Correspondence

Coronary Heart Disease in Women

N Engl J Med 2000; 343:1891-1894December 21, 2000

Article

To the Editor:

We would view with caution the conclusion of Herrington and colleagues (Aug. 24 issue)1 that women with established coronary heart disease should not use estrogen replacement with an expectation of a cardiovascular benefit. The results of their study apply only to the use of conjugated equine estrogens at a dose of 0.625 mg daily, alone or in combination with medroxyprogesterone acetate. Their findings may not be relevant to other estrogens and progestogens used in hormone-replacement therapy.

The effects of estrogens on the risk of cardiovascular disease vary according to the type of estrogen, the dose, and the route of administration. For example, conjugated equine estrogens may have adverse effects on glucose and insulin metabolism, thereby increasing the risk of atheroma; these effects are not seen with estradiol-17β. Conjugated equine estrogens raise insulin levels and impair glucose tolerance,2 but such effects are not seen with estradiol-17β given orally3 or transdermally.2 The dose of estrogen may also be important. High doses may lead to an increase in thrombogenesis and perhaps to abnormalities of vascular remodeling.

We do not understand why the dose of 0.625 mg of conjugated equine estrogens, which is used to relieve vasomotor symptoms in 50-year-old women, is also assumed to be the correct dose for the prevention of heart disease in women some 15 to 20 years older. Randomized clinical trials of different regimens of hormone-replacement therapy with more appropriate doses of estrogen are urgently needed before any conclusions can be reached about the effectiveness of hormone-replacement therapy for the prevention of cardiovascular disease.

John C. Stevenson, M.B., F.R.C.P.
Imperial College School of Medicine, London W2 1NY, United Kingdom

Marcus Flather, M.B., F.R.C.P.
Royal Brompton Hospital, London SW3 6NP, United Kingdom

Peter Collins, M.D., F.R.C.P.
Imperial College School of Medicine, London SW3 6NP, United Kingdom

3 References

1
Herrington DM, Reboussin DM, Brosnihan KB, et al. Effects of estrogen replacement on the progression of coronary-artery atherosclerosis. N Engl J Med 2000;343:522-529
Full Text | Web of Science | Medline

2
Godsland IF, Gangar K, Walton C, et al. Insulin resistance, secretion, and elimination in postmenopausal women receiving oral or transdermal hormone replacement therapy. Metabolism 1993;42:846-853
CrossRef | Web of Science | Medline

3
Crook D, Godsland IF, Hull J, Stevenson JC. Hormone replacement therapy with dydrogesterone and 17β-oestradiol: effects on serum lipoproteins and glucose tolerance during 24 month follow up. Br J Obstet Gynaecol 1997;104:298-304
CrossRef | Medline

To the Editor:

In their report, Herrington et al. assert that angiographic end points are a good proxy for clinical outcomes, despite the fact that angiography tells us little about the composition of a lesion, its mechanical properties, and its propensity to rupture. Most coronary lesions that cause a myocardial infarction appear angiographically to be insignificant,1 and studies have demonstrated that many women with angina have angiographically normal coronary arteries.2 The responsiveness of coronary arteries to changes in oxygen demands by the myocardium depends not only on the degree of flow-limiting stenosis but also on the vasomotor tone of the arteries, endothelial function, and the extent of collateral arteries.3 Even trials of lipid-lowering therapy 4 have demonstrated a clinical benefit out of proportion to observed reductions in coronary stenosis. Thus, although knowing the degree of stenosis can be helpful, clinical outcomes also seem to depend on a variety of variables that angiography does not measure.

Apparently, over 50 percent of the women in the study by Herrington et al. had no symptoms of heart disease and qualified for inclusion solely on the basis of angiographic abnormalities (at least 30 percent stenosis in an epicardial coronary artery). As clinicians, we would be interested in knowing whether these asymptomatic women had the same outcome as those with symptomatic disease.

Nassim P. Assefi, M.D.
Caroline S. Rhoads, M.D.
Harborview Medical Center, Seattle, WA 98104

4 References

1
Little WC, Downes TR, Applegate RJ. The underlying coronary lesion in myocardial infarction: implications for coronary angiography. Clin Cardiol 1991;14:868-874
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2
Sullivan AK, Holdright DR, Wright CA, Sparrow JL, Cunningham D, Fox KM. Chest pain in women: clinical, investigative, and prognostic features. BMJ 1994;308:883-886
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3
Rosenschein U, Topol EJ. Uncoupling clinical outcomes and coronary angiography: a review and perspective of recent trials in coronary artery disease. Am Heart J 1996;132:910-920
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4
Brown BG, Zhao XQ, Sacco DE, Albers JJ. Lipid lowering and plaque regression: new insights into prevention of plaque disruption and clinical events in coronary disease. Circulation 1993;87:1781-1791
Web of Science | Medline

To the Editor:

On the basis of their analysis of data from the Nurses' Health Study, Hu et al. (Aug. 24 issue)1 conclude that diet and lifestyle are of paramount importance in the primary prevention of coronary disease. This conclusion, which is echoed in the accompanying editorial by Nabel,2 is not substantiated by their findings.

Hu et al. report a 31 percent reduction in the incidence of coronary disease between 1980–1982 and 1992–1994 in the total cohort of nurses. However, inspection of Figure 1 of their article reveals that some 60 percent of this total reduction in incidence was due to a single dramatic decrease in incidence in one age group, women 65 years of age or older, during just one interval, from 1986–1988 to 1988–1990. This is hardly the gradual pattern one would expect if the decreasing incidence were due to changes in lifestyle and diet.

Furthermore, the authors assume that if two changes occur simultaneously, then one is the cause of the other. For example, they ascribe a substantial proportion of the decline in coronary disease to the concomitant increase in the use of hormone-replacement therapy, yet two recent prospective, randomized studies, by Hulley et al.3 and Herrington et al.,4 cast serious doubt on the purported benefit of hormone replacement for preventing coronary disease. Thus, Hu and colleagues would be well advised to avoid categorical statements to the effect that certain changes in lifestyle account for or explain changes in the incidence of coronary disease.

Finally, changes in dietary fat composition notwithstanding, I take issue with the authors' statement that during the study period, “diet improved substantially.” A diet that leads to a 38 percent increase in the prevalence of overweight, with the average body-mass index (the weight in kilograms divided by the square of the height in meters) increasing from 24.5 to 26.1, can hardly be considered im-proved.

Mayer Bassan, M.D.
Clallit Health Services, Jerusalem 94110, Israel

4 References

1
Hu FB, Stampfer MJ, Manson JE, et al. Trends in the incidence of coronary heart disease and changes in diet and lifestyle in women. N Engl J Med 2000;343:530-537
Full Text | Web of Science | Medline

2
Nabel EG. Coronary heart disease in women -- an ounce of prevention. N Engl J Med 2000;343:572-574
Full Text | Web of Science | Medline

3
Hulley S, Grady D, Bush T, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 1998;280:605-613
CrossRef | Web of Science | Medline

4
Herrington DM, Reboussin DM, Brosnihan KB, et al. Effects of estrogen replacement on the progression of coronary-artery atherosclerosis. N Engl J Med 2000;343:522-529
Full Text | Web of Science | Medline

To the Editor:

We wish to clarify some statements about raloxifene hydrochloride, a selective estrogen-receptor modulator (SERM), that Dr. Nabel made in her editorial. Dr. Nabel correctly noted that raloxifene “does not affect the endometrium” but also stated that further research is needed to determine “the correct progestin compound to use with estrogen or a SERM in women with an intact uterus.” Although it is correct to state that a progestin must be administered concomitantly with estrogen in postmenopausal women with a uterus, in order to prevent endometrial hyperplasia and endometrial cancer, this is not the case for raloxifene. Clinical trials have demonstrated that raloxifene does not stimulate the uterus,1 and concomitant administration of progestin is therefore not required.

In contrast, tamoxifen citrate, also a SERM, is known to stimulate the uterus, and its use has been associated with a significant increase in endometrial cancer2; to date, however, it has not been shown that the stimulatory effect of tamoxifen on the uterus can be ameliorated by the use of progestin.

Dr. Nabel states that raloxifene “decreases bone loss.” To clarify, raloxifene has been proved not only to decrease bone loss but also to increase bone mineral density in the spine, hip, and total body. Furthermore, raloxifene is indicated for both the prevention and the treatment of vertebral fractures in postmenopausal women.3

Pamela Wang Anderson, M.D.
Elena Moscarelli, M.D.
Eli Lilly, Indianapolis, IN 46285

3 References

1
Goldstein SR, Scheele WH, Rajagopalan SK, Wilkie JL, Walsh BW, Parsons AK. A 12-month comparative study of raloxifene, estrogen and placebo on the postmenopausal endometrium. Obstet Gynecol 2000;95:95-103
CrossRef | Web of Science | Medline

2
Gail MH, Costantino JP, Bryant J, et al. Weighing the risks and benefits of tamoxifen treatment for preventing breast cancer. J Natl Cancer Inst 1999;91:1829-1846
CrossRef | Web of Science | Medline

3
Ettinger B, Black DM, Mitlak BH, et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. JAMA 1999;282:637-645
CrossRef | Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: Assefi and Rhoads question whether angiographic end points are useful for assessing the clinical efficacy of an antiatherosclerotic intervention. The data are quite clear on this point. The overwhelming majority of angiographic trials of statin therapy have shown a 35 to 75 percent reduction in the progression of angiographically defined coronary disease,1 which is remarkably concordant with the 25 to 38 percent reduction in clinical events observed in the subsequent statin trials with clinical end points.2 Furthermore, long-term follow-up of participants in angiographic trials clearly shows that differences in progression during the trial are strongly predictive of future clinical events.3

We readily acknowledge that several characteristics of coronary lesions, including their composition, mechanical properties, and endothelial function, are not measured by angiography. However, we are unaware of any large prospective studies verifying that these characteristics are correlated with the risk of future events — or, more critically, that changing these characteristics is associated with a reduction in the risk.

Table 1Table 1Mean Change in the Minimal Coronary-Artery Diameter According to the Treatment Group and the Presence or Absence of Reported Chest Pain at Base Line. shows the mean change in the minimal coronary-artery diameter among the subjects in our study according to the treatment group and the presence or absence of chest pain at base line.

Stevenson et al. ask why we assumed that 0.625 mg of conjugated estrogen would be effective. The answer is simply that at the inception of our trial, the overwhelming majority of observational studies, studies involving animal models, and studies with intermediate end points suggested that this dose would be effective.4,5 We agree wholeheartedly that randomized clinical trials are needed to determine whether other forms or doses of estrogen may be more effective. In the meantime, we do not find data on intermediate end points, such as those cited by Stevenson and colleagues, sufficiently compelling to make distinctions in clinical practice between conjugated estrogens and other hormone-replacement options for the secondary prevention of coronary heart disease. Finally, contrary to the assertion by Stevenson et al., we believe at least one conclusion can now be reached about the cardiovascular effectiveness of hormone-replacement therapy: in women with established coronary disease, the most commonly used form of hormone-replacement therapy in the United States does not appear to reduce the risk of clinical cardiovascular events (as shown by the Heart and Estrogen/Progestin Replacement Study) or slow the progression of the underlying disease process responsible for these events (as shown by our study).

David M. Herrington, M.D., M.H.S.
Wake Forest University School of Medicine, Winston-Salem, NC 27157-1045

David Waters, M.D.
San Francisco General Hospital, San Francisco, CA 94110

5 References

1
Ballantyne CM, Herd JA, Dunn JK, Jones PH, Farmer JA, Gotto AM Jr. Effects of lipid lowering therapy on progression of coronary and carotid artery disease. Curr Opin Lipidol 1997;8:354-361
CrossRef | Web of Science | Medline

2
LaRosa JC, He J, Vupputuri S. Effect of statins on risk of coronary disease: a meta-analysis of randomized controlled trials. JAMA 1999;282:2340-2346
CrossRef | Web of Science | Medline

3
Waters DD, Azar RR. Postscripts from the Post-Coronary Artery Bypass Graft trial: the sustained benefit of more aggressive cholesterol lowering and the enigma of low-dose anticoagulation. Circulation 2000;102:144-146
Web of Science | Medline

4
Stevenson JC. Mechanisms whereby oestrogens influence arterial health. Eur J Obstet Gynecol Reprod Biol 1996;65:39-42
CrossRef | Web of Science | Medline

5
Gerhard M, Ganz P. How do we explain the clinical benefits of estrogen? From bedside to bench. Circulation 1995;92:5-8
Web of Science | Medline

Author/Editor Response

In response to Dr. Bassan: Figure 1 of our article clearly shows a decline in the incidence of coronary heart disease over time in all age groups, although the decline among women 65 years of age or older appears to be the most dramatic (from 422 per 100,000 person-years in 1986–1988 to 244 per 100,000 in 1992–1994). The high incidence in the 1986–1988 period in this age group may reflect statistical instability due to the small number of cases of coronary heart disease (13 cases) during this period.

Support for the dietary and lifestyle factors examined in our study comes from the results of clinical trials (e.g., in the case of fish oil and the ratio of polyunsaturated to saturated fats) and substantial epidemiologic and metabolic data (e.g., in the case of cereal fiber and trans fat), or the factors are generally accepted as major risk factors for coronary disease (e.g., in the case of smoking and obesity). Although the short-term trials reported by Hulley et al.1 and Herrington et al.2 did not show a benefit of postmenopausal hormone use among women with preexisting coronary disease, the question of whether hormone therapy is beneficial in the primary prevention of coronary heart disease remains unresolved. In the Nurses' Health Study, a large increase in the use of hormone therapy over time appeared to coincide with a trend toward a decrease in the risk of coronary disease. We estimated that the increase in hormone use statistically explained a 9 percent decline in the risk of coronary disease, although dietary changes and the cessation of smoking appeared to have a more important role. Obviously, for definitive evidence regarding the role of hormone use in the primary prevention of coronary disease, we must await the results of long-term prevention trials.

The prevalence of obesity has increased in our cohort, a finding that is consistent with national data. It is not clear, however, what factors have contributed to this increase. In our cohort, the intake of saturated and trans fats declined over time, whereas the intake of polyunsaturated fat, cereal fiber, marine n–3 fatty acids, and folate increased. However, the dietary glycemic load due to a high intake of refined carbohydrates also increased. There is some evidence that a diet with a high glycemic index may increase hunger and promote overeating, which may lead to weight gain and obesity.3 Furthermore, although there was no appreciable change in recreational exercise over time in our cohort, the time spent in sedentary activities, including sitting in the car and watching television, may have increased. This change could have a substantial role in promoting obesity.4,5

Frank B. Hu, M.D., Ph.D.
Meir J. Stampfer, M.D., Dr.Ph.
Walter C. Willett, M.D., Dr.Ph.
Harvard School of Public Health, Boston, MA 02115

5 References

1
Hulley S, Grady D, Bush T, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 1998;280:605-613
CrossRef | Web of Science | Medline

2
Herrington DM, Reboussin DM, Brosnihan KB, et al. Effects of estrogen replacement on the progression of coronary-artery atherosclerosis. N Engl J Med 2000;343:522-529
Full Text | Web of Science | Medline

3
Roberts SB. High-glycemic index foods, hunger, and obesity: is there a connection? Nutr Rev 2000;58:163-169
CrossRef | Web of Science | Medline

4
Tucker LA, Friedman GM. Television viewing and obesity in adult males. Am J Public Health 1989;79:516-518
CrossRef | Web of Science | Medline

5
Tucker LA, Bagwell M. Television viewing and obesity in adult females. Am J Public Health 1991;81:908-911
CrossRef | Web of Science | Medline

Author/Editor Response

The editorialist replies:

To the Editor: Dr. Bassan is rightly concerned about the increase in obesity among women enrolled in the Nurses' Health Study. However, Hu et al. did not directly measure complex variables that lead to obesity but, instead, reported the results obtained with their semiquantitative food-frequency questionnaire, which focused primarily on fat intake. An understanding of how diet and physical activity contribute to obesity should be an important component of future studies in this population of women.

Bassan also comments on the role of hormone-replacement therapy in the prevention of coronary artery disease in women. This is a complex and controversial issue. It is important to recognize, however, that the findings reported by Hulley et al.1 and Herrington et al.,2 which involve the use of hormone-replacement therapy for the secondary prevention of coronary artery disease in women, may not have a direct bearing on the role of hormone-replacement therapy in primary prevention, as reported by Hu et al.

I appreciate the comments of Drs. Anderson and Moscarelli, which make it clear that the use of raloxifene does not require the concomitant administration of progestin.

Elizabeth G. Nabel, M.D.
National Heart, Lung, and Blood Institute, Bethesda, MD 20892

2 References

1
Hulley S, Grady D, Bush T, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 1998;280:605-613
CrossRef | Web of Science | Medline

2
Herrington DM, Reboussin DM, Brosnihan KB, et al. Effects of estrogen replacement on the progression of coronary-artery atherosclerosis. N Engl J Med 2000;343:522-529
Full Text | Web of Science | Medline

Citing Articles (3)

Citing Articles

1
G. M. Sare, L. J. Gray, P. M.W. Bath. (2008) Association between hormone replacement therapy and subsequent arterial and venous vascular events: a meta-analysis. European Heart Journal 29:16, 2031-2041
CrossRef
2
John C. Stevenson. (2004) Hormone replacement therapy: Review, update, and remaining questions after the women’s health initiative study. Current Osteoporosis Reports 2:1, 12-16
CrossRef
3
Ira Wolinsky, Dorothy Klimis-Zacas, Anastasia Kalea. 2003. Nutritional Issues of Cardiovascular Disease in Women. , 257-293.
CrossRef