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. 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, borderline-high, or high total cholesterol levels. 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. 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 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. 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. 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. The meta-analyses, which 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. 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 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. 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. 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 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. 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. Several of the recent meta-analyses found that the 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.