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Discussion

Middle-aged Men

The evidence in favor of screening and treatment of lipid disorders is strongest for middle-aged men (aged 45 to 70 years), particularly those of European ancestry, with elevated levels of LDL-C and moderate to high short-term risk of CHD events. The populations in these studies appear similar to those found in primary care practice. The probability of finding abnormal lipids and sufficient CHD risk to warrant treatment is high in this age group.

Postmenopausal Women

AFCAPS was the only primary prevention trial that enrolled postmenopausal women. The women in AFCAPS were older: mean age of 63 years compared with 58 years for men. These women appeared to have a relative risk reduction for first CHD events similar to that for men, but they had fewer CHD deaths. The trial was not designed with sufficient power to examine total mortality effects for either men or women (37).

Evidence from secondary prevention trials suggests that women will achieve reductions in total CHD events similar to those for men if they have similar baseline levels of risk. In the short term (up to 5 years), these total reductions will take the form primarily of fewer nonfatal MIs rather than fewer CHD deaths (60-63). The effect on total mortality for women remains unclear: the Scandinavian Simvastatin Survival Study of secondary prevention found a relative risk of 1.16 (95% CI=0.68 to 1.99) for total mortality (62). Data on total mortality for women have not yet been published from the other major trials of secondary prevention or primary prevention, and we have insufficient long-term data to measure the longitudinal effects of CHD event reduction on total and CHD mortality.

Thus, reducing lipid levels appears to be effective in reducing CHD events in postmenopausal women with abnormal lipids, but the magnitude of that effect appears smaller than that among men, at least in part because middle-aged women with lipid disorders are at lower absolute risk than middle-aged men. Accurate global risk assessment is important, because women tend to have higher TC levels but lower CHD risk than men of similar ages.

Elderly Men and Women

Few elderly people (older than age 70 years) have been studied in primary prevention settings. Some epidemiologic studies have found that the relative risk of elevated cholesterol is attenuated in elderly patients. However, older people generally have high levels of absolute risk of CHD events, so lipid-lowering therapy is likely to be effective in these patients, assuming that their risk of competing causes of mortality is not too high (i.e., that their life expectancy is sufficient to allow them to realize the benefits of therapy). Data from secondary prevention trials suggest that lipid lowering is as effective, or more effective, in older patients than in younger patients (11,63,64).

Young Adults

Whether screening for and treating lipid disorders in men aged 20 to 35 years and women aged 20 to 45 years yield important benefits is controversial (65,66).

Screening to identify and treat young adults at high immediate risk of CHD. Young adults in general are at very low absolute risk of CHD events over the short-to-medium term (5 to 10 years). Even if treatment of lipid disorders in young adults reduces risk to the same or greater extent that it does in middle-aged men, the benefits in terms of absolute risk reduction over that time period will be very small.

Screening has been considered as a means of identifying and treating the small number of patients with extreme lipid levels who would not be recognized as being at risk of CHD events on the basis of a family history of early CHD events, family history of lipid abnormalities, or the presence of two or more other CHD risk factors. If unrecognized, some patients, mainly those with extreme lipid levels from genetic lipid disorders, may have CHD events before universal screening begins at age 35 or 45 years. The actual number of people who would fit in this category has not been well quantified but appears to be small. About 10% of men aged 20 to 34 years and 7% of women aged 20 to 44 years have LDL-C levels greater than 160 mg/dL (8). The proportion that would qualify for screening because of having diabetes, a family history of premature CHD or familial hyperlipidemia, or multiple other risk factors has not been reported (17).

Treating young adults to reduce long-term CHD risk. The crucial issue for deciding whether to screen younger adults is the incremental effectiveness of earlier treatment compared with delayed treatment for preventing CHD events in middle age. High TC levels in young adults are clearly predictive of higher rates of future CHD events. Data from a cohort of Johns Hopkins University medical students show that the relative risk of future CHD events and CHD mortality among men aged 20 to 25 years who had cholesterol levels above the 75th percentile was two times greater than the relative risk among those at the 25th percentile (67).

Ideally, we would like to have information from a randomized controlled trial that examined the effect of early screening and treatment (compared with delayed screening and treatment) on CHD events and mortality. Because such a study does not exist and is unlikely to be performed owing to the long period of follow-up that would be required (30 years), we must use indirect data to examine the magnitude of the potential incremental benefit from early screening and treatment.

Such indirect evidence is presented in a systematic review and meta-analysis by Law et al. (68). These investigators estimated the magnitude of the risk attributable to lipid disorders at different ages from observational cohort data. They then examined the risk for CHD in people treated for lipid disorders. After 5 to 10 years of treatment, the CHD risk for people who had their cholesterol lowered to a given level was similar to the CHD risk for people whose cholesterol had been at that lower level throughout their lives. They concluded that the majority (about 80%) of the risk reduction from lipid therapy can be achieved after 5 to 10 years of treatment; the incremental benefit from beginning therapy earlier is, therefore, relatively small. In a similar meta-analysis and meta-regression, Fager and Wiklund (69) reached the same conclusion.

With the use of the Law et al. (68) results, one might conclude that the preferred approach is to delay screening and treatment until about 5 to 10 years before the time that the absolute risk of CHD events begins to rise to meaningful absolute levels. This approach will theoretically minimize the potential adverse effects of long-term therapy and unnecessary drug costs without reducing benefit substantially. Others have challenged this interpretation and its implications, based on data from angiographic and autopsy studies and the higher attributable risk from cholesterol in younger people (66).

Special Populations

The clinical approach to screening and treating African Americans does not appear to differ materially from the approach to Caucasian populations. Average TC levels do not differ meaningfully between African-American and Caucasian populations, although HDL-C levels are higher for African Americans. Although trial data on African Americans are scarce, there is no good reason to believe that African Americans will respond differently than European Americans at any given level of risk. Harms of drug therapy do not appear to be increased (70). However, formulas to calculate CHD risk (7,32) have been developed mostly in patients of European descent and may not generalize well to African Americans. Fewer data exist about the prevalence of lipid disorders and the benefits of screening and treatment among Native-American, African-American, and Hispanic populations. Further research and wider recruitment in clinical trials would enable investigators to develop better estimates of the benefits of screening and treatment in people of non-European descent.

Future Research

The effectiveness of screening to reduce CHD is well established in men of European ancestry. Data for minorities, women, and older and younger adults, however, remain scarce, and more research on the benefits of screening and treatment in these populations is warranted. Of high priority is the efficacy of lipid therapy in men of non-European descent and in all women, the elderly, and younger people with multiple risk factors or with diabetes. The effect of screening on stroke, although clear in secondary prevention trials, remains unproven in primary prevention. Strategies to improve dietary interventions and more information on the effectiveness of dietary therapy are needed. The optimal frequency of screening and the age at which screening should be initiated or discontinued are both unsettled issues, and further data on improving the accuracy and efficiency of different screening strategies are needed as well. Because clinicians require practical approaches to assessing the risk of individual patients, additional research in this arena is also called for. Although hypertriglyceridemia is a risk factor for CHD, the importance of screening for this condition and the effectiveness of interventions to control it remain to be established; the role of novel risk factors such as homocysteine or C-reactive protein also deserve attention. Finally, analysis of the optimal sequencing and combinations of different efforts to decrease CHD events (e.g., aspirin, treatment of hypertension, smoking cessation activities) would help to clarify the timing and role of lipid-lowering therapy.

Summary: Whom to Screen and Treat

The evidence is good that identifying middle-aged men with lipid disorders and treating those with sufficient CHD risk reduces CHD events and CHD mortality. Treating those at highest risk (greater than 1.5% risk of CHD events per year) may also reduce total mortality. Screening middle-aged women, the elderly, and young adults with multiple risk factors and treating those at increased risk also appears to reduce CHD events. The balance of benefits and harms from screening and treating young adults is not clear from the available evidence but is unlikely to be large compared with starting at age 35 years in men and age 45 years in women.

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Acknowledgements

This study was developed by the Research Triangle Institute-University of North Carolina at Chapel Hill (RTI-UNC) Evidence-based Practice Center under contract to the Agency for Healthcare Research and Quality (Contract No. 290-97-0011), Rockville, MD. We acknowledge the assistance of Jacqueline Besteman, J.D., M.A., EPC Program Officer; Sonya Sutton, BSPH, and Sheila White, of Research Triangle Institute; and Mark Dowell, M.A., of the UNC Cecil R. Sheps Center for Health Services Research.

This article is based on a more comprehensive Systematic Evidence Review which is available online at http://www.ahrq.gov/clinic/serfiles.htm.

The systematic evidence review on which this article is based was reviewed by content experts, including Scott M. Grundy, M.D., Ph.D., Southwestern Medical Center at Dallas; Robert Baron, M.D., University of California, San Francisco; Matthew Gilman, M.D., Harvard Medical School and Harvard Pilgrim Health Care; and Thomas Newman, M.D., University of California, San Francisco; professional organizations, including the American Academy of Family Physicians, the American Academy of Pediatrics, the American College of Obstetricians and Gynecologists, the American College of Physicians/American Society of Internal Medicine, the American College of Preventive Medicine, and the Canadian Task Force on Preventive Health Care; and U.S. Public Health Service agencies, including the Centers for Disease Control and Prevention, National Heart, Lung and Blood Institute, the National Institutes of Health; and the Veterans' Administration. Review by these individuals and groups does not necessarily imply endorsement of this article or of the accompanying recommendations of the U.S. Preventive Services Task Force.

The authors of this article are responsible for its contents, including any clinical or treatment recommendations. No statement in this article should be construed as an official position of the Agency for Healthcare Research and Quality, the U.S. Department of Health and Human Services, the Department of Defense, or Merck and Co.

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Author Affiliations

[a]Pignone: Department of Medicine, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC.
[b]Phillips: Office for Prevention and Health Services Assessment, Air Force Medical Operations Agency, San Antonio, TX.
[c]Atkins: Center for Practice and Technology Assessment, Agency for Healthcare Research and Quality, U.S. Department of Health and Human Services, Rockville, MD.
[d]Teutsch: Outcomes Research and Management, Merck & Co, Inc, West Point, PA.
[e]Mulrow: Department of Medicine, Audie Murphy VA Medical Center, San Antonio, TX.
[f]Lohr: Research Triangle Institute, Research Triangle Park, and University of North Carolina at Chapel Hill, Program on Health Outcomes and School of Public Health, Chapel Hill, NC.

Copyright and Source Information

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Source: Pignone MP, Phillips CJ, Atkins D, Teutsch SM, Mulrow CD, Lohr, KN. Screening and treating adults for lipid disorders. Am J Prev Med 2001;20 (3S):77-89 (http://www.elsevier.com/locate/ajpmonline).

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