, and in view of the conflicting results among

individual trials, we believe that our decision to systematically display and

discuss the results of the meta-analyses that synthesized results across

trials on the five health outcomes we were interested in was an

appropriate and efficient way to summarize this large body of data.

Although the meta-analysts we studied differed in what they included and

excluded, most of them excluded outmoded treatments such as hormone

treatment in men. We have stated in the report that clinical trials using the

more recently prescribed statin drugs are not well represented in the

meta-analyses we reviewed. They do not include, for example, the results

of 4S or WOSCOPS. However, they do include, to a greater or lesser degree,

all the cholesterol-lowering randomized clinical trials that were available

when the Adult Treatment Panel II guidelines were published.

2. Table II.2 displays the odds ratios for CHD, non-CHD, and total fatalities.

Across the meta-analyses that examined primary prevention trials, we

found no statistically significant differences in CHD fatality rates between

1

T. Colton, L. S. Freedman, and A. L. Johnson (eds.), “Proceedings of the Workshop on Methodologic

Issues in Overviews of Randomized Clinical Trials, May 1986,” Statistics in Medicine, 6:3 (1987),

217-410.

Page 91 GAO/PEMD-96-7 Cholesterol Treatment
Appendix VI 

Comments From the U.S. Department of

Health and Human Services

treatment and nontreatment groups. Further, a statistically significant

increase in the non-CHD fatality rate for treated participants was in fact

obtained in 5 of the 6 meta-analyses that examined this outcome. The

failure to achieve statistically significant reductions in fatality rates from

all causes in primary prevention trials should be viewed in the light of

Gould’s 1995 meta-analysis, which shows an adverse effect for treatment

with fibrates. This drug class predominates in primary prevention trials

using drug interventions.

3. Terge Pedersen and other 4S investigators have cautioned that the

study’s results should not be extrapolated to studies using other statin

drugs, given differences in the cholesterol-lowering efficacy of various

drugs. However, we note that both the 4S and WOSCOPS trials—which

showed no statistical differences between treatment and nontreatment

groups in deaths from noncardiovascular causes—support meta-analysis

findings that increased non-CHD fatality rates in treatment groups were

associated not with lowering cholesterol but with particular

cholesterol-lowering treatments. We agree that safety and efficacy have

been demonstrated for simvastatin and pravastatin for the types of

primary and secondary patients who participated in these trials. It is also

important to recognize that patients may be expected to continue with

drug treatment (especially for primary prevention) for a period

considerably longer than the 5-year duration of these trials, even while

information is not yet complete about the long-term safety of the statin

drugs.

4. A consideration of the cost-effectiveness of cholesterol-lowering

treatment must also account for costs associated with prevention. For

example, the 3.5-percent absolute CHD mortality risk reduction in 4S means

that to prevent the death of one patient diagnosed with CHD, an estimated

29 patients would have to be treated with simvastatin at trial dosages. The

WOSCOPS authors estimate that 1,000 middle-aged men with

hypercholesterolemia and no prior evidence of myocardial infarction

would have to be treated for 5 years to prevent 7 deaths from

cardiovascular causes. They note that such findings compare favorably

with treatment for mild hypertension in middle-aged persons.

Nevertheless, any cost-benefit ratio will be less in a primary prevention

setting than in a secondary prevention setting, because patients are treated

whose risk levels are lower.

5. Clinical trials do constitute the most important type of evidence for the

benefit of a medical intervention, because less-rigorously designed

Page 92 GAO/PEMD-96-7 Cholesterol Treatment
Appendix VI 

Comments From the U.S. Department of

Health and Human Services

cross-country comparisons and other descriptive studies may be

confounded by many factors. However, the largest portions of the U.S.

population have not been well-represented in cholesterol-lowering trials,

including among others women, women and men minorities, young men,

elderly persons, and persons with cholesterol levels lower than 250 mg/dl.

Past cholesterol-lowering trials have usually been conducted with

middle-aged, high-risk, white men and are thus limited in how well they

can comment on the benefits of lowering cholesterol for others. When

others have been included in trials, the data sets they provide are usually

too small to analyze, leaving in question the applicability of

cholesterol-lowering from one group to another.

The contrast that has been best studied is that between people who have

already had a heart attack and those who have not. Generally, this can be

understood as a contrast between very high-risk persons and those whose

risk is lower, although even the primary trials tend to focus on individuals

with multiple risks for CHD. The meta-analyses we reviewed consistently

found a pattern of greater CHD benefit in secondary than in primary trials.

6. NHLBI cites selected research other than clinical trials in order to support

the broad application of the benefits found in the trial results with

high-risk men to other groups. Yet different treatments are recommended

for men and for women in the guidelines. In 1993, NHLBI revised the NCEP

guidelines to “delay” the application of cholesterol-lowering drugs to

beyond age 55 for women. Similarly, NHLBI invited doctors to consider

estrogen replacement rather than cholesterol-lowering drugs beyond

menopause. Many of the women who display signs of high risk for CHD are

older; indeed, elderly persons as a group are disproportionately women. A

recent review found no direct evidence of benefit in lowering cholesterol

among elderly persons and mixed evidence that higher cholesterol levels

are associated with CHD.

2

2

Walter H. Ettinger and William R. Hazzard, “Dyslipotroteinemia in Older People,” in Basil M. Rifkind

(ed.), Lowering Cholesterol in High-Risk Individuals and Populations (New York: Marcel Dekker,

1995).

Page 93 GAO/PEMD-96-7 Cholesterol Treatment
Appendix VII 

Major Contributors to This Report

Program Evaluation

and Methodology

Division

John E. Oppenheim, Assistant Director

Barbara Chapman, Project Manager

Valerie J. Caracelli, Senior Social Science Analyst

Harry Conley, Chief Statistician

Penny Pickett, Communications Analyst

Venkareddy Chennareddy, Referencer

Acknowledgment Douglas M. Sloane, Senior Social Science Analyst, General Government

Division, also contributed important statistical advice.

Page 94 GAO/PEMD-96-7 Cholesterol Treatment
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Meta-Analyses We

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The headings below are the names we have given in our text and tables to

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1

Two other data sources that some meta-analyses cite but that were not identified with any one trial

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Trials,” Lancet, 2 (1971), 203-06, and D. K. Wysowski and T. P. Gross, “Deaths Due to Accidents and

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Excel Bradford, R.H., et al. “Expanded Clinical Evaluation of Lovastatin

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Meta-Analyses We

Omitted

We omitted the meta-analyses listed in this section for one or more of the

following reasons. The appropriate reasons are indicated by the numbers

in parentheses at the ends of the entries. (1) The data and procedures were

insufficiently reported. (2) The meta-analysis was not concerned with the

clinical outcomes we studied. (3) The meta-analysis was not based

primarily on more than two randomized trials of a year or more in

duration. (4) The meta-analysts did not mathematically cumulate results

across studies. (5) The meta-analysis was not published in English. (6) The

meta-analysis was not published in any language. (7) The meta-analysis

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(973389) Page 107 GAO/PEMD-96-7 Cholesterol Treatment
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