Editorials
Effects of Omega-3 Fatty Acids on Cardiovascular Health
The potential beneficial effects of omega-3 polyunsaturated fatty acids on cardiovascular health have become of substantial interest to patients, physicians, researchers, and policy makers. In this issue of American Family Physician, Covington provides a clinical review1 of omega-3 fatty acids. Recently, the American Heart Association released a scientific statement,2 and the Agency for Healthcare Research and Quality (AHRQ) commissioned an evidence report.3 The question of interest is whether increasing the intake of omega-3 fatty acids from foods or supplements can prevent or treat chronic diseases, particularly atherosclerotic cardiovascular disease.
The two principal dietary sources of omega-3 fatty acids are seafood and certain plant oils. Fish (particularly "fatty fish" such as tuna, salmon, and mackerel) and fish oils provide eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Some oils, such as canola, walnut, soybean, rapeseed, and flaxseed, are rich in alpha-linolenic acid (ALA). Omega-3 fatty acids are termed "essential" fatty acid, because they are required for normal development and function of the retina and brain. In humans, ALA is inefficiently converted to DHA and EPA.
Over the past several decades, research has fueled interest in omega-3 fatty acids. Initial reports were ecologic studies that documented low rates of ischemic heart disease in populations such as Greenland Inuits that consume large quantities of fatty fish. Subsequently, results of longitudinal, observational studies found an inverse association between consumption of fish or fish oil and ischemic heart disease.
In other studies,3 fish oil suppressed arrhythmias, stabilized atherosclerotic plaque, reduced inflammation, improved endothelial function, lowered triglyceride concentrations, and reduced blood pressure. Hence, there is a reasonably strong biologic basis to believe that an increased intake of omega-3 fatty acids could be cardioprotective.
The most persuasive evidence of cardioprotection comes from randomized trials with clinical cardiovascular outcomes.4 To date, more than 10 such trials of the use of omega-3 fatty acids have been conducted in patients with previous cardiovascular disease, but only one trial was conducted in persons without preexisting cardiovascular disease. Many of the trials, including the only primary prevention trial, had a small sample size and, accordingly, were underpowered.
The most salient of the available trials are the Diet and Reinfarction Trial (DART)5 and the GISSI Prevenzione trial.6 In DART, which enrolled 2,033 men with a previous myocardial infarction, those who received advice to increase their intake of fatty fish had a 29 percent reduced risk of total mortality over two years. However, during a follow-up study of DART participants, the early reduction in risk observed in those assigned to the fish advice group was followed by increased risk over the course of the next three to nine years.7
The GISSI trial tested the effects of two types of supplements (omega-3 fatty acid and vitamin E), taken alone or in combination, in 11,324 patients with a previous myocardial infarction. Over the course of three and one-half years, the groups assigned to take an omega-3 fatty acid supplement experienced a nearly 15 percent reduced risk of the primary trial outcome (death, nonfatal myocardial infarction, or stroke), while vitamin E had no effect. Interestingly, the benefit occurred rapidly, within three months of randomization8; these findings support the hypothesis that the beneficial effects of omega-3 fatty acids result, at least in part, from their antiarrhythmic or antithrombotic properties.
Although the evidence from prospective observational studies and clinical trials led the American Heart Association to issue dietary recommendations for the consumption of fish and omega-3 fatty acids,2 it is well recognized that the research data supporting a cardioprotective effect of fish and omega-3 fatty acids is not nearly as robust as the evidence supporting other therapies.
Those familiar with the vitamin E and beta-carotene "sagas" would be hesitant to make firm recommendations for the use of omega-3 supplements without strong and consistent evidence from randomized trials. After a flurry of observational studies documenting an impressive inverse association between the use of vitamin E supplements and ischemic heart disease, large-scale trials showed striking null results.6 Trials of beta-carotene documented that supplementation increased, rather than decreased, the risk of lung cancer.9
Other concerns pertain to the supply of omega-3 fatty acid supplements, which may be inadequate in the setting of widespread consumption, and the quality of supplements, which is not standardized. While I doubt that moderate consumption of omega-3 fatty acids will prove to be harmful, we need evidence of benefit before we routinely recommend omega-3 fatty acid supplements to the general population. Clinical trials most likely will be initiated but, given the time required to design and conduct such trials, near-term answers are unlikely. In the interim, the American Heart Association guidelines2 remain prudent policy.
Lawrence J. Appel, M.D., M.P.H., is professor of medicine, epidemiology, and international health at the Welch Center for Prevention, Epidemiology and Clinical Research, Johns Hopkins Medical Institutions, Baltimore.
Address correspondence to Lawrence J. Appel, M.D., M.P.H., Johns Hopkins Medical Institutions, 2024 E. Monument St., Ste. 2-600, Baltimore, MD 21205-2223 (e-mail: lappel@jhmi.edu). Reprints are not available from the author.
References
1. Covington M. Omega-3 fatty acids. Am Fam Physician 2004;70:133-40.
2. Kris-Etherton PM, Harris WS, Appel LJ; American Heart Association. Nutrition Committee. Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease [published correction appears in Circulation 2003;107:512]. Circulation 2002;106:2747-57.
3. Effects of omega-3 fatty acids on cardiovascular risk factors and intermediate markers of cardiovascular disease. Evid Rep Technol Assess (Summ) 2004;93:1-6.
4. Wang C, Chung M, Balk E, Kupelnick B, DeVine D, Lawrence A, et al. Effects of omega-3 fatty acids on cardiovascular disease. File Inventory, Evidence Report/Technology Assessment No. 94. AHRQ Publication No. 04-E009-2. Rockville, Md.: Agency for Healthcare Research and Quality, March 2004.
5. Burr ML, Fehily AM, Gilbert JF, Rogers S, Holliday RM, Sweetnam PM, et al. Effects of changes in fat, fish, and fibre intakes on death and myocardial reinfarction: diet and reinfarction trial (DART). Lancet 1989;2:757-61.
6. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico. Lancet 1999;354:447-55.
7. Ness AR, Hughes J, Elwood PC, Whitley E, Smith GD, Burr ML. The long-term effect of dietary advice in men with coronary disease: follow-up of the Diet and Reinfarction trial (DART). Eur J Clin Nutr 2002;56:512-8.
8. Marchioli R, Barzi F, Bomba E, Chieffo C, DiGregorio D, DiMascio R, et al. Early protection against sudden death by n-3 polyunsaturated fatty acids after myocardial infarction: time-course analysis of the results of the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI)-Prevenzione. Circulation 2002;105:1897-903.
9. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. N Engl J Med 1994;330:1029-35.
Should Risk Factors for Breast Cancer Influence Evaluation of Breast Abnormalities?
KATRINA ARMSTRONG, M.D.
When a woman presents with a breast complaint, initial management nearly always includes a clinical breast examination and an imaging study. Frequently, risk factors for breast cancer are assessed. Individualized risk predictions employing more formalized tools, such as the Gail model1 or the Claus model,2 are being used increasingly in screening populations. However, an important question remains: in symptomatic women, are risk factors for breast cancer still clinically important? Unfortunately, the answer is unclear.
The Steering Committee on Clinical Practice Guidelines for the Care and Treatment of Breast Cancer3 states that when a woman presents with a breast lump or a suspicious change in breast texture, her risk factors for breast cancer should be noted, but the presence or absence of risk factors should not influence decisions about further work-up. Similarly, recommendations for evaluation and follow-up of mammographic abnormalities generally are made without regard to individual breast cancer risk. However, improved use of breast cancer risk factors has the potential to reduce the number of biopsies performed in women who do not have cancer and to increase the percentage of positive biopsies.
In response to a topic nomination by Kaiser Permanente Northern California, the Agency for Healthcare Research and Quality (AHRQ) funded a systematic review of the literature.4 The objective was to assess published evidence on the relationship between risk factors, breast abnormalities (clinical symptoms or mammographic findings), and breast cancer, and to provide practical recommendations for applying this information.
The systematic review4 found that although many studies reported breast cancer incidence in association with risk factors (menstrual status, hormone therapy, pregnancy history, family history, age) or abnormal breast findings, relatively few studies reported the incidence in association with both. In addition, the literature suffers from a lack of standardization of terms for reporting information about breast disease. Hence, reported results vary, depending on whether breast cancer incidence is derived from the number of lesions or the number of affected patients.
The literature on mammography also is problematic. Although mammographic results almost always are given, variations in reporting formats make it impossible to combine data in a useful way. The Breast Imaging Reporting and Data System (BI-RADS) terminology was developed for the purpose of standardizing mammogram reports.5,6 Widespread use of the BI-RADS nomenclature (e.g., in studies that relate cancer incidence by age to BI-RADS scores) could make data integration possible.7-11
Thus, although risk factors for breast cancer are well established and commonly used to direct evaluation in other clinical scenarios, current evidence does not permit assessment of the impact of individual risk factors on the likelihood that a breast abnormality represents cancer. Family history,12-19 pregnancy and menstrual history,13,14 and hormone therapy20 lacked a consistent evidence base for inferring any conclusions about the risk of cancer when these factors were associated with a clinical or mammographic abnormality. The only exception is patient age. In this instance, studies show that age over 50 years greatly increases the risk of breast cancer in women with a clinical or mammographic abnormality.
At this time, no published evidence supports modifying the work-up of breast symptoms or mammographic abnormalities based on risk factors other than age.
We thank the extended MetaWorks team members, the members of the Technical Expert Panel, peer reviewers, representatives from Kaiser Permanente Northern California, and the AHRQ for their contributions to this project.
Susan Ross, M.D., is chief scientific advisor at MetaWorks, Inc., Medford, Mass.
Rhonda P. Estok, R.N., B.S.N., is clinical information specialist at MetaWorks, Inc.
Cindy Levine, M.D., currently is clinical instructor at Harvard Medical School, Boston, and Beth Israel Deaconess Medical Center North, Chelsea, Mass. Previously she was assistant medical director at MetaWorks, Inc.
Katrina Armstrong, M.D., is assistant professor of medicine at the University of Pennsylvania School of Medicine, Philadelphia.
Address correspondence to Susan Ross, M.D., MetaWorks, Inc., 10 President's Landing, Medford, MA 02155. Reprints are not available from the authors.
References
1. Gail MH, Brinton LA, Byar DP, Corle KD, Green SB, Schairer C, et al. Projecting individualized probabilities of developing breast cancer for white females who are being examined annually. J Natl Cancer Inst 1989;81:1879-86.
2. Claus EB, Risch N, Thompson WD. Autosomal dominant inheritance of early-onset breast cancer. Implications for risk prediction. Cancer 1994;73:643-51.
3. The palpable breast lump: information and recommendations to assist decision-making when a breast lump is detected. The Steering Committee on Clinical Practice Guidelines for the Care and Treatment of Breast Cancer. Canadian Association of Radiation Oncologists. CMAJ 1998;158(suppl 3):S3-8.
4. Diagnosis and management of specific breast abnormalities. Rockville, Md.: Agency for Healthcare Research and Quality, Dept. of Health and Human Services, 2001; evidence report/technology assessment, 1530-4396, no. 33; AHRQ publication no. 01-E 046.
5. Barton MB, Elmore JG, Fletcher SW. Breast symptoms among women enrolled in a health maintenance organization: frequency, evaluation and outcome. Ann Intern Med 1999;130:651-7.
6. Liberman L, Abramson AF, Squires FB, Glassman JR, Morris EA, Dershaw DD. The Breast Imaging Reporting and Data System: positive predictive value of mammographic features and final assessment categories. AJR Am J Roentgenol 1998;171:35-40.
7. Sickles EA. Nonpalpable, circumscribed, noncalcified solid breast masses: likelihood of malignancy based on lesion size and age of patient. Radiology 1994;192:439-42.
8. Flynn MB, Amin EA, Martin RC II. Mobile mammography screening: the James Graham Brown Cancer Center three year experience. Implications for public and professional education. J Ky Med Assoc 1998;96:17-20.
9. Cimitan M, Volpe R, Candiani E, Gusso G, Ruffo R, Borsatti E, et al. The use of thallium-201 in the preoperative detection of breast cancer: an adjunct to mammography and ultrasonography. Eur J Nucl Med 1995;22:1110-7.
10. Viera MR, Weinholtz JH. Technetium-99m tetrofosmin scintigraphy in the diagnosis of breast cancer. Eur J Surg Oncol 1996;22:331-4.
11. Sillar R, Howarth D, Clark D. The initial Australian experience of technetium-99m sestamibi scintimammography: a complementary test in the management of breast cancer. Aust N Z J Surg 1997;67:433-7.
12. Brendlinger DL, Robinson R, Sylvest V, Burton S. Stereotactic core breast biopsy. An alternative. Va Med Q 1994;121:179-84.
13. Byrne C, Schairer C, Wolfe J, Parekh N, Salane M, Brinton LA, et al. Mammographic features and breast cancer risk: effects with time, age, and menopause status. J Natl Cancer Inst 1995;87:1622-9.
14. Lee MM, Petrakis NL, Wrensch MR, King EB, Miike R, Sickles E. Association of abnormal nipple aspirate cytology and mammographic pattern and density. Cancer Epidemiol Biomarkers Prev 1994;3:33-6.
15. Harkins K, Tartter PI, Hermann G, Squitieri R, Brower ST, Keller RJ. Multivariate analysis of roentgenologic characteristics and risk factors for nonpalpable carcinoma of the breast. J Am Coll Surg 1994;178:149-54.
16. Janes RH, Bouton MS. Initial 300 consecutive stereotactic core-needle breast biopsies by a surgical group. Am J Surg 1994;168:533-6.
17. Kerin MJ, O'Hanlon DM, Khalid AA, Kent PJ, McCarthy PA, Given HF. Mammographic assessment of the symptomatic nonsuspicious breast. Am J Surg 1997;173:181-4.
18. Shaw AD, Gazet JC, Ford HT. The importance of the non-palpable lesion in women under 50, detected by mammography on self-referral for screening, symptoms or follow up. Eur J Surg Oncol 1995;21:284-6.
19. Tran DQ, Wilkerson DK, Namm J, Zeis MA, Cottone FJ. Needle-localized breast biopsy for mammographic abnormalities: a community hospital experience. Am Surg 1999;65:283-8.
20. Harvey JA. Use and cost of breast imaging for postmenopausal women undergoing hormone replacement therapy. AJR Am J Roentgenol 1999;172:1615-9.
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